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Polymer Self-Assembly Induced Enhancement of Ice Recrystallization Inhibition

Cite this: J. Am. Chem. Soc. 2021, 143, 19, 7449–7461
Publication Date (Web):May 4, 2021
https://doi.org/10.1021/jacs.1c01963

Copyright © 2021 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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Ice binding proteins modulate ice nucleation/growth and have huge (bio)technological potential. There are few synthetic materials that reproduce their function, and rational design is challenging due to the outstanding questions about the mechanisms of ice binding, including whether ice binding is essential to reproduce all their macroscopic properties. Here we report that nanoparticles obtained by polymerization-induced self-assembly (PISA) inhibit ice recrystallization (IRI) despite their constituent polymers having no apparent activity. Poly(ethylene glycol), poly(dimethylacrylamide), and poly(vinylpyrrolidone) coronas were all IRI-active when assembled into nanoparticles. Different core-forming blocks were also screened, revealing the core chemistry had no effect. These observations show ice binding domains are not essential for macroscopic IRI activity and suggest that the size, and crowding, of polymers may increase the IRI activity of “non-active” polymers. It was also discovered that poly(vinylpyrrolidone) particles had ice crystal shaping activity, indicating this polymer can engage ice crystal surfaces, even though on its own it does not show any appreciable ice recrystallization inhibition. Larger (vesicle) nanoparticles are shown to have higher ice recrystallization inhibition activity compared to smaller (sphere) particles, whereas ice nucleation activity was not found for any material. This shows that assembly into larger structures can increase IRI activity and that increasing the “size” of an IRI does not always lead to ice nucleation. This nanoparticle approach offers a platform toward ice-controlling soft materials and insight into how IRI activity scales with molecular size of additives.

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Introduction

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Ice binding proteins (IBPs) (1,2) (and also polysaccharides (3,4)) are a diverse class of biological macromolecules that achieve the molecular recognition of ice crystals in the presence of a large excess of water. INPs include those classed as antifreeze proteins (AFPs), which can depress the freezing point of water (and can also raise the melting point) (5) and are ice recrystallization (growth) inhibitors (IRI). Ice nucleating proteins (INPs) that promote ice formation are another distinct class. (6−8) There are a huge range of technological challenges where IBPs (or synthetic mimics) could have impact, spanning the cryopreservation of donor cells and tissues, (9−13) protecting infrastructure against freeze/thaw damage, (14,15) and improving the texture of frozen foods. (16,17) Inspired by IBPs, there has been significant interest in the development of synthetic materials that can modulate ice growth and/or materials that can enhance cellular cryopreservation. (18−22) Synthetic materials have advantages in terms of scalability, cost, and tunability compared to biological ones, but there is real need to understand their function and to address questions around how the size and nanoscale dimensions may impact activity. (23−26)
Poly(vinyl alcohol) (PVA) is established as a uniquely potent polymeric IRI, even though its exact mechanism of action is still under study. (27,28) Graphene oxide has been reported to interact with ice, (29−31) and the self-assembly of saffranine leads to ice binding aggregates. (32,33) Ben and co-workers have shown that short glycopeptides, (34) or even some surfactants, (35) can inhibit ice growth but do not lead to altered ice crystal morphologies. It has been discovered that thermal hysteresis activity (a macroscopic property which requires ice face binding) does not scale with IRI activity in several ice binding proteins, (36,37) and hence there is increasing evidence that ice binding is not a prerequisite for the macroscopic effect of IRI. Removing the need for ice binding (which needs precision placement of the interacting groups) would simplify the design process and enable a new range of IRI-active materials to emerge with potentially easier design rules.
In the absence of ice binding, there is emerging evidence that materials with hydrophobic patches can display moderate IRI (but less than AFPs) (38) such as self-assembled metallohelices, (39) ROMP-derived polymers, (40) or nanocellulose. (41) Balcerzak et al. synthesized a library of sequentially modified lysine derivatives showing increased hydrophobicity lead to more IRI. (42) In many cases, IRI activity increases with molecular weight, observed for proteins (43) and polymers, (27) and in self-assembly. (32,44) However, it is more complicated than “more polymers on a surface, or larger structures, are always better”; the incorporation of PVA (IRI active and ice binder) as the corona of micelles (45,46) or grafted to gold nanoparticles (47) led to no increase in activity, potentially due to the low surface density of the polymers. Similarly, dendrimer or gold nanoparticle conjugated AFPs showed no enhancement on a per-protein subunit basis but on a molar basis led to large enhancements in both IRI and thermal hysteresis activity. (48,49) Ice nucleating proteins (a distinct class of IBPs) have to be sufficiently large to match the minimum ice cluster size, (50,51) and it is proposed that a key difference in activity between larger ice nucleating proteins and smaller antifreeze proteins is their size. (23,52,53) Considering this evidence, it is clear that the impact of macromolecular size, but also crowding, plays a role in understanding IRI (but also other properties such as thermal hysteresis) but that there are size limits on what can be obtained by using linear polymers; increasing the size of proteins (e.g., linear assemblies of repeat units) is not practical and will not lead to identical folding or display of surfaces. Hence, there is a need to discover new platforms where nanoscale dimensions and composition can be tuned.
Polymerization-induced self-assembly (PISA) is a powerful approach for in situ development of block copolymer nanoparticles to generate multivalent nanomaterials at high concentrations of controlled morphology and size. (54−56) During aqueous PISA, a water-soluble corona-forming block is chain-extended by using specific water-miscible (dispersion PISA) or water-immiscible (emulsion PISA) monomers that gradually form a second, insoluble core block (as the length of the core-forming block increases), resulting in nanoparticle formation. Higher-order morphologies such as worm-like micelles and polymersomes are typically being observed, resulting in higher packing density for the copolymer chains compared to spherical (micellar) particles. (57,58) The versatility of this method has allowed the synthesis of nanoparticles for drug delivery, (59−62) cell storage, (63−65) and permeable nanoreactors, (66−69) and has been extensively reviewed. (70−73) PVA-graft-macroinitiators have been reported to lead to polymer nanoparticles with enhanced IRI (compared to the already very potent IRI activity of PVA), potentially due to the high local PVA density arising from PISA. (74) However, the use of nanoparticle engineering to discover emergent AFP mimetic materials from components with no intrinsic IRI activity has not been explored.
Considering the above, we herein report the unexpected enhancement of IRI activity of polymerization-induced self-assembly derived nanoparticles from constituent components with no IRI activity of their own. A panel of nanoparticles with variation in size, corona-forming, and core-forming block chemistry/functionality were synthesized. In each case IRI activity was unexpectedly increased relative to the homopolymer, but only in the largest (vesicular) nanoparticles, providing a previously unreported mechanism to generate IRI-active materials. By use of complementary ice nucleation assays, it was found that the size increase did not substantially increase ice nucleation activity, showing that making IRI-active materials larger does not lead to ice nucleation in all cases. This demonstrates that self-assembled nanomaterials and multivalent presentation is a crucial tool to understand, and translate to application, ice growth modifiers.

Results and Discussion

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To investigate the hypothesis that aggregation and crowding of non-ice binding polymers in a nanoparticle format may induce IRI activity, a PISA strategy was followed to obtain polymer nanoparticles with tunable sizes and morphologies. Deionized water gives false positives in the ice growth assays used (below) as a eutectic phase where ice/water coexistence is essential, and hence saline solutes (or other solutes) are required. (38) Therefore, to perform PISA, we first chose to use diacetone acrylamide (DAAm) as the core-forming monomer, which we have recently discovered to promote saline stability in PISA formulations (Figure 1A), unlike many other monomers. (74) A series of aqueous dispersion polymerizations in the presence of [NaCl] = 0.05 M were performed for DAAm via thermally initiated RAFT polymerization using a PEG-based macromolecular chain transfer agent (macro-CTA, PEG45 mCTA, Mn,SEC = 4.1 kg mol–1, ĐM = 1.1) as the corona-forming polymer. For these experiments the concentration of monomer was held constant at 10% w/w, the [macro-CTA]:[initiator] ratio was maintained at 1:0.1, and the [monomer]/[macro-CTA] ratio was varied to target different core-block degrees of polymerization. The polymerizations were carried out at 60 °C with 2,2′-azobis(2-methylpropionamidine) dihydrochloride (V-50) as the water-soluble initiator. A gradual turbidity increase was noticed for polymerization solutions with increasing DPPDAAm, indicating the onset of particle formation typically observed in PISA. Quantitative monomer conversions (>95%) were achieved in all cases, as determined by 1H NMR spectroscopic analysis in methanol-d4 of the crude samples (Figure S5).

Figure 1

Figure 1. Synthesis of PEG-corona PISA-derived nanoparticles. (A) Synthesis of PEG45-b-PDAAmn diblock copolymer nanoparticles via aqueous RAFT-mediated PISA using a commercially available PEG45 macro-CTA ([solids] = 10% w/w, [NaCl] = 0.05 M). (B) Normalized SEC RI molecular weight distributions. Mn,SEC and ĐM values were calculated from PMMA standards with DMF + 5 mM NH4BF4 as the eluent. (C) Evolution of Mn (black circles) and ĐM (red circles) values with increasing targeted DPPDAAm. (D) Zeta potential values for PEG45-b-PDAAmn diblock copolymer nanoparticles. (E) Representative dry-state images of PEG45-b-PDAAmn diblock copolymer nanoparticles, stained with 1 wt % uranyl acetate (UA) solution. (F) Intensity-weighted size distributions along with average Dh and PD values (the error shows the standard deviation from five repeat measurements).

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SEC analysis of PEG45-b-PDAAmn diblock copolymers in DMF + 5 mM NH4BF4 revealed the controlled character of the aqueous RAFT-PISA process (Figure 1B), with symmetric, monomodal molecular weight distributions shifting linearly toward higher molecular weight (Mn) values upon increasing the DP of PDAAm. A small low Mw shoulder of unconsumed macro-CTA was apparent, due to a small amount of unfunctionalized PEG. Calculated Mn values agreed well with theoretically expected values, while dispersity values remained relatively low for the polymerizations targeting DPs of 12, 25, 50, and 100 (ĐM ≤ 1.6) but was higher for DP 150 (ĐM = 2.1) throughout (Figure 1C and Table S1). The absence of charges on the outer surface of the obtained nanoparticles was confirmed by electrophoretic analysis at neutral pH (measured zeta potential <±5 mV) (Figure 1D).
DLS analysis of PEG45-b-PDAAmn formulations revealed the formation of particles with multiple populations and high polydispersity (PD) values for the lower DPs of PDAAm, consistent with worm-like micelles or nanoparticles with mixed morphologies. (54,75) Single particle populations with low PD values were observed for DPPDAAm ≥ 50, indicating the formation of uniform assemblies (Figure 1F). A single-exponential decay, smooth autocorrelation function with optimal signal-to-noise ratio was also recorded (Y-intercept >0.9) for all formulations (Figure S6). Dry-state TEM supported the DLS findings and showed an evolution in morphology as the DP of the core-forming PDAAm block increased from spheres (DPPDAAm = 12) to mixed morphologies of worms and spheres (DPPDAAm = 25) to mixed worms, bilayer lamella and vesicles (DPPDAAm = 50) to perforated vesicles (DPPDAAm = 100), and finally to single-phase vesicles of uniform size (DPPDAAm = 150) (Figure 1E and Figure S7). Cryogenic TEM analysis (cryo-TEM) was also performed on PEG45-b-PDAAM100 vesicles and confirmed a perforation with uniform pores on the surface of the vesicles. (76,77) It has previously been reported that PISA diblock formulations with PDAAm as core-forming block have a composition-dependent thermoresponsive behavior. (78−80) Therefore, PEG45-b-PDAAm100 was also synthesized by using 2,2′-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (VA-044) at lower temperature, and its morphology was studied via TEM imaging (see Figure S8). This revealed uniform spherical vesicles being formed with perforated bilayer surface with fewer and less uniform pores but indicates that it is not a temperature-induced effect, but its investigation is beyond the scope of this work.
Next, IRI activity was assessed by the “splat” assay. This assay involves seeding a large number of small ice crystals, which are then allowed to grow at −8 °C. (27,81) IRI-active materials will slow ice growth, resulting in smaller crystals relative to the negative control (saline), and the results are plotted as the mean grain size (MGS). To conduct these assays, it is essential to have some salt to prevent false negatives (any additive in pure water in this assay leads to ice growth inhibition). (38,81) To ensure colloidal stability, 0.05 M NaCl was used here (as opposed to the more common 0.137 M), which was validated to not produce false positive/negatives in the IRI assays, but this lower concentration must be considered when comparing to other reported activities as it is non-identical for each saline concentration (see Figure S9). Figure 2A shows dose–response curves for the PEG-based particles, compared to the PEG macroinitiator, with concentrations normalized to PEG concentration (as the coronal component) to enable comparison of multivalent effects. Remarkably, all the formulations showed some IRI activity. Considering PEG is widely used as a negative control (as it does not bind ice), the induction of observable IRI was unexpected. It is important to note that any material of sufficiently high concentration can inhibit ice growth, and this is not an on/off property. (38) Larger particles (Dh = 350 and 730 nm corresponding to DPPDAAm of 100 and 150, respectively) showed higher activity than the smaller (Dh = 42 nm for DPPDAAm = 12), demonstrating that size and potential packing of the corona (due to less curvature for large particles compared to small) are crucial to IRI activity, although this cannot be proved at this stage. The largest particles inhibited all growth at a PEG concentration of 5 mg mL–1, placing them in the medium activity range of antifreeze protein mimetics (less active than PVA or antifreeze proteins). (38,43) Cryomicrographs of annealed ice wafers (Figure 2B) visualize this unexpected activity and clearly demonstrate that a self-assembly strategy to induce IRI activity into soft materials is possible and that particle size is a tool to control the magnitude of activity. (38) In the case of PEG45-b-PDAAm100 vesicles with perforated topologies, their IRI activity was compared with a formulation synthesized at lower temperature and showed no significant difference in IRI activities (Figure S10). To further explore the dynamics of this system, PEG45-b-PDAAM100 block copolymer vesicles were annealed for different time points (t = 30 and 60 min) showing complete inhibition even after this time (Figure S13). Colloidal stability for PEG45-b-PDAAm150 vesicles upon multiple freeze–thaw cycles was assessed by DLS analysis and showed the particles were recovered with no significant changes in their hydrodynamic diameter (Dh) (Figure S11). The IRI activity as a function of total solid (polymer) concentration is also plotted in Figure S12. This shows that even when the core-polymer mass is included (which is not in contact with ice/water), the nanoparticles are still more active than a PEG (corona) alone on a mass basis. The larger particles were also still more active, and hence the activity is not an artifact of concentration calculations and the nanoparticle size is a key criteria. To further demonstrate the IRI activity, an alternative assay was conducted in 45 wt % sucrose (“sucrose sandwich”) which has a lower ice fraction. (43)Figure S14 shows nucleated ice crystals, which after 30 min have grown significantly (recrystallized) in the presence of PEG45 macro-CTA, while Figure S15 shows that a solution containing 10 mg mL–1 of PEG45-b-PDAAm150 nanoparticles displays inhibition of ice recrystallization, demonstrating activity in a range of different formulations.

Figure 2

Figure 2. Assessment of ice recrystallization inhibition activity for PEG-based nanoparticles. (A) IRI activity summary of PEG45-b-PDAAmn nanoparticles corrected to [PEG]. Error bars are ± SD from a minimum of three repeats (key: S, spherical micelles; W, worm-like micelles; V, vesicles). The percent mean grain size (MGS) was reported relative to saline control ([NaCl] = 0.05 M). (B) Example cryomicrographs of ice wafers from the “splat” assay of PEG45-b-PDAAmn nanoparticles, [PEG] = 10 mg mL–1.

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To evaluate whether the observations made above were only due to the PEG corona (as the component with most solvent interactions), a higher Mw PEG macro-CTA (PEG113 mCTA) was employed, and the composition of the core-forming block was separately examined. Few PISA core-forming monomers are reported to be saline-tolerant. (82) We employed an acrylamide-based monomer that can undergo PISA, N-(isobutoxymethyl)acrylamide (iBuOMAm), which was selected based on in silico computation/experimental study by O’Reilly and co-workers. (83)iBuoMAm was polymerized via aqueous RAFT in the presence of [NaCl] = 0.05 M by using PEG45 mCTA at 10% w/w solids content targeting a DPPiBuoMAm of 100. The prepared PEG45-b-PiBuOMAm100 diblock copolymer possessed bimodal molecular weight distribution due to unconsumed PEG mCTA with relatively low dispersity value, as determined by SEC analysis (Mn,SEC = 25.1 kg mol–1, ĐM = 1.6) (Figure S16). Dynamic light scattering (DLS) analysis revealed the formation of nanoparticles with a monomodal size distribution and mean hydrodynamic diameter (Dh) of 357.9 ± 1.3 nm and low polydispersity (PD = 0.24 ± 0.01) (Figure 3A). Dry-state transmission electron microscopy (TEM) imaging confirmed the development of uniform PEG45-b-PiBuOMAm100 porous spherical nanoparticles and uniform size (Figure S12D). Cryo-TEM imaging of PEG45-b-PiBuOMAm100 nanoparticles in solution confirmed the formation of perforated spherical nanoparticles (Figure S16E). A higher Mw PEG macroinitiator (PEG113 mCTA—to probe effect of coronal chain length) was subsequently used for the polymerization of DAAm to yield PEG113-b-PDAAm100 and PEG113-b-PDAAm400 (to enable comparison of the same morphology with PEG45-b-PDAAM100 vesicles) diblock copolymer nanoparticles. TEM and DLS analyses showed the formation of uniform spherical nanoparticles and unilamellar vesicles for DPPDAAm = 100 and 400, respectively (Figure 3B, Figures S17 and S18), with monomodal size distributions, mean hydrodynamic diameters (Dh) of 96.6 ± 1.8 nm (DPPDAAm = 100) and 280.8 ± 8.2 nm (DPPDAAm = 400), and low polydispersities (PD = 0.20 ± 0.04 and 0.08 ± 0.04). These particles were tested for IRI and were found to show nearly identical activity to those that had PDAAm cores (above). Additionally, PEG113-b-PDAAm400 vesicles showed higher IRI activities compared to PEG45-b-PDAAm100 vesicles. This experiment proves that the nanoparticle size and morphologies were crucial for IRI activity, but not the nature of the core-forming block (other than its role in ensuring saline stability), primarily because of its inaccessibility by the solvent molecules (Figure 3C).

Figure 3

Figure 3. Synthesis, characterization, and ice recrystallization inhibition activity of PEG-coronal nanoparticles using PiBuOMAm- and PDAAm-based cores. (A) PEG45-b-PiBuOMAm100, (B) PEG113-b-PDAAm100 (i), and PEG113-b-PDAAm400 vesicles (ii) synthesized at [solids] = 10% w/w via aqueous RAFT-mediated PISA in the presence of [NaCl] = 0.05 M with commercially available PEG45 and PEG113 macro-RAFT agents. Insets show intensity-weighted size distributions along with average Dh and PD values (the error shows the standard deviation from five repeat measurements) and representative dry-state TEM images stained with 1 wt % uranyl acetate (UA) solution. (C) IRI activity summary corrected to [PEG].

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With the above observation of PEG activity and confirmation that the nature of core was not crucial, we envisioned that introducing a different corona composition, as it is the component that is in direct contact with the aqueous/ice phases, would result in different IRI activities. PEG is not known to present IRI, so as it was important to compare it to other PISA-derived particles with a linear non-ionic hydrophilic corona-forming polymer, with similar repeat unit dimensions (to avoid comb-type PEG-(meth)acrylates which might affect packing density). Here, poly(vinylpyrrolidone) (PVP) was employed for the first time as a steric stabilizing block for performing PISA by using DAAm as the core-forming monomer (Figure 4). Initially, N-vinylpyrrolidone (NVP) was polymerized by using xanthate chain transfer of 2-(ethoxycarbonothioyl)sulfanyl propanoate (EXEP) (see Supporting Information for full synthetic procedure, Figures S3 and S4) via photoinitiated RAFT/MADIX to ensure maximum end-group fidelity (PVP40, Mn,SEC RI = 4600 g mol–1, ĐM = 1.3) (Figure S19). (84,85) Then, a series of aqueous dispersion polymerizations in the presence of [NaCl] = 0.05 M were performed for DAAm via RAFT by using the synthesized PVP40 macromolecular chain transfer agent. The concentration of monomer was held constant at 20% w/w, and the [monomer]/[macro-CTA] ratio was varied to target DPPDAAm = 25, 50, 100, and 200. A gradual turbidity increase was noticed for polymerization solutions with increasing DPPDAAm, indicating the onset of particle formation. Quantitative monomer conversions (>97%) were achieved in all cases after 6 h, as determined by 1H NMR spectroscopic analysis in methanol-d4 of the crude samples (Figure S20 and Table S2).

Figure 4

Figure 4. Summary of PISA formulation using non-PEG-based coronas. (A) Synthesis of PVP40-b-PDAAmn diblock copolymer nanoparticles via aqueous RAFT/MADIX-mediated PISA. PVP40 macro-CTA was synthesized by photoinitiated RAFT polymerization ([solids] = 20% w/w, [NaCl] = 0.05 M). (B) Representative dry-state TEM images of PVP40-b-PDAAmn diblock copolymer nanoparticles, stained with 1 wt % uranyl acetate (UA) solution. (C) Normalized intensity-weighted size distributions obtained by DLS. (D) Zeta potential values for PVP40-b-PDAAmn diblock copolymer nanoparticles. (E) Synthesis of PDMAC40-b-PDAAm200 diblock copolymer vesicles via aqueous RAFT-mediated PISA using a PDMAC40 macro-CTA ([solids] = 20% w/w, [NaCl] = 0.05 M). (F) (i) Representative dry state and (ii) cryo-TEM images; (iii) intensity-weighted size distribution along with average Dh and PD values (the error shows the standard deviation from five repeat measurements). Inset: autocorrelation function.

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SEC analysis of PVP40-b-PDAAmn diblock copolymers revealed a rather uncontrolled character of chain extensions of PVP40 macro-CTA with high dispersity values (ĐM > 2.0) as would be expected for this macroinitiator (Figure S21). (86) PVP is known to undergo undesirable side reactions in aqueous media, leading to poor RAFT control and incomplete monomer conversions, (87,88) and it can only be readily copolymerized with a limited set of other lesser activated monomers (LAM), such as vinyl acetate or acrylics, (89,90) but no LAM dispersion PISA monomer is known, necessitating this approach. It is crucial to note that a relatively high proportion of PVP stabilizer chains remained unreacted at the end of the polymerization, leading to bimodal molecular weight distributions and is discussed in terms of the IRI activity below. Peak deconvolution was also performed on SEC curves for resulting block copolymer nanoparticles (Figures S23–S26), and the ratios of the areas between chain extended and unconsumed PVP macro-CTA are summarized in Table S3.
Dry-state TEM analysis showed an evolution in morphology upon increasing the DP of the core-forming block from spheres (DPPDAAm = 25 and 50) to mixed morphologies of spheres and vesicles (DPPDAAm = 100) to pure single-phase vesicles of uniform size (Figure 4B). For DPPDAAm = 100, the appearance of mixed spheres and vesicles can be attributed to the high dispersity values with a large proportion of PVP stabilizer chains being chain-extended to different degrees. Cryo-TEM analysis further confirmed the resulting morphologies (Figure S27). DLS analysis supported TEM findings and revealed the stable formation of particles with single populations and low polydispersity (PD) values (Figure 4C and Figure S28). The absence of charges on the outer surface of the obtained nanoparticles was also confirmed by electrophoretic analysis at neutral pH (measured zeta potential <±5 mV) (Figure 4D).
A stabilizing block of poly(N-dimethylacrylamide) (PDMAC) was also employed to perform PISA by using DAAm as the core-forming monomer (Figure 4E). DMAC was initially polymerized in dioxane at 70 °C by using 2-(((butylthio)carbonothiolyl)thio)propanoic acid as the chain transfer agent (see Supporting Information for full synthetic procedure, Figures S5 and S6). The resulting homopolymer was analyzed by 1H NMR and SEC (PDMAC40, Mn,SEC RI = 4800 g mol–1, ĐM = 1.1) (Figure S30). This water-soluble polymer precursor was chain-extended with DAAm via RAFT aqueous dispersion polymerization at 60 °C and 20% w/w solids in the presence of [NaCl] = 0.05 M, targeting a final DPPDAAm of 200. This system has been extensively studied in the past, and previous synthetic procedures were followed to achieve vesicular morphologies. (79,80,91−93) Quantitative monomer conversion (>98%) was achieved after 6 h, as determined by 1H NMR spectroscopic analysis in methanol-d4 of the crude sample (Figure S31). The prepared PDMAC40-b-PDAAm200 diblock copolymer possessed monomodal molecular weight with relatively low dispersity value, as determined by SEC analysis in DMF + 5 mM NH4BF4 (Mn,SEC = 31600 g mol–1, ĐM = 1.5) (Figure S32). Dynamic light scattering (DLS) analysis revealed the formation of nanoparticles with a monomodal size distribution and mean hydrodynamic diameter (Dh) of 308.8 ± 5.5 nm and low polydispersity (PD = 0.12 ± 0.02) (Figure 4Fiii). Dry-state and cryo-TEM imaging finally confirmed the development of single-phase unilamellar vesicles (Figure 4Fi,ii).
Figure 5 shows the IRI activity of the non-PEG-based corona formulations. For PVP, the same particle size dependence on activity as seen for PEG was observed with larger particles (vesicles) being more active than smaller ones (micelles), and both were more active than the macro-CTA alone. It is crucial to note that due to inefficient macroinitiation (see above), the PVP particles as synthesized included a population of free polymer chains. The particle IRI activity (shown in Figure 5) was determined after removal of unreacted PVP40 macro-CTA (by centrifugation, Figures S21 and S22). The presented PVP concentration was determined from deconvolution of the SEC traces (Figures S23–S26 and Table S3). IRI activity before removing excess PVP40 is also shown in Figure S29 for comparison. PDMAC-based particles also showed enhancement relative to the homopolymer alone, with the magnitude similar to the PVP-based particles (Figure 5C). Comparing vesicular particles whereby the PDAAm core-block DP was similar (Figure 5D) shows that all presented similar activity, and hence the formation of self-assembled structures rather than the chemical nature of the corona-forming block is the key requirement. All the data are summarized (independent of chemical composition) as MGS versus diameter in Figure S33, confirming that particle size correlated to activity. We should highlight this does prove a mechanism but does show that nanoparticle engineering is a tool to control the macroscopic IRI activity.

Figure 5

Figure 5. Ice recrystallization inhibition (IRI) activity of PVP and PDMAC-based nanoparticles. (A) PVP40-b-PDAAmn nanoparticles corrected to total PVP concentration in particle format. (B) PVP40-b-PDAAmn nanoparticles at [PVP] = 10 mg.mL–1. (C) PDMAC40-b-PDAAm200 diblock copolymer vesicles and PDMAC40 corrected to [PDMAC]. (D) Comparison of IRI activity for diblock copolymer vesicles of PVP40-b-PDAAm200, PDMAC40-b-PDAAm200, and PEG45-b-PDAAm150. Error bars are ± SD from a minimum of three repeats. The percent mean grain size (MGS) was reported relative to saline control. [PVP] was recalibrated based on chain extended PVP40 present particle format after estimating amount of unconsumed PVP40 macro-CTA based on Table S3 data.

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The key property investigated here, IRI, is a macroscopic observation which could be caused by a range of molecular-level mechanisms from single, or multiple, ice face binding or disruption of water transfer at the ice/water interface without actual binding. (35,41,94) IRI is also known to increase with molecular weight for many materials, and hence the effective very high Mw of a nanoparticle could provide a simple reason for the observations here. It is important to again highlight that IRI is not a binary on/off property but that sufficient concentrations of any material can induce it. (38) To investigate whether the particles were affecting ice crystal morphology, which may indicate ice binding (as opposed to a non-specific “size” related effect), crystals were grown in sucrose solution (which leads to segregated ice crystals whose morphology can be viewed). Figure 6A shows ice crystals grown with a PEG-coronal nanoparticle formulation (PEG45-b-PDAAm100) did not induce significant faceting (Figure S34). This fits a hypothesis that the PEG-coronal nanoparticle activity enhancement is not due to ice binding. In contrast, PVP alone (Figure 6B and Figure S35) showed some weak faceting of the crystals and formation of dendritic morphologies. However, the PVP-coronal nanoparticles (PVP40-b-PDAAm200) resulted in extensive dendritic ice crystals (Figure 6C and Figure S36). This would imply that PVP, while itself only having weak (or no) IRI activity, (27) when assembled in the correct format can engage ice or affect the morphology of ice produced. The increased faceting could be due to the nanoparticles spanning between multiple ice faces due to their large size. This is an exciting observation as if ice crystal morphology can be probed or modulated by these easy-to-make synthetic soft materials, it opens doors to fundamental studies on the ice interface, without needing protein engineering as well as potential applications. It also suggests that the enhanced activity seen for PEG/PDMAC coronas (without ice engagement) still apply when using coronas with some affinity for ice.

Figure 6

Figure 6. Ice binding and ice nucleation analysis of nanoparticles. (A) Modified “sucrose sandwich” ice shaping assay images for 1 mg mL–1 of PEG45-b-PDAAm100 nanoparticles in 45 wt % sucrose solution; (B) 1 mg mL–1 of PVP40 and (C) 1 mg mL–1 of PVP40-b-PDAAm200. (D) Assessment of ice nucleation activity in microliter droplets showing immersion mode fraction frozen curves as a function of temperature for droplets containing 1 mg mL–1 PEG45-b-PDAAm150, PDMAC40-b-PDAAm200, and PVP40-b-PDAAm200 along with their corresponding macro-CTAs (E) and PVP40-b-PDAAmn (n = 25, 50, 100, 200) nanoparticle series. Example temperature errors bars are included on selected data points on panels D and E.

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With the above observations that the PISA particle format led to increased IRI activity and ice shaping, the ability of the particles to nucleate ice was next studied. On cooling, pure water can persist as liquid to temperatures as low as −40 °C. This phenomenon is known as supercooling, and some substances such as INPs are capable of inducing a stable ice nucleus in supercooled water: known as heterogeneous ice nucleation. A feature of ice nucleating proteins, INPs (as discussed in the Introduction), is that assembly of small domains into larger ones is essential for activity, as macromolecules must be of a similar scale to the classical nucleation theory derived critical ice cluster size to nucleate ice at a given temperature. (50,51) The ice critical cluster size increases rapidly as temperature approaches the melting point. For example, the critical ice cluster has a diameter of about 20 nm at −5 °C. (51) This means large aggregates of (for example) bacterial ice nucleating proteins are required to induce ice nucleation close to 0 °C. There is theoretical evidence that molecular size is a key criteria for ice nucleation, (23) and it has been observed experimentally that some AFPs can also nucleate ice, with the size of the AFP being an essential descriptor. (52,53) Given that some of the polymer particles synthesized bind ice, all show IRI and are large compared to ice critical nuclei; it might be thought that they would be capable of nucleating ice at warm temperatures as seen for higher molecular weight antifreeze proteins. To test this, microliter ice nucleation assays were undertaken by using a bespoke apparatus described in the Supporting Information. This instrument freezes around 50 droplets per experiment to establish the spread of likely nucleation temperatures for a given heterogeneous nucleator. The ice nucleation temperatures of 1 mg mL–1 nanoparticle and polymer solution are reported in Figure 6D,E. It was found that the PEG- and PDMAC-based formulations nucleated ice at average temperatures of −25.8 and −26.8 °C, respectively, only slightly warmer than the average freezing temperature of pure water on the instrument, −28.1 °C. PVP and the various PVP-based nanoparticles tested nucleated at average temperatures between −23.6 and −24.5 °C. Notably, the fraction frozen curves for PVP and PVP40-b-PDAAm200 were very similar. While the PEG- and PDMAC-derived nanoparticles do nucleate ice at slightly warmer temperatures than their precursor polymers, the difference is not large. Figure 6E shows a slight increase in nucleation temperature with increasing particle size for PVP-derived nanoparticles; however, the enhancement is not large. The nucleation data show that aggregation of polymers into particles does not substantially enhance ice nucleation effectiveness. This supports the theory that correct long- and short-range structure, as well as sufficient size, is required for a nucleant to be highly effective. These combined observations support emerging evidence that the observation macroscopic properties of ice binding proteins are not always caused by the same underlying molecular mechanisms (36−38) and that a particular property can be dialled into a material. There is an opportunity to achieve desirable levels of ice growth inhibition (for a specific application) by deploying nanoparticle formulations such as those presented here, even if their overall activity is substantially weaker than IBPs, and indeed their mechanism is non-specific.

Conclusions

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We report that biomimetic ice recrystallization inhibition activity can be introduced into polymer nanoparticles from components which themselves have no ice binding or associated activity. Saline-tolerant polymerization induced self-assembly (PISA) was exploited to obtain nanoparticles of controlled size and morphology by using a library of different corona-forming polymers [poly(ethylene glycol), poly(vinylpyrrolidone) (for the first time via dispersion PISA), and poly(dimethylacrylamide)] and core-forming blocks [poly(diacetone acrylamide) and poly((isobutoxymethyl)acrylamide)]. In all cases, ice recrystallization inhibition was observed despite the constituent homopolymers (i.e., corona-forming blocks) having no activity themselves, suggesting that size and confinement of the coronal blocks can enhance this macroscopic property. Larger particles (vesicles) were more active than smaller ones (micelles/spheres and intermediate morphologies), confirming that the size and nanoarchitecture of the particles were crucial for inducing activity. The activity enhancement relative to linear polymers was seen both in terms of the total coronal mass (as the solvent-contacting component) or as the total mass (including the core), showing this was not simply due to the increased mass applied in a nanoparticle formulation. The core-forming blocks were also varied, and this had minimal or no impact on the observable ice recrystallization inhibition activity, confirming this was a general effect. In the case of poly(vinylpyrrolidone) coronal particles, there was observation of ice shaping, suggesting these particles may engage specific ice faces, which was not seen with the polymers alone. This additional binding did not lead to significantly higher IRI activity though, suggesting IRI was dominated by their size and packing density for each morphology. Ice nucleation was also studied, but no activity was seen. This was a crucial observation as it has been reported that larger assemblies of antifreeze proteins can lead to ice nucleation activity but that the assembly of these polymers does not lead to ice nucleation. This may suggest a unique mechanism, but the huge structural differences between the particles and AFPs make a real comparison difficult. The data here also supports emerging evidence that the magnitude of each macroscopic property associated with ice binding proteins mimics does not scale equally between all materials. The exact molecular mechanism for this increased activity is not clear and may be simply related to the overall size and molecular weight of the particles, which exceeds what is accessible with linear polymers. However, the PVP data supports that increased ice binding can occur in these assemblies. These observations show that coronal confinement of polymers can induce the macroscopic effect of ice recrystallization inhibition but that the same is not true for ice-nucleation activity, providing evidence that simply enlarging IRI-active components does not guarantee ice nucleation. While the overall magnitude of activity here is less than ice binding proteins, there is huge technological potential in the development of freeze-stable colloids, exploiting this size-driven enhancement to translate to applications, as well as a tool to study the fundamentals of ice-binding/modifying materials.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.1c01963.

  • Full synthetic details and characterization of polymers and nanomaterials (PDF)

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Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

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  • Corresponding Author
    • Matthew I. Gibson - Department of Chemistry, University of Warwick, Gibbet Hill Road, CV4 7AL Coventry, U.K.;  Warwick Medical School, University of Warwick, Gibbet Hill Road, CV4 7AL Coventry, U.K.;  Orcidhttp://orcid.org/0000-0002-8297-1278;  Email: [email protected]
  • Authors
    • Panagiotis G. Georgiou - Department of Chemistry, University of Warwick, Gibbet Hill Road, CV4 7AL Coventry, U.K.;  Orcidhttp://orcid.org/0000-0001-8968-1057
    • Huba L. Marton - Department of Chemistry, University of Warwick, Gibbet Hill Road, CV4 7AL Coventry, U.K.;  Orcidhttp://orcid.org/0000-0001-7547-6001
    • Alexander N. Baker - Department of Chemistry, University of Warwick, Gibbet Hill Road, CV4 7AL Coventry, U.K.;  Orcidhttp://orcid.org/0000-0001-6019-3412
    • Thomas R. Congdon - Department of Chemistry, University of Warwick, Gibbet Hill Road, CV4 7AL Coventry, U.K.
    • Thomas F. Whale - Department of Chemistry, University of Warwick, Gibbet Hill Road, CV4 7AL Coventry, U.K.
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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M.I.G. thanks the ERC for a Consolidator Grant (866056) and the Royal Society for an Industry Fellowship (191037) joint with Cytivia. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Grant Agreement No. 814236. BBSRC-funded MIBTP program (BB/M01116X/1) and Cytivia are thanked for supporting H.M. T.F.W. thanks the Leverhulme Trust and the University of Warwick for supporting an Early Career Fellowship (ECF-2018-127). T.R.C. thanks the BBSRC Emerging Innovations Grant ref BB/S506783/1. The Warwick Polymer Research Technology Platform is acknowledged for SEC analysis, and the Warwick Electron Microscopy Research Technology Platform is acknowledged for TEM. We also acknowledge the University of Warwick Advanced Bioimaging Research Technology Platform supported by BBSRC ALERT14 Award BB/M01228X/1 and Dr. S. Bakker for cryo-TEM. The BBSRC-funded MIBTP program (BB/M01116X/1) and Iceni Diagnostics Ltd. are thanked for a studentship for A.N.B.

References

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    Journal of Experimental Biology (1996), 199 (9), 2071-2076CODEN: JEBIAM; ISSN:0022-0949. (Company of Biologists)
    Antifreeze protein (AFP) types I, II and III were tested for their ability to protect red blood cells from lysis during warming, after cryopreservation in hydroxyethyl starch. All 3 types reduced hemolysis to 25% of control values at similar micromolar concns. but enhanced lysis as the AFP concn. approached millimolar levels. Site-directed mutants of type III AFP with different thermal hysteresis activities were tested for their ability to protect the cryopreserved cells from lysis. Their relative efficacy in protecting the cells correlated closely with their thermal hysteresis activity. Cryomicroscopy indicated that the protection of red cells by type III AFP and the mutant forms was due to inhibition of ice recrystn.
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  13. 13
    John Morris, G.; Acton, E. Controlled Ice Nucleation in Cryopreservation - A Review. Cryobiology 2013, 66 (2), 85– 92,  DOI: 10.1016/j.cryobiol.2012.11.007
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    13
    Controlled ice nucleation in cryopreservation - A review
    John Morris, G.; Acton, Elizabeth
    Cryobiology (2013), 66 (2), 85-92CODEN: CRYBAS; ISSN:0011-2240. (Elsevier Ltd.)
    We review here for the first time, the literature on control of ice nucleation in cryopreservation. Water and aq. solns. have a tendency to undercool before ice nucleation occurs. Control of ice nucleation has been recognized as a crit. step in the cryopreservation of embryos and oocytes but is largely ignored for other cell types. We review the processes of ice nucleation and crystal growth in the soln. around cells and tissues during cryopreservation with an emphasis on non IVF applications. The extent of undercooling that is encountered during the cooling of various cryocontainers is defined and the methods that have been employed to control the nucleation of ice are examd. The effects of controlled ice nucleation on the structure of the sample and the outcome of cryopreservation of a range of cell types and tissues are presented and the phys. events which define the cellular response are discussed.Nucleation of ice is the most significant uncontrolled variable in conventional cryopreservation leading to sample to sample variation in cell recovery, viability and function and should be controlled to allow standardisation of cryopreservation protocols for cells for biobanking, cell based assays or clin. application. This intervention allows a way of increasing viability of cells and reducing variability between samples and should be included as std. operating procedures are developed.
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  14. 14
    Frazier, S. D.; Matar, M. G.; Osio-Norgaard, J.; Aday, A. N.; Delesky, E. A.; Srubar, W. V. Inhibiting Freeze-Thaw Damage in Cement Paste and Concrete by Mimicking Nature’s Antifreeze. Cell Reports Phys. Sci. 2020, 1 (6), 100060,  DOI: 10.1016/j.xcrp.2020.100060
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    Valarezo, W. O.; Lynch, F. T.; McGhee, R. J. Aerodynamic Performance Effects Due to Small Leading-Edge Ice (Roughness) on Wings and Tails. J. Aircr. 1993, 30 (6), 807– 812,  DOI: 10.2514/3.46420
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    Sidebottom, C.; Buckley, S.; Pudney, P.; Twigg, S.; Jarman, C.; Holt, C.; Telford, J.; McArthur, A.; Worrall, D.; Hubbard, R. Heat-Stable Antifreeze Protein from Grass. Nature 2000, 406 (6793), 256,  DOI: 10.1038/35018639
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    Phytochemistry: Heat-stable antifreeze protein from grass
    Sidebottom, Chris; Buckley, Sarah; Pudney, Paul; Twigg, Sarah; Jarman, Carl; Holt, Chris; Telford, Julia; McArthur, Andrew; Worrall, Dawn; Hubbard, Rod; Lillford, Peter
    Nature (London) (2000), 406 (6793), 256CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    There is no expanded citation for this reference.
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    Regand, A.; Goff, H. D. Ice Recrystallization Inhibition in Ice Cream as Affected by Ice Structuring Proteins from Winter Wheat Grass. J. Dairy Sci. 2006, 89 (1), 49– 57,  DOI: 10.3168/jds.S0022-0302(06)72068-9
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    17
    Ice recrystallization inhibition in ice cream as affected by ice structuring proteins from winter wheat grass
    Regand, A.; Goff, H. D.
    Journal of Dairy Science (2006), 89 (1), 49-57CODEN: JDSCAE; ISSN:0022-0302. (American Dairy Science Association)
    Ice recrystn. in quiescently frozen sucrose solns. that contained some of the ingredients commonly found in ice cream and in ice cream manufd. under com. conditions, with or without ice structuring proteins (ISP) from cold-acclimated winter wheat grass ext. (AWWE), was assessed by bright field microscopy. In sucrose solns., crit. differences in moisture content, viscosity, ionic strength, and other properties derived from the presence of other ingredients (skim milk powder, corn syrup solids, locust bean gum) caused a redn. in ice crystal growth. Significant ISP activity in retarding ice crystal growth was obsd. in all solns. (44% for the most complex mix) contg. 0.13% total protein from AWWE. In heat-shocked ice cream, ice recrystn. rates were significantly reduced 40 and 46% with the addn. of 0.0025 and 0.0037% total protein from AWWE. The ISP activity in ice cream was not hindered by its inclusion in mix prior to pasteurization. A synergistic effect between ISP and stabilizer was obsd., as ISP activity was reduced in the absence of stabilizer in ice cream formulations. A remarkably smoother texture for ice creams contg. ISP after heat-shock storage was evident by sensory evaluation. The efficiency of ISP from AWWE in controlling ice crystal growth in ice cream was demonstrated.
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    Stubbs, C.; Bailey, T. L.; Murray, K.; Gibson, M. I. Polyampholytes as Emerging Macromolecular Cryoprotectants. Biomacromolecules 2020, 21 (7), 7– 17,  DOI: 10.1021/acs.biomac.9b01053
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    18
    Polyampholytes as Emerging Macromolecular Cryoprotectants
    Stubbs, Christopher; Bailey, Trisha L.; Murray, Kathryn; Gibson, Matthew I.
    Biomacromolecules (2020), 21 (1), 7-17CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
    A review. Cellular cryopreservation is a platform technol. which underpins cell biol., biochem., biomaterials, diagnostics, and the cold chain for emerging cell-based therapies. This technique relies on effective methods for banking and shipping to avoid the need for continuous cell culture. The most common method to achieve cryopreservation is to use large vols. of org. solvent cryoprotective agents which can promote either a vitreous (ice free) phase or dehydrate and protect the cells. These methods are very successful but are not perfect: not all cell types can be cryopreserved and recovered, and the cells do not always retain their phenotype and function post-thaw. This Perspective Article will introduce polyampholytes as emerging macromol. cryoprotective agents and demonstrate they have the potential to impact a range of fields from cell-based therapies to basic cell biol. and may be able to improve, or replace, current solvent-based cryoprotective agents. Polyampholytes have been shown to be remarkable (mammalian cell) cryopreservation enhancers, but their mechanism of action is unclear, which may include membrane protection, solvent replacement, or a yet unknown protective mechanism, but it seems the modulation of ice growth (recrystn.) may only play a minor role in their function, unlike other macromol. cryoprotectants. This article will discuss their synthesis and summarize the state-of-the-art, including hypotheses of how they function, to introduce this exciting area of biomacromol. science.
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  19. 19
    Graham, B.; Bailey, T. L.; Healey, J. R. J.; Marcellini, M.; Deville, S.; Gibson, M. I. Polyproline as a Minimal Antifreeze Protein Mimic That Enhances the Cryopreservation of Cell Monolayers. Angew. Chem. 2017, 129 (50), 16157– 16160,  DOI: 10.1002/ange.201706703
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    Voets, I. K. From Ice-Binding Proteins to Bio-Inspired Antifreeze Materials. Soft Matter 2017, 13 (28), 4808– 4823,  DOI: 10.1039/C6SM02867E
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    20
    From ice-binding proteins to bio-inspired antifreeze materials
    Voets, I. K.
    Soft Matter (2017), 13 (28), 4808-4823CODEN: SMOABF; ISSN:1744-6848. (Royal Society of Chemistry)
    Ice-binding proteins (IBP) facilitate survival under extreme conditions in diverse life forms. IBPs in polar fishes block further growth of internalized environmental ice and inhibit ice recrystn. of accumulated internal crystals. Algae use IBPs to structure ice, while ice adhesion is crit. for the Antarctic bacterium Marinomonas primoryensis. Successful translation of this natural cryoprotective ability into man-made materials holds great promise but is still in its infancy. This review covers recent advances in the field of ice-binding proteins and their synthetic analogs, highlighting fundamental insights into IBP functioning as a foundation for the knowledge-based development of cheap, bio-inspired mimics through scalable prodn. routes. Recent advances in the utilization of IBPs and their analogs to e.g. improve cryopreservation, ice-templating strategies, gas hydrate inhibition and other technologies are presented.
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    He, Z.; Liu, K.; Wang, J. Bioinspired Materials for Controlling Ice Nucleation, Growth, and Recrystallization. Acc. Chem. Res. 2018, 51 (5), 1082– 1091,  DOI: 10.1021/acs.accounts.7b00528
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    Bioinspired Materials for Controlling Ice Nucleation, Growth, and Recrystallization
    He, Zhiyuan; Liu, Kai; Wang, Jianjun
    Accounts of Chemical Research (2018), 51 (5), 1082-1091CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review. Ice formation, mainly consisting of ice nucleation, ice growth, and ice recrystn., is ubiquitous and crucial in wide-ranging fields from cryobiol. to atm. physics. Despite active research for more than a century, the mechanism of ice formation is still far from satisfactory. Meanwhile, nature has unique ways of controlling ice formation and can provide resourceful avenues to unravel the mechanism of ice formation. For instance, antifreeze proteins (AFPs) protect living organisms from freezing damage via controlling ice formation, for example, tuning ice nucleation, shaping ice crystals, and inhibiting ice growth and recrystn. In addn., AFP mimics can have applications in cryopreservation of cells, tissues, and organs, food storage, and anti-icing materials. Therefore, continuous efforts have been made to understand the mechanism of AFPs and design AFP inspired materials.In this Account, the authors first review the authors' recent research progress in understanding the mechanism of AFPs in controlling ice formation. A Janus effect of AFPs on ice nucleation was discovered, which was achieved via selectively tethering the ice-binding face (IBF) or the non-ice-binding face (NIBF) of AFPs to solid surfaces and studying specifically the effect of the other face on ice nucleation. Through mol. dynamics (MD) simulation anal., the authors obsd. ordered hexagonal ice-like water structure atop the IBF and disordered water structure atop the NIBF. Therefore, the interfacial water plays a crit. role in controlling ice formation.Next, the design and fabrication of AFP mimics with capabilities in tuning ice nucleation and controlling ice shape and growth, as well as inhibiting ice recrystn are discussed. For example, the authors tuned ice nucleation via modifying solid surfaces with supercharged unfolded polypeptides (SUPs) and polyelectrolyte brushes (PBs) with different counterions. The authors found graphene oxide (GO) and oxidized quasi-carbon nitride quantum dots (OQCNs) had profound effects in controlling ice shape and inhibiting ice growth. The authors also studied the ion-specific effect on ice recrystn. inhibition (IRI) with a large variety of anions and cations. All functionalities are achieved by tuning the properties of interfacial water on these materials, which reinforces the importance of the interfacial water in controlling ice formation. Finally, the authors review the development of novel application-oriented materials emerging from the authors' enhanced understanding of ice formation, for example, ultralow ice adhesion coatings with aq. lubricating layer, cryopreservation of cells by inhibiting ice recrystn., and two-dimensional (2D) and three-dimensional (3D) porous materials with tunable pore sizes through recrystd. ice crystal templates. This Account sheds new light on the mol. mechanism of ice formation and will inspire the design of unprecedented functional materials based on controlled ice formation.
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  22. 22
    Gibson, M. I. Slowing the Growth of Ice with Synthetic Macromolecules: Beyond Antifreeze(Glyco) Proteins. Polym. Chem. 2010, 1 (8), 1141– 1152,  DOI: 10.1039/c0py00089b
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    22
    Slowing the growth of ice with synthetic macromolecules: beyond antifreeze(glyco) proteins
    Gibson, Matthew I.
    Polymer Chemistry (2010), 1 (8), 1141-1152CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
    A review. Biol. antifreezes are a relatively large and diverse class of proteins (and very recently expanded to include lipopolysaccharides) which are capable of interacting with ice crystals in such a manner as to influence and, under the correct conditions, to prevent their growth. These properties allow for the survival of organisms which are either continuously or sporadically exposed to subzero temps. which would otherwise lead to cryo-injury/death. These proteins have been found in a range of organisms, including plants, bacteria, insects and fish, and the proteins themselves have a diverse range of chem. structures ranging from the highly conserved antifreeze glycoproteins (AFGPs) to the more diverse antifreeze proteins AFPs. Their unique abilities to non-colligatively decrease the f.p. of aq. solns., inhibit ice recrystn. and induce dynamic ice shaping suggest they will find many applications from cell/tissue/organ cryostorage, frozen food preservatives, texture enhancers or even as cryosurgery adjuvants. However, these applications have been limited by a lack of available material and also underlying questions regarding their mode of activity. The aim of this review article is to highlight the potential of polymeric materials to act as synthetic mimics of antifreeze(glyco) proteins, as well as to summarize the current general challenges in designing compds. capable of mimicking AF(G)Ps. This will cover the basic properties and modes of action of AF(G)Ps along with the methods commonly used to evaluate their activity. This section is essential to specifically define the 'antifreeze' terminol. in terms of these proteins' unique function and to distinguish them from conventional antifreezes. A detailed evaluation of the processes involved in AF(G)P activity is beyond the scope of this review, but the reader will be pointed towards relevant literature. This will then be placed in the context of modern polymer science, with a focus on the ability of synthetic polymers to display some type of specific antifreeze activity, which will be summarized. Finally, the potential applications of these materials will be highlighted and future avenues for their research and the challenges faced in achieving these goals suggested.
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  23. 23
    Qiu, Y.; Hudait, A.; Molinero, V. How Size and Aggregation of Ice-Binding Proteins Control Their Ice Nucleation Efficiency. J. Am. Chem. Soc. 2019, 141 (18), 7439– 7452,  DOI: 10.1021/jacs.9b01854
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    23
    How Size and Aggregation of Ice-Binding Proteins Control Their Ice Nucleation Efficiency
    Qiu, Yuqing; Hudait, Arpa; Molinero, Valeria
    Journal of the American Chemical Society (2019), 141 (18), 7439-7452CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Organisms that thrive at cold temps. produce ice-binding proteins to manage the nucleation and growth of ice. Bacterial ice-nucleating proteins (INP) are typically large and form aggregates in the cell membrane, while insect hyperactive antifreeze proteins (AFP) are sol. and generally small. Expts. indicate that larger ice-binding proteins and their aggregates nucleate ice at warmer temps. Nevertheless, a quant. understanding of how size and aggregation of ice-binding proteins det. the temp. Thet at which proteins nucleate ice is still lacking. Here, we address this question using mol. simulations and nucleation theory. The simulations indicate that the 2.5 nm long antifreeze protein TmAFP nucleates ice at 2 ± 1 °C above the homogeneous nucleation temp., in good agreement with recent expts. We predict that the addn. of ice-binding loops to TmAFP increases Thet, but not enough to compete in efficiency with the bacterial INP. We implement an accurate procedure to det. Thet of surfaces of finite size using classical nucleation theory, and, after validating the theory against Thet of the proteins in mol. simulations, we use it to predict Thet of the INP of Ps. syringae as a function of the length and no. of proteins in the aggregates. We conclude that assemblies with at most 34 INP already reach the Thet = -2 °C characteristic of this bacterium. Interestingly, we find that Thet is a strongly varying nonmonotonic function of the distance between proteins in the aggregates. This indicates that, to achieve max. freezing efficiency, bacteria must exert exquisite, subangstrom control of the distance between INP in their membrane.
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    Biggs, C. I.; Bailey, T. L.; Ben Graham; Stubbs, C.; Fayter, A.; Gibson, M. I. Polymer Mimics of Biomacromolecular Antifreezes. Nat. Commun. 2017, 8 (1), 1546,  DOI: 10.1038/s41467-017-01421-7
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    24
    Polymer mimics of biomacromolecular antifreezes
    Biggs Caroline I; Bailey Trisha L; Ben Graham; Stubbs Christopher; Fayter Alice; Gibson Matthew I; Gibson Matthew I
    Nature communications (2017), 8 (1), 1546 ISSN:.
    Antifreeze proteins from polar fish species are remarkable biomacromolecules which prevent the growth of ice crystals. Ice crystal growth is a major problem in cell/tissue cryopreservation for transplantation, transfusion and basic biomedical research, as well as technological applications such as icing of aircraft wings. This review will introduce the rapidly emerging field of synthetic macromolecular (polymer) mimics of antifreeze proteins. Particular focus is placed on designing polymers which have no structural similarities to antifreeze proteins but reproduce the same macroscopic properties, potentially by different molecular-level mechanisms. The application of these polymers to the cryopreservation of donor cells is also introduced.
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  25. 25
    Sun, T.; Lin, F.-H.; Campbell, R. L.; Allingham, J. S.; Davies, P. L. An Antifreeze Protein Folds with an Interior Network of More than 400 Semi-Clathrate Waters. Science 2014, 343 (6172), 795– 798,  DOI: 10.1126/science.1247407
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    25
    An Antifreeze Protein Folds with an Interior Network of More Than 400 Semi-Clathrate Waters
    Sun, Tianjun; Lin, Feng-Hsu; Campbell, Robert L.; Allingham, John S.; Davies, Peter L.
    Science (Washington, DC, United States) (2014), 343 (6172), 795-798CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    When polypeptide chains fold into a protein, hydrophobic groups are compacted in the center with exclusion of water. We report the crystal structure of the antifreeze protein (AFP) Maxi, a large isoform of the 3-kD alanine-rich AFP from Pseudopleuronectes americanus, that retains ∼400 waters in its core. The putative ice-binding residues of this dimeric, four-helix bundle protein point inwards and coordinate the interior waters into two intersecting polypentagonal networks. The bundle makes minimal protein contacts between helixes, but is stabilized by anchoring to the semi-clathrate water monolayers through backbone carbonyl groups in the protein interior. The ordered waters extend outwards to the protein surface and likely are involved in ice binding. This protein fold supports both the anchored-clathrate water mechanism of antifreeze protein adsorption to ice and the water-expulsion mechanism of protein folding.
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  26. 26
    Marshall, C. B.; Daley, M. E.; Sykes, B. D.; Davies, P. L. Enhancing the Activity of a β-Helical Antifreeze Protein by the Engineered Addition of Coils. Biochemistry 2004, 43 (37), 11637– 11646,  DOI: 10.1021/bi0488909
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    26
    Enhancing the Activity of a β-Helical Antifreeze Protein by the Engineered Addition of Coils
    Marshall, Christopher B.; Daley, Margaret E.; Sykes, Brian D.; Davies, Peter L.
    Biochemistry (2004), 43 (37), 11637-11646CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
    The effectiveness of natural antifreeze proteins in inhibiting the growth of a seed ice crystal seems to vary with protein size. Here we have made use of the extreme regularity of the β-helical antifreeze protein from the beetle Tenebrio molitor to explore systematically the relationship between antifreeze activity and the area of the ice-binding site. Each of the 12-amino acid, disulfide-bonded central coils of the β-helix contains a Thr-Xaa-Thr ice-binding motif. By adding coils to, and deleting coils from, the seven-coil parent antifreeze protein, we have made a series of constructs with 6-11 coils. Misfolded forms of these antifreezes were removed by ice affinity purifn. to accurately compare the specific activity of each construct. There was a 10-100-fold gain in activity upon going from six to nine coils, depending on the concn. that was compared. Activity was maximal for the nine-coil construct, which gave a f.p. depression of 6.5 C° at 0.7 mg/mL, but actually decreased for the 10- and 11-coil constructs. This small loss in activity might result from the accumulation of a slight mismatch between the spacing of the ice-binding threonine residues and the O atoms of the ice lattice.
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  27. 27
    Congdon, T.; Notman, R.; Gibson, M. I. Antifreeze (Glyco)Protein Mimetic Behavior of Poly(Vinyl Alcohol): Detailed Structure Ice Recrystallization Inhibition Activity Study. Biomacromolecules 2013, 14 (5), 1578– 1586,  DOI: 10.1021/bm400217j
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    27
    Antifreeze (Glyco)protein Mimetic Behavior of Poly(vinyl alcohol): Detailed Structure Ice Recrystallization Inhibition Activity Study
    Congdon, Thomas; Notman, Rebecca; Gibson, Matthew I.
    Biomacromolecules (2013), 14 (5), 1578-1586CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
    This manuscript reports a detailed study on the ability of poly(vinyl alc.) to act as a biomimetic surrogate for AF(G)Ps ("antifreeze(glyco)proteins"), with a focus on the specific property of ice-recrystn. inhibition (IRI). Despite over 40 years of study, the underlying mechanisms that govern the action of biol. antifreezes are still poorly understood, which is in part due to their limited availability and challenging synthesis. Poly(vinyl alc.) (PVA) has been shown to display remarkable ice recrystn. inhibition activity despite its major structural differences to native antifreeze proteins. Here, controlled radical polymn. is used to synthesize well-defined PVA, which has enabled us to obtain the first quant. structure-activity relationships, to probe the role of mol. wt. and comonomers on IRI activity. Crucially, it was found that IRI activity is "switched on" when the polymer chain length increases from 10 and 20 repeat units. Substitution of the polymer side chains with hydrophilic or hydrophobic units was found to diminish activity. Hydrophobic modifications to the backbone were slightly more tolerated than side chain modifications, which implies an unbroken sequence of hydroxyl units is necessary for activity. These results highlight the idea that although hydrophobic domains are key components of IRI activity, the random inclusion of addnl. hydrophobic units does not guarantee an increase in activity and that the actual polymer conformation is important.
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    Naullage, P. M.; Lupi, L.; Molinero, V. Molecular Recognition of Ice by Fully Flexible Molecules. J. Phys. Chem. C 2017, 121 (48), 26949– 26957,  DOI: 10.1021/acs.jpcc.7b10265
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    28
    Molecular Recognition of Ice by Fully Flexible Molecules
    Naullage, Pavithra M.; Lupi, Laura; Molinero, Valeria
    Journal of Physical Chemistry C (2017), 121 (48), 26949-26957CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    Cold-acclimatized organisms produce antifreeze proteins that enable them to prevent ice growth and recrystn. at subfreezing conditions. Flatness and rigidity of the ice-binding sites of antifreeze proteins are considered key for their recognition of ice. However, the most potent synthetic ice recrystn. inhibitor (IRI) found to date is polyvinyl alc. (PVA), a fully flexible mol. The ability to tune the architecture and functionalization of PVA makes it a promising candidate to replace antifreeze proteins in industrial applications ranging from cryopreservation of organs to de-icing of turbine blades. However, an understanding of how PVA recognizes ice remains elusive, hampering the design of more effective IRIs. Here, we used large-scale mol. dynamics simulations to elucidate the mechanism by which PVA recognizes ice. We found that the polymer selectively bound to the prismatic faces of ice through a cooperative zipper mechanism. The binding was driven by H-bonding, facilitated by distance matching between the OH groups in PVA and water at the ice surface. Strong, cooperative binding to ice results from the different scaling of the free energy gains on binding per monomer, and the loss of translational and configurational entropy of the chain. We explained why branching of PVA does not improve its IRI activity, and used the new mol. understanding to propose principles for the design of macromols. that bind efficiently to the basal and prismatic planes of ice, producing hyperactive synthetic antifreeze mols. that could compete with the most effective antifreeze proteins.
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    Whale, T. F.; Rosillo-Lopez, M.; Murray, B. J.; Salzmann, C. G. Ice Nucleation Properties of Oxidized Carbon Nanomaterials. J. Phys. Chem. Lett. 2015, 6 (15), 3012– 3016,  DOI: 10.1021/acs.jpclett.5b01096
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    29
    Ice Nucleation Properties of Oxidized Carbon Nanomaterials
    Whale, Thomas F.; Rosillo-Lopez, Martin; Murray, Benjamin J.; Salzmann, Christoph G.
    Journal of Physical Chemistry Letters (2015), 6 (15), 3012-3016CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)
    Heterogeneous ice nucleation is an important process in many fields, particularly atm. science, but is still poorly understood. All known inorg. ice nucleating particles are relatively large in size and tend to be hydrophilic. Hence it is not obvious that carbon nanomaterials should nucleate ice. However, in this paper we show that four different readily water-dispersible carbon nanomaterials are capable of nucleating ice. The tested materials were carboxylated graphene nanoflakes, graphene oxide, oxidized single walled carbon nanotubes and oxidized multiwalled carbon nanotubes. The carboxylated graphene nanoflakes have a diam. of ∼30 nm and are among the smallest entities obsd. so far to nucleate ice. Overall, carbon nanotubes were found to nucleate ice more efficiently than flat graphene species, and less oxidized materials nucleated ice more efficiently than more oxidized species. These well-defined carbon nanomaterials may pave the way to bridging the gap between exptl. and computational studies of ice nucleation.
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  30. 30
    Geng, H.; Liu, X.; Shi, G.; Bai, G.; Ma, J.; Chen, J.; Wu, Z.; Song, Y.; Fang, H.; Wang, J. Graphene Oxide Restricts Growth and Recrystallization of Ice Crystals. Angew. Chem., Int. Ed. 2017, 56 (4), 997– 1001,  DOI: 10.1002/anie.201609230
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    Graphene Oxide Restricts Growth and Recrystallization of Ice Crystals
    Geng, Hongya; Liu, Xing; Shi, Guosheng; Bai, Guoying; Ma, Ji; Chen, Jingbo; Wu, Zhuangyuan; Song, Yanlin; Fang, Haiping; Wang, Jianjun
    Angewandte Chemie, International Edition (2017), 56 (4), 997-1001CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The authors show graphene oxide (GO) greatly suppresses the growth and recrystn. of ice crystals, and ice crystals display a hexagonal shape in the GO dispersion. Preferred adsorption of GO on the ice crystal surface in liq. H2O leads to curved ice crystal surface. Therefore, the growth of ice crystal is suppressed owing to the Gibbs-Thompson effect, i.e., the curved surface lowers the freezing temp. Mol. dynamics simulation anal. reveals that oxidized groups on the basal plane of GO form more H bonds with ice in comparison with liq. H2O because of the honeycomb hexagonal scaffold of graphene, giving a mol.-level mechanism for controlling ice formation. Application of GO for cryopreservation shows that addn. of only 0.01% of GO to a culture medium greatly increases the motility (from 24.3% to 71.3 %) of horse sperms. This work reports the control of growth of ice with GO, and opens a new avenue for the application of 2D materials.
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  31. 31
    Biggs, C. I.; Packer, C.; Hindmarsh, S.; Walker, M.; Wilson, N. R.; Rourke, J. P.; Gibson, M. I. Impact of Sequential Surface-Modification of Graphene Oxide on Ice Nucleation. Phys. Chem. Chem. Phys. 2017, 19 (33), 21929– 21932,  DOI: 10.1039/C7CP03219F
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    Impact of sequential surface-modification of graphene oxide on ice nucleation
    Biggs, Caroline I.; Packer, Christopher; Hindmarsh, Steven; Walker, Marc; Wilson, Neil R.; Rourke, Jonathan P.; Gibson, Matthew I.
    Physical Chemistry Chemical Physics (2017), 19 (33), 21929-21932CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
    Base-washed graphene-oxide which has been sequentially-modified by thiol-epoxy chem., results in materials with ice-nucleation activity. The role of hydrophilic and hydrophobic grafts and polymers was evaluated with the most potent functioning at just 0.25 wt.%. These 2D hybrid materials may find use in cryopreservation and fundamental studies on ice formation.
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  32. 32
    Drori, R.; Li, C.; Hu, C.; Raiteri, P.; Rohl, A. L.; Ward, M. D.; Kahr, B. A Supramolecular Ice Growth Inhibitor. J. Am. Chem. Soc. 2016, 138 (40), 13396– 13401,  DOI: 10.1021/jacs.6b08267
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    A Supramolecular Ice Growth Inhibitor
    Drori, Ran; Li, Chao; Hu, Chunhua; Raiteri, Paolo; Rohl, Andrew L.; Ward, Michael D.; Kahr, Bart
    Journal of the American Chemical Society (2016), 138 (40), 13396-13401CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Safranine O, a synthetic dye, was found to inhibit growth of ice at mM concns. with an activity comparable to that of highly evolved antifreeze glycoproteins. Safranine inhibits growth of ice crystals along the crystallog. a-axis, resulting in bipyramidal needles extended along the <0001> directions as well as and plane-specific thermal hysteresis (TH) activity. The interaction of safranine with ice is reversible, distinct from the previously reported behavior of antifreeze proteins. Spectroscopy and mol. dynamics indicate that safranine forms aggregates in aq. soln. at μM concns. Metadynamics simulations and aggregation theory suggested that as many as 30 safranine mols. were preorganized in stacks at the concns. where ice growth inhibition was obsd. The simulations and single-crystal x-ray structure of safranine revealed regularly spaced amino and Me substituents in the aggregates, akin to the ice-binding site of antifreeze proteins. Collectively, these observations suggest an unusual link between supramol. assemblies of small mols. and functional proteins.
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  33. 33
    Fayter, A.; Huband, S.; Gibson, M. I. X-Ray Diffraction to Probe the Kinetics of Ice Recrystallization Inhibition. Analyst 2020, 145, 3666– 3677,  DOI: 10.1039/C9AN02141H
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    33
    X-ray diffraction to probe the kinetics of ice recrystallization inhibition
    Fayter, Alice; Huband, Steven; Gibson, Matthew I.
    Analyst (Cambridge, United Kingdom) (2020), 145 (10), 3666-3677CODEN: ANALAO; ISSN:0003-2654. (Royal Society of Chemistry)
    Understanding the nucleation and growth of ice is crucial in fields ranging from infrastructure maintenance, to the environment, and to preserving biologics in the cold chain. Ice binding and antifreeze proteins are potent ice recrystn. inhibitors (IRI), and synthetic materials that mimic this function have emerged, which may find use in biotechnol. To evaluate IRI activity, optical microscopy tools are typically used to monitor ice grain size either by end-point measurements or as a function of time. However, these methods provide 2-dimensional information and image anal. is required to ext. the data. Here we explore using wide angle X-ray scattering (WAXS/X-ray powder diffraction (XRD)) to interrogate 100's of ice crystals in 3-dimensions as a function of time. Due to the random organization of the ice crystals in the frozen sample, the no. of orientations measured by XRD is proportional to the no. of ice crystals, which can be measured as a function of time. This method was used to evaluate the activity for a panel of known IRI active compds., and shows strong agreement with results obtained from cryo-microscopy, as well as being advantageous in that time-dependent ice growth is easily extd. Diffraction anal. also confirmed, by comparing the obtained diffraction patterns of both ice binding and non-binding additives, that the obsd. hexagonal ice diffraction patterns obtained cannot be used to det. which crystal faces are being bound. This method may help in the discovery of new IRI active materials as well as enabling kinetic anal. of ice growth.
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  34. 34
    Balcerzak, A. K.; Capicciotti, C. J.; Briard, J. G.; Ben, R. N. Designing Ice Recrystallization Inhibitors: From Antifreeze (Glyco)Proteins to Small Molecules. RSC Adv. 2014, 4 (80), 42682– 42696,  DOI: 10.1039/C4RA06893A
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    34
    Designing ice recrystallization inhibitors: from antifreeze (glyco)proteins to small molecules
    Balcerzak, Anna K.; Capicciotti, Chantelle J.; Briard, Jennie G.; Ben, Robert N.
    RSC Advances (2014), 4 (80), 42682-42696CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
    A review. Ice recrystn. occurs during cryopreservation and is correlated with reduced cell viability after thawing. Therefore, ice recrystn. inhibition (IRI) activity is a very desirable property for an effective cryoprotectant. Antifreeze proteins (AFPs) and antifreeze glycoproteins (AFGPs) were the first compds. discovered with this property, however they are poor cryoprotectants due to their unique ability to bind to ice and alter habits of ice crystals. Consequently, AFGP analogs with "custom-tailored" antifreeze activity have been developed which exhibit potent IRI activity but do not bind to ice. Subsequent to this, it was reported that simple mono- and disaccharides exhibit moderate IRI activity and this has ultimately facilitated the discovery of several small carbohydrate-based ice recrystn. inhibitors with IRI activity similar to that of native AFGP-8. This represents a major advancement in the field of ice recrystn. inhibitors (IRIs). The recent developments of IRIs will be reviewed, focusing on novel small mols. that have great potential for use as cryoprotectants.
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  35. 35
    Capicciotti, C. J.; Leclere, M.; Perras, F. A.; Bryce, D. L.; Paulin, H.; Harden, J.; Liu, Y.; Ben, R. N. Potent Inhibition of Ice Recrystallization by Low Molecular Weight Carbohydrate-Based Surfactants and Hydrogelators. Chem. Sci. 2012, 3 (5), 1408– 1416,  DOI: 10.1039/c2sc00885h
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    35
    Potent inhibition of ice recrystallization by low molecular weight carbohydrate-based surfactants and hydrogelators
    Capicciotti, Chantelle J.; Leclere, Mathieu; Perras, Frederic A.; Bryce, David L.; Paulin, Hilary; Harden, James; Liu, Yun; Ben, Robert N.
    Chemical Science (2012), 3 (5), 1408-1416CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    Ice recrystn. inhibition (IRI) activity is a very desirable property for an effective cryoprotectant. This property was first obsd. in biol. antifreezes (BAs), which cannot be utilized in cryopreservation due to their ability to bind to ice. To date, potent IRI active compds. have been limited to BAs or synthetic C-linked AFGP analogs (1 and 2), all of which are large peptide-based mols. This paper describes the first example of low mol. wt. carbohydrate-based derivs. that exhibit potent IRI activity. Non-ionic surfactant n-octyl-β-d-galactopyranoside (4) exhibited potent IRI activity at a concn. of 22 mM, whereas hydrogelator N-octyl-d-gluconamide (5) exhibited potent IRI activity at a low concn. of 0.5 mM. Thermal hysteresis measurements and solid-state NMR expts. indicated that these derivs. are not exhibiting IRI activity by binding to ice. For non-ionic surfactant derivs. (3 and 4), we demonstrated that carbohydrate hydration is important for IRI activity and that the formation of micelles in soln. is not a prerequisite for IRI activity. Furthermore, using solid-state NMR and rheol. we demonstrated that the ability of hydrogelators 5 and 6 to form a hydrogel is not relevant to IRI activity. Structure-function studies indicated that the amide bond in 5 is an essential structural feature required for potent IRI activity.
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  36. 36
    Gruneberg, A. K.; Graham, L. A.; Eves, R.; Agrawal, P.; Oleschuk, R. D.; Davies, P. L. Ice Recrystallization Inhibition Activity Varies with Ice-Binding Protein Type and Does Not Correlate with Thermal Hysteresis. Cryobiology 2021, 99, 28– 39,  DOI: 10.1016/j.cryobiol.2021.01.017
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    36
    Ice recrystallization inhibition activity varies with ice-binding protein type and does not correlate with thermal hysteresis
    Gruneberg, Audrey K.; Graham, Laurie A.; Eves, Robert; Agrawal, Prashant; Oleschuk, Richard D.; Davies, Peter L.
    Cryobiology (2021), 99 (), 28-39CODEN: CRYBAS; ISSN:0011-2240. (Elsevier Ltd.)
    Ice-binding proteins (IBPs) inhibit the growth of ice through surface adsorption. In some freeze-resistant fishes and insects, circulating IBPs serve as antifreeze proteins to stop ice growth by lowering the f.p. Plants are less able to avoid freezing and some use IBPs to minimize the damage caused in the frozen state by ice recrystn., which is the growth of large ice grains at the expense of small ones. Here we have accurately and reproducibly measured the ice recrystn. inhibition (IRI) activity of over a dozen naturally occurring IBPs from fishes, insects, plants, and microorganisms using a modified on serial dilns. of IBPs whose concns. were detd. by amino acid anal. The endpoint of IRI, which was scored as the lowest protein concn. at which no recrystn. was obsd., varied for the different IBPs over two orders of magnitude from 1000 nM to 5 nM. Moreover, there was no apparent correlation between their IRI levels and reported antifreeze activities. IBPs from insects and fishes had similar IRI activity, even though the insect IBPs are typically 10x more active in f.p. depression. Plant IBPs had weak antifreeze activity but were more effective at IRI. Bacterial IBPs involved in ice adhesion showed both strong f.p. depression and IRI. Two trends did emerge, including that basal plane binding IBPs correlated with stronger IRI activity and larger IBPs had higher IRI activity.
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  37. 37
    Olijve, L. L. C.; Meister, K.; DeVries, A. L.; Duman, J. G.; Guo, S.; Bakker, H. J.; Voets, I. K. Blocking Rapid Ice Crystal Growth through Nonbasal Plane Adsorption of Antifreeze Proteins. Proc. Natl. Acad. Sci. U. S. A. 2016, 113 (14), 3740– 3745,  DOI: 10.1073/pnas.1524109113
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    37
    Blocking rapid ice crystal growth through nonbasal plane adsorption of antifreeze proteins
    Olijve, Luuk L. C.; Meister, Konrad; DeVries, Arthur L.; Duman, John G.; Guo, Shuaiqi; Bakker, Huib J.; Voets, Ilja K.
    Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (14), 3740-3745CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Antifreeze proteins (AFPs) are a unique class of proteins that bind to growing ice crystal surfaces and arrest further ice growth. AFPs have gained a large interest for their use in antifreeze formulations for water-based materials, such as foods, waterborne paints, and organ transplants. Instead of commonly used colligative antifreezes such as salts and alcs., the advantage of using AFPs as an additive is that they do not alter the physicochem. properties of the water-based material. Here, the authors report the 1st comprehensive evaluation of thermal hysteresis (TH) and ice recrystn. inhibition (IRI) activity of all major classes of AFPs using cryoscopy, sonocrystn., and recrystn. assays. The results showed that TH activities detd. by cryoscopy and sonocrystn. differed markedly, and that TH and IRI activities were not correlated. The absence of a distinct correlation in antifreeze activity pointed to a mechanistic difference in ice growth inhibition by the different classes of AFPs: blocking fast ice growth requires rapid nonbasal plane adsorption, whereas basal plane adsorption is only relevant at long annealing times and at small undercooling. These findings clearly demonstrated that biomimetic analogs of antifreeze (glyco)proteins should be tailored to the specific requirements of the targeted application.
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  38. 38
    Biggs, C. I.; Stubbs, C.; Graham, B.; Fayter, A. E. R.; Hasan, M.; Gibson, M. I. Mimicking the Ice Recrystallization Activity of Biological Antifreezes. When Is a New Polymer “Active”?. Macromol. Biosci. 2019, 19 (7), 1900082,  DOI: 10.1002/mabi.201900082
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    Mitchell, D. E.; Clarkson, G.; Fox, D. J.; Vipond, R. A.; Scott, P.; Gibson, M. I. Antifreeze Protein Mimetic Metallohelices with Potent Ice Recrystallization Inhibition Activity. J. Am. Chem. Soc. 2017, 139 (29), 9835– 9838,  DOI: 10.1021/jacs.7b05822
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    39
    Antifreeze Protein Mimetic Metallohelices with Potent Ice Recrystallization Inhibition Activity
    Mitchell, Daniel E.; Clarkson, Guy; Fox, David J.; Vipond, Rebecca A.; Scott, Peter; Gibson, Matthew I.
    Journal of the American Chemical Society (2017), 139 (29), 9835-9838CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Antifreeze proteins are produced by extremophile species to control ice formation and growth, and they have potential applications in many fields. There are few examples of synthetic materials which can reproduce their potent ice recrystn. inhibition property. We report that self-assembled enantiomerically pure, amphipathic metallohelicies inhibited ice growth at just 20 μM. Structure-property relationships and calcns. support the hypothesis that amphipathicity is the key motif for activity. This opens up a new field of metallo-org. antifreeze protein mimetics and provides insight into the origins of ice-growth inhibition.
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    Graham, B.; Fayter, A. E. R.; Houston, J. E.; Evans, R. C.; Gibson, M. I. Facially Amphipathic Glycopolymers Inhibit Ice Recrystallization. J. Am. Chem. Soc. 2018, 140 (17), 5682– 5685,  DOI: 10.1021/jacs.8b02066
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    Facially amphipathic glycopolymers inhibit ice recrystallization
    Graham, Ben; Fayter, Alice E. R.; Houston, Judith E.; Evans, Rachel C.; Gibson, Matthew I.
    Journal of the American Chemical Society (2018), 140 (17), 5682-5685CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Antifreeze glycoproteins (AFGPs) from polar fish are the most potent ice recrystn. (growth) inhibitors known, and synthetic mimics are required for low-temp. applications such as cell cryopreservation. Here we introduce facially amphipathic glycopolymers that mimic the three-dimensional structure of AFGPs. Glycopolymers featuring segregated hydrophilic and hydrophobic faces were prepd. by ring-opening metathesis polymn., and their rigid conformation was confirmed by small-angle neutron scattering. Ice recrystn. inhibition (IRI) activity was reduced when a hydrophilic oxo-ether was installed on the glycan-opposing face, but significant activity was restored by incorporating a hydrophobic dimethylfulvene residue. This biomimetic strategy demonstrates that segregated domains of distinct hydrophilicity/hydrophobicity are a crucial motif to introduce IRI activity, which increases our understanding of the complex ice crystal inhibition processes.
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    Li, T.; Zhao, Y.; Zhong, Q.; Wu, T. Inhibiting Ice Recrystallization by Nanocelluloses. Biomacromolecules 2019, 20 (4), 1667– 1674,  DOI: 10.1021/acs.biomac.9b00027
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    Inhibiting Ice Recrystallization by Nanocelluloses
    Li, Teng; Zhao, Ying; Zhong, Qixin; Wu, Tao
    Biomacromolecules (2019), 20 (4), 1667-1674CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
    Biocompatible materials with ice recrystn. inhibition (IRI) activity have potential applications in several fields. Emerging studies have assocd. the IRI activity of antifreeze proteins/glycoproteins and several mimics of synthetic materials with a facially amphipathic structure. Nanocelluloses are a new family of renewable materials that demonstrate amphiphilicity. Herein the IRI activity of cellulose nanocrystals (CNCs) and 2,2,6,6-tetramethylpiperidine-1-oxyl oxidized cellulose nanofibrils (TEMPO-CNFs) is reported. In 0.01 M NaCl, ice recrystn. was effectively inhibited by 5.0 mg/mL CNCs or 2.0 mg/mL TEMPO-CNFs. In phosphate-buffered saline, observable IRI activity was found with 30.0 mg/mL CNCs. IRI assays in sucrose solns. showed that the decreased IRI activity of nanocelluloses in saline was caused by the aggregation of nanocelluloses due to charge screening. Neither thermal hysteresis nor dynamic ice shaping activity was obsd. in nanocelluloses. These findings may lead to the use of nanocelluloses as novel ice recrystn. inhibitors.
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    Balcerzak, A. K.; Febbraro, M.; Ben, R. N. The Importance of Hydrophobic Moieties in Ice Recrystallization Inhibitors. RSC Adv. 2013, 3 (10), 3232– 3236,  DOI: 10.1039/c3ra23220d
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    The importance of hydrophobic moieties in ice recrystallization inhibitors
    Balcerzak, Anna K.; Febbraro, Michela; Ben, Robert N.
    RSC Advances (2013), 3 (10), 3232-3236CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
    Structurally diverse lysine-based surfactants/gelators and anti-ice nucleating agents (anti-INAs) were investigated as ice recrystn. inhibitors (IRIs). The results indicate that long alkyl chains are important for potent IRI activity and that the position of these alkyl chains is essential. Addnl., no correlation was found between IRI activity and crit. micelle concns., gelation or anti-ice nucleation activity, although the counterion of some lysine surfactants did affect IRI activity.
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  43. 43
    Budke, C.; Dreyer, A.; Jaeger, J.; Gimpel, K.; Berkemeier, T.; Bonin, A. S.; Nagel, L.; Plattner, C.; Devries, A. L.; Sewald, N. Quantitative Efficacy Classification of Ice Recrystallization Inhibition Agents. Cryst. Growth Des. 2014, 14 (9), 4285– 4294,  DOI: 10.1021/cg5003308
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    Quantitative Efficacy Classification of Ice Recrystallization Inhibition Agents
    Budke, Carsten; Dreyer, Axel; Jaeger, Jasmin; Gimpel, Kerstin; Berkemeier, Thomas; Bonin, Anna S.; Nagel, Lilly; Plattner, Carolin; DeVries, Arthur L.; Sewald, Norbert; Koop, Thomas
    Crystal Growth & Design (2014), 14 (9), 4285-4294CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    Exptl. investigations of ice recrystn. inhibition (IRI) efficacy have been performed for a large no. of different substances, including natural antifreeze proteins (AFP) and antifreeze glycoproteins (AFGP), several synthetic AFGP analogs, as well as synthetic polymers. Here we define IRI efficacy as that concn. at which the ice recrystn. rate is dominated by the IRI compd. The investigated 39 compds. show IRI efficacies from about 2 mmol L-1 for the least effective compd. still showing activity to about 1 nmol L-1, which corresponds to the highest efficacy found for natural AFGP samples. Hence, the assay employed allows for a quant. comparison of IRI efficacy over a range of at least 6 orders of magnitude, thereby enabling studies of distinguishing effects induced by even subtle structural variations in AFGP analogs that were synthesized. Our results show that AFGP are by far the most effective IRI agents in our assay, and we surmise that this particular efficacy may be due to their disaccharide moieties. This supposition is supported by the fact that IRI efficacy is strongly reduced for monosaccharide AFGP analogs, as well as for AFGP analogs with acetyl-protected monosaccharide moieties.
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    Adam, M. K.; Jarrett-Wilkins, C.; Beards, M.; Staykov, E.; MacFarlane, L. R.; Bell, T. D. M.; Matthews, J. M.; Manners, I.; Faul, C. F. J.; Moens, P. D. J. 1D Self-Assembly and Ice Recrystallization Inhibition Activity of Antifreeze Glycopeptide-Functionalized Perylene Bisimides. Chem. - Eur. J. 2018, 24 (31), 7834– 7839,  DOI: 10.1002/chem.201800857
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    1D Self-Assembly and Ice Recrystallization Inhibition Activity of Antifreeze Glycopeptide-Functionalized Perylene Bisimides
    Adam, Madeleine K.; Jarrett-Wilkins, Charles; Beards, Michael; Staykov, Emiliyan; MacFarlane, Liam R.; Bell, Toby D. M.; Matthews, Jacqueline M.; Manners, Ian; Faul, Charl F. J.; Moens, Pierre D. J.; Ben, Robert N.; Wilkinson, Brendan L.
    Chemistry - A European Journal (2018), 24 (31), 7834-7839CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Antifreeze glycoproteins (AFGPs) are polymeric natural products that have drawn considerable interest in diverse research fields owing to their potent ice recrystn. inhibition (IRI) activity. Self-assembled materials have emerged as a promising class of biomimetic ice growth inhibitor, yet the development of AFGP-based supramol. materials that emulate the aggregative behavior of AFGPs have not yet been reported. This work reports the first example of the 1D self-assembly and IRI activity of AFGP-functionalized perylene bisimides (AFGP-PBIs). Glycopeptide-functionalized PBIs underwent 1D self-assembly in water and showed modest IRI activity, which could be tuned through substitution of the PBI core. This work presents essential proof-of-principle for the development of novel IRIs as potential supramol. cryoprotectants and glycoprotein mimics.
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    Olijve, L. L. C.; Hendrix, M. M. R. M.; Voets, I. K. Influence of Polymer Chain Architecture of Poly(Vinyl Alcohol) on the Inhibition of Ice Recrystallization. Macromol. Chem. Phys. 2016, 217 (8), 951– 958,  DOI: 10.1002/macp.201500497
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    Influence of Polymer Chain Architecture of Poly(vinyl alcohol) on the Inhibition of Ice Recrystallization
    Olijve, Luuk L. C.; Hendrix, Marco M. R. M.; Voets, Ilja K.
    Macromolecular Chemistry and Physics (2016), 217 (8), 951-958CODEN: MCHPES; ISSN:1022-1352. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Poly(vinyl alc.) (PVA) is a water-sol. synthetic polymer well-known to effectively block the recrystn. of ice. The effect of polymer chain architecture on the ice recrystn. inhibition (IRI) by PVA remains unexplored. In this work, the synthesis of PVA mol. bottlebrushes is described via a combination of atom-transfer radical polymn. and reversible addn.-fragmentation chain-transfer polymn. The facile prepn. of the PVA bottlebrushes is performed via the selective hydrolysis of the chloroacetate esters of the poly(vinyl chloroacetate) (PVClAc) side chains of a PVClAc precursor bottlebrush. The IRI efficacy of the PVA bottlebrush is quant. compared to linear PVA. The results show that even if the PVA chains are densely grafted onto a rigid polymer backbone, the IRI activity of PVA is maintained, demonstrating the flexibility in PVA polymer chain architecture for the design of synthetic PVA-based ice growth inhibitors.
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  46. 46
    Sproncken, C. C. M.; Surís-Valls, R.; Cingil, H. E.; Detrembleur, C.; Voets, I. K. Complex Coacervate Core Micelles Containing Poly(Vinyl Alcohol) Inhibit Ice Recrystallization. Macromol. Rapid Commun. 2018, 39, 1700814,  DOI: 10.1002/marc.201700814
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    Stubbs, C.; Wilkins, L. E.; Fayter, A. E. R.; Walker, M.; Gibson, M. I. Multivalent Presentation of Ice Recrystallization Inhibiting Polymers on Nanoparticles Retains Activity. Langmuir 2019, 35 (23), 7347– 7353,  DOI: 10.1021/acs.langmuir.8b01952
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    47
    Multivalent Presentation of Ice Recrystallization Inhibiting Polymers on Nanoparticles Retains Activity
    Stubbs, Christopher; Wilkins, Laura E.; Fayter, Alice E. R.; Walker, Marc; Gibson, Matthew I.
    Langmuir (2019), 35 (23), 7347-7353CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
    Poly(vinyl alc.) (PVA) has emerged as the most potent mimic of antifreeze (glyco)proteins ice recrystn. inhibition (IRI) activity, despite its lack of structural similarities and flexible, rather than rigid, backbone. The precise spacing of hydroxyl groups is hypothesized to enable PVA to recognize the prism planes of ice but not the basal plane, due to hydroxyl pattern matching of the ice surface giving rise to the macroscopic activity. Here, well-defined PVA derived from reversible addn.-fragmentation chain-transfer (RAFT) polymn. is immobilized onto gold nanoparticles to enable the impact of nanoscale assembly and confinement on the obsd. IRI activity. Unlike previous reports using star-branched or bottle-brush PVAs, the nanoparticle-PVA retains all IRI activity compared to polymers in soln. Evidence is presented to show that this is due to the low grafting densities on the particle surface meaning the chains are free to explore the ice faces, rather than being constrained as in star-branched polymers. These results demonstrate a route to develop more functional IRI's and inclusion of metallic particle cores for imaging and assocd. applications in cryobiol.
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  48. 48
    Stevens, C. A.; Drori, R.; Zalis, S.; Braslavsky, I.; Davies, P. L. Dendrimer-Linked Antifreeze Proteins Have Superior Activity and Thermal Recovery. Bioconjugate Chem. 2015, 26 (9), 1908– 1915,  DOI: 10.1021/acs.bioconjchem.5b00290
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    48
    Dendrimer-Linked Antifreeze Proteins Have Superior Activity and Thermal Recovery
    Stevens, Corey A.; Drori, Ran; Zalis, Shiran; Braslavsky, Ido; Davies, Peter L.
    Bioconjugate Chemistry (2015), 26 (9), 1908-1915CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    By binding to ice, antifreeze proteins (AFPs) depress the f.p. of a soln. and inhibit ice recrystn. if freezing does occur. Previous work showed that the activity of an AFP was incrementally increased by fusing it to another protein. Even larger increases in activity were achieved by doubling the no. of ice-binding sites by dimerization. Here, the authors have combined the two strategies by linking multiple outward-facing AFPs to a dendrimer to significantly increase both the size of the mol. and the no. of ice-binding sites. Using a heterobifunctional crosslinker, the authors attached between 6 and 11 type III AFPs to a second-generation polyamidoamine (G2-PAMAM) dendrimer with 16 reactive termini. This heterogeneous sample of dendrimer-linked type III constructs showed a >4-fold increase in f.p. depression over that of monomeric type III AFP. This multimerized AFP was particularly effective at ice recrystn. inhibition activity, likely because it can simultaneously bind multiple ice surfaces. Addnl., attachment to the dendrimer has afforded the AFP superior recovery from heat denaturation. Linking AFPs together via polymers can generate novel reagents for controlling ice growth and recrystn.
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  49. 49
    Wilkins, L. E.; Hasan, M.; Fayter, A. E. R.; Biggs, C.; Walker, M.; Gibson, M. I. Site-Specific Conjugation of Antifreeze Proteins onto Polymer-Stabilized Nanoparticles. Polym. Chem. 2019, 10, 2986– 2990,  DOI: 10.1039/C8PY01719K
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    49
    Site-specific conjugation of antifreeze proteins onto polymer-stabilized nanoparticles
    Wilkins, Laura E.; Hasan, Muhammad; Fayter, Alice E. R.; Biggs, Caroline; Walker, Marc; Gibson, Matthew I.
    Polymer Chemistry (2019), 10 (23), 2986-2990CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
    Antifreeze proteins (AFPs) have many potential applications, ranging from cryobiol. to aerospace, if they can be incorporated into materials. Here, a range of engineered AFP mutants were prepd. and site-specifically conjugated onto RAFT polymer-stabilized gold nanoparticles to generate new hybrid multivalent ice growth inhibitors. Only the SNAP-tagged AFPs lead to potent 'antifreeze' active nanomaterials with His-Tag capture resulting in no activity, showing the mode of conjugation is essential. This versatile strategy will enable the development of multivalent AFPs for translational and fundamental studies.
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  50. 50
    Ogawa, S.; Koga, M.; Osanai, S. Anomalous Ice Nucleation Behavior in Aqueous Polyvinyl Alcohol Solutions. Chem. Phys. Lett. 2009, 480 (1), 86– 89,  DOI: 10.1016/j.cplett.2009.08.046
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    50
    Anomalous ice nucleation behavior in aqueous polyvinyl alcohol solutions
    Ogawa, S.; Koga, M.; Osanai, S.
    Chemical Physics Letters (2009), 480 (1-3), 86-89CODEN: CHPLBC; ISSN:0009-2614. (Elsevier B.V.)
    The effect of polymers on the ice nucleation temp. (T f) was studied in a W/O emulsion using ∼5 μm diam. droplets by differential scanning calorimetry (DSC). Four types of polymers were used. Among them, only poly(vinyl alc.) (PVA) showed the addnl. effect of increasing the T f of the aq. solns. This increase was logarithmic with the concn. of PVA and the difference in mol. wt. did not have any significant effect on T f for the same wt. concn. It was shown that the no. of the structural unit (CH2CHOH) was the key parameter for the increasing degree of T f.
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  51. 51
    Pummer, B. G.; Budke, C.; Augustin-Bauditz, S.; Niedermeier, D.; Felgitsch, L.; Kampf, C. J.; Huber, R. G.; Liedl, K. R.; Loerting, T.; Moschen, T. Ice Nucleation by Water-Soluble Macromolecules. Atmos. Chem. Phys. 2015, 15 (8), 4077– 4091,  DOI: 10.5194/acp-15-4077-2015
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    Ice nucleation by water-soluble macromolecules
    Pummer, B. G.; Budke, C.; Augustin-Bauditz, S.; Niedermeier, D.; Felgitsch, L.; Kampf, C. J.; Huber, R. G.; Liedl, K. R.; Loerting, T.; Moschen, T.; Schauperl, M.; Tollinger, M.; Morris, C. E.; Wex, H.; Grothe, H.; Poeschl, U.; Koop, T.; Froehlich-Nowoisky, J.
    Atmospheric Chemistry and Physics (2015), 15 (8), 4077-4091CODEN: ACPTCE; ISSN:1680-7324. (Copernicus Publications)
    Cloud glaciation is critically important for the global radiation budget (albedo) and for initiation of pptn. But the freezing of pure water droplets requires cooling to temps. as low as 235 K. Freezing at higher temps. requires the presence of an ice nucleator, which serves as a template for arranging water mols. in an ice-like manner. It is often assumed that these ice nucleators have to be insol. particles. We point out that also free macromols. which are dissolved in water can efficiently induce ice nucleation: the size of such ice nucleating macromols. (INMs) is in the range of nanometers, corresponding to the size of the crit. ice embryo. As the latter is temp.-dependent, we see a correlation between the size of INMs and the ice nucleation temp. as predicted by classical nucleation theory. Different types of INMs have been found in a wide range of biol. species and comprise a variety of chem. structures including proteins, saccharides, and lipids. Our investigation of the fungal species Acremonium implicatum, Isaria farinosa, and Mortierella alpina shows that their ice nucleation activity is caused by proteinaceous water-sol. INMs. We combine these new results and literature data on INMs from fungi, bacteria, and pollen with theor. calcns. to develop a chem. interpretation of ice nucleation and water-sol. INMs. This has atm. implications since many of these INMs can be released by fragmentation of the carrier cell and subsequently may be distributed independently. Up to now, this process has not been accounted for in atm. models.
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  52. 52
    Eickhoff, L.; Dreischmeier, K.; Zipori, A.; Sirotinskaya, V.; Adar, C.; Reicher, N.; Braslavsky, I.; Rudich, Y.; Koop, T. Contrasting Behavior of Antifreeze Proteins: Ice Growth Inhibitors and Ice Nucleation Promoters. J. Phys. Chem. Lett. 2019, 10 (5), 966– 972,  DOI: 10.1021/acs.jpclett.8b03719
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    52
    Contrasting Behavior of Antifreeze Proteins: Ice Growth Inhibitors and Ice Nucleation Promoters
    Eickhoff, Lukas; Dreischmeier, Katharina; Zipori, Assaf; Sirotinskaya, Vera; Adar, Chen; Reicher, Naama; Braslavsky, Ido; Rudich, Yinon; Koop, Thomas
    Journal of Physical Chemistry Letters (2019), 10 (5), 966-972CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)
    Several types of natural mols. interact specifically with ice crystals. Small antifreeze proteins (AFPs) adsorb to particular facets of ice crystals, thus inhibiting their growth, whereas larger ice-nucleating proteins (INPs) can trigger the formation of new ice crystals at temps. much higher than the homogeneous ice nucleation temp. of pure water. It has been proposed that both types of proteins interact similarly with ice and that, in principle, they may be able to exhibit both functions. Here we investigated two naturally occurring antifreeze proteins, one from fish, type-III AFP, and one from beetles, TmAFP. We show that in addn. to ice growth inhibition, both can also trigger ice nucleation above the homogeneous freezing temp., providing unambiguous exptl. proof for their contrasting behavior. Our anal. suggests that the predominant difference between AFPs and INPs is their mol. size, which is a very good predictor of their ice nucleation temp.
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    Bissoyi, A.; Reicher, N.; Chasnitsky, M.; Arad, S.; Koop, T.; Rudich, Y.; Braslavsky, I. Ice Nucleation Properties of Ice-Binding Proteins from Snow Fleas. Biomolecules 2019, 9 (10), 532,  DOI: 10.3390/biom9100532
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    Ice nucleation properties of ice-binding proteins from snow fleas
    Bissoyi, Akalabya; Reicher, Naama; Chasnitsky, Michael; Arad, Sivan; Koop, Thomas; Rudich, Yinon; Braslavsky, Ido
    Biomolecules (2019), 9 (10), 532CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)
    Ice-binding proteins (IBPs) are found in many organisms, such as fish and hexapods, plants, and bacteria that need to cope with low temps. Ice nucleation and thermal hysteresis are two attributes of IBPs. While ice nucleation is promoted by large proteins, known as ice nucleating proteins, the smaller IBPs, referred to as antifreeze proteins (AFPs), inhibit the growth of ice crystals by up to several degrees below the m.p., resulting in a thermal hysteresis (TH) gap between melting and ice growth. Recently, we showed that the nucleation capacity of two types of IBPs corresponds to their size, in agreement with classical nucleation theory. Here, we expand this finding to addnl. IBPs that we isolated from snow fleas (the arthropod Collembola), collected in northern Israel. Chem. analyses using CD and Fourier-transform IR spectroscopy data suggest that these IBPs have a similar structure to a previously reported snow flea antifreeze protein. Further expts. reveal that the ice-shell purified proteins have hyperactive antifreeze properties, as detd. by nanoliter osmometry, and also exhibit low ice-nucleation activity in accordance with their size.
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    Blanazs, A.; Madsen, J.; Battaglia, G.; Ryan, A. J.; Armes, S. P. Mechanistic Insights for Block Copolymer Morphologies: How Do Worms Form Vesicles?. J. Am. Chem. Soc. 2011, 133 (41), 16581– 16587,  DOI: 10.1021/ja206301a
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    Mechanistic Insights for Block Copolymer Morphologies: How Do Worms Form Vesicles?
    Blanazs, Adam; Madsen, Jeppe; Battaglia, Giuseppe; Ryan, Anthony J.; Armes, Steven P.
    Journal of the American Chemical Society (2011), 133 (41), 16581-16587CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Amphiphilic diblock copolymers composed of two covalently linked, chem. distinct chains can be considered to be biol. mimics of cell membrane-forming lipid mols., but with typically more than an order of magnitude increase in mol. wt. These macromol. amphiphiles are known to form a wide range of nanostructures (spheres, worms, vesicles, etc.) in solvents that are selective for one of the blocks. However, such self-assembly is usually limited to dil. copolymer solns. (<1%), which is a significant disadvantage for potential com. applications such as drug delivery and coatings. In principle, this problem can be circumvented by polymn.-induced block copolymer self-assembly. Here the authors detail the synthesis and subsequent in situ self-assembly of amphiphilic AB diblock copolymers in a one pot concd. aq. dispersion polymn. formulation. The authors show that spherical micelles, wormlike micelles, and vesicles can be predictably and efficiently obtained (within 2 h of polymn., >99% monomer conversion) at relatively high solids in purely aq. soln. Furthermore, careful monitoring of the in situ polymn. by transmission electron microscopy reveals various novel intermediate structures (including branched worms, partially coalesced worms, nascent bilayers, "octopi", "jellyfish", and finally pure vesicles) that provide important mechanistic insights regarding the evolution of the particle morphol. during the sphere-to-worm and worm-to-vesicle transitions. This environmentally benign approach (which involves no toxic solvents, is conducted at relatively high solids, and requires no addnl. processing) is readily amenable to industrial scale-up, since it is based on com. available starting materials.
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    Warren, N. J.; Armes, S. P. Polymerization-Induced Self-Assembly of Block Copolymer Nano-Objects via RAFT Aqueous Dispersion Polymerization. J. Am. Chem. Soc. 2014, 136 (29), 10174– 10185,  DOI: 10.1021/ja502843f
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    Polymerization-Induced Self-Assembly of Block Copolymer Nano-objects via RAFT Aqueous Dispersion Polymerization
    Warren, Nicholas J.; Armes, Steven P.
    Journal of the American Chemical Society (2014), 136 (29), 10174-10185CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A review. In this Perspective, we discuss the recent development of polymn.-induced self-assembly mediated by reversible addn.-fragmentation chain transfer (RAFT) aq. dispersion polymn. This approach has quickly become a powerful and versatile technique for the synthesis of a wide range of bespoke org. diblock copolymer nano-objects of controllable size, morphol., and surface functionality. Given its potential scalability, such environmentally-friendly formulations are expected to offer many potential applications, such as novel Pickering emulsifiers, efficient microencapsulation vehicles, and sterilizable thermo-responsive hydrogels for the cost-effective long-term storage of mammalian cells.
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    Warren, N. J.; Mykhaylyk, O. O.; Ryan, A. J.; Williams, M.; Doussineau, T.; Dugourd, P.; Antoine, R.; Portale, G.; Armes, S. P. Testing the Vesicular Morphology to Destruction: Birth and Death of Diblock Copolymer Vesicles Prepared via Polymerization-Induced Self-Assembly. J. Am. Chem. Soc. 2015, 137 (5), 1929– 1937,  DOI: 10.1021/ja511423m
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    56
    Testing the Vesicular Morphology to Destruction: Birth and Death of Diblock Copolymer Vesicles Prepared via Polymerization-Induced Self-Assembly
    Warren, Nicholas J.; Mykhaylyk, Oleksandr O.; Ryan, Anthony J.; Williams, Mark; Doussineau, Tristan; Dugourd, Philippe; Antoine, Rodolphe; Portale, Giuseppe; Armes, Steven P.
    Journal of the American Chemical Society (2015), 137 (5), 1929-1937CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Small angle X-ray scattering (SAXS), electrospray ionization charge detection mass spectrometry (CD-MS), dynamic light scattering (DLS), and transmission electron microscopy (TEM) are used to characterize poly(glycerol monomethacrylate)55-poly(2-hydroxypropyl methacrylate)x (G55-Hx) vesicles prepd. by polymn.-induced self-assembly (PISA) using a reversible addn.-fragmentation chain transfer (RAFT) aq. dispersion polymn. formulation. A G55 chain transfer agent is utilized to prep. a series of G55-Hx diblock copolymers, where the mean d.p. (DP) of the membrane-forming block (x) is varied from 200 to 2000. TEM confirms that vesicles with progressively thicker membranes are produced for x = 200-1000, while SAXS indicates a gradual redn. in mean aggregation no. for higher x values, which is consistent with CD-MS studies. Both DLS and SAXS studies indicate minimal change in the overall vesicle diam. between x = 400 and 800. Fitting SAXS patterns to a vesicle model enables calcn. of the membrane thickness, degree of hydration of the membrane, and the mean vesicle aggregation no. The membrane thickness increases at higher x values, hence the vesicle lumen must become smaller if the external vesicle dimensions remain const. Geometric considerations indicate that this growth mechanism lowers the total vesicle interfacial area and hence reduces the free energy of the system. However, it also inevitably leads to gradual ingress of the encapsulated water mols. into the vesicle membrane, as confirmed by SAXS anal. Ultimately, the highly plasticized membranes become insufficiently hydrophobic to stabilize the vesicle morphol. when x exceeds 1000, thus this PISA growth mechanism ultimately leads to vesicle "death".
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    Doncom, K. E. B.; Blackman, L. D.; Wright, D. B.; Gibson, M. I.; O’Reilly, R. K. Dispersity Effects in Polymer Self-Assemblies: A Matter of Hierarchical Control. Chem. Soc. Rev. 2017, 46 (14), 4119– 4134,  DOI: 10.1039/C6CS00818F
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    Dispersity effects in polymer self-assemblies: a matter of hierarchical control
    Doncom, Kay E. B.; Blackman, Lewis D.; Wright, Daniel B.; Gibson, Matthew I.; O'Reilly, Rachel K.
    Chemical Society Reviews (2017), 46 (14), 4119-4134CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. Advanced applications of polymeric self-assembled structures require a stringent degree of control over such aspects as functionality location, morphol. and size of the resulting assemblys. A loss of control in the polymeric building blocks of these assemblys can have drastic effects upon the final morphol. or function of these structures. Gaining precise control over various aspects of the polymers, such as chain lengths and architecture, blocking efficiency and compositional distribution is a challenge and, hence, measuring the intrinsic mass and size dispersity within these areas is an important aspect of such control. It is of great importance that a good handle on how to improve control and accurately measure it is achieved. Addnl. dispersity of the final structure can also play a large part in the suitability for a desired application. In this Tutorial Review, we aim to highlight the different aspects of dispersity that are often overlooked and the effect that a lack of control can have on both the polymer and the final assembled structure.
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    Czajka, A.; Armes, S. P. In Situ SAXS Studies of a Prototypical RAFT Aqueous Dispersion Polymerization Formulation: Monitoring the Evolution in Copolymer Morphology during Polymerization-Induced Self-Assembly. Chem. Sci. 2020, 11 (42), 11443– 11454,  DOI: 10.1039/D0SC03411H
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    58
    In situ SAXS studies of a prototypical RAFT aqueous dispersion polymerization formulation: monitoring the evolution in copolymer morphology during polymerization-induced self-assembly
    Czajka, Adam; Armes, Steven P.
    Chemical Science (2020), 11 (42), 11443-11454CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    Small-angle X-ray scattering (SAXS) is used to characterize the in situ formation of diblock copolymer spheres, worms and vesicles during reversible addn.-fragmentation chain transfer (RAFT) aq. dispersion polymn. of 2-hydroxypropyl methacrylate at 70°C using a poly(glycerol monomethacrylate) steric stabilizer. The 1H NMR spectroscopy indicates more than 99% HPMA conversion within 80 min, while transmission electron microscopy and dynamic light scattering studies are consistent with the final morphol. being pure vesicles. Anal. of time-resolved SAXS patterns for this prototypical polymn.-induced self-assembly (PISA) formulation enables the evolution in copolymer morphol., particle diam., mean aggregation no., solvent vol. fraction, surface d. of copolymer chains and their mean inter-chain sepn. distance at the nanoparticle surface to be monitored. Furthermore, the change in vesicle diam. and membrane thickness during the final stages of polymn. supports an 'inward growth' mechanism.
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    Qiu, L.; Xu, C.-R.; Zhong, F.; Hong, C.-Y.; Pan, C.-Y. Fabrication of Functional Nano-Objects through RAFT Dispersion Polymerization and Influences of Morphology on Drug Delivery. ACS Appl. Mater. Interfaces 2016, 8 (28), 18347– 18359,  DOI: 10.1021/acsami.6b04693
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    59
    Fabrication of Functional Nano-objects through RAFT Dispersion Polymerization and Influences of Morphology on Drug Delivery
    Qiu, Liang; Xu, Chao-Ran; Zhong, Feng; Hong, Chun-Yan; Pan, Cai-Yuan
    ACS Applied Materials & Interfaces (2016), 8 (28), 18347-18359CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
    To study the influence of self-assembled morphologies on drug delivery, four different nano-objects, spheres, nanorods, nanowires, and vesicles having aldehyde-based polymer as core, were successfully prepd. via alc. RAFT dispersion polymn. of p-(methacryloxyethoxy)benzaldehyde (MAEBA) using poly((N,N'-dimethylamino)ethyl methacrylate) (PDMAEMA) as a macro chain transfer agent (macro-CTA) for the first time. The morphologies and sizes of the four nano-objects were characterized by TEM and DLS, and the spheres with av. diam. (D) of 70 nm, the nanorods with D of 19 nm and length of 140 nm, and the vesicles with D of 137 nm were used in the subsequent cellular internalization, in vitro release, and intracellular release of the drug. The anticancer drug doxorubicin (DOX) was conjugated onto the core polymers of nano-objects through condensation reaction between aldehyde groups of the PMAEBA with primary amine groups in the DOX. Because the arom. imine is stable under neutral conditions, but is decompd. in a weakly acidic soln., in vitro release of the DOX from the DOX-loaded nano-objects was investigated in the different acidic solns. All of the block copolymer nano-objects show very low cytotoxicity to HeLa cells up to the concn. of 1.2 mg/mL, but the DOX-loaded nano-objects reveal different cell viability and their IC50s increase as the following order: nanorods-DOX < vesicles-DOX < spheres-DOX. The IC50 of nanowires-DOX is the biggest among the four nano-objects owing to their too large size to be internalized. Endocytosis tests demonstrate that the internalization of vesicles-DOX by the HeLa cells is faster than that of the nanorods-DOX, and the spheres-DOX are the slowest to internalize among the studied nano-objects. Relatively more nanorods localized in the acidic organelles of the HeLa cells lead to faster intracellular release of the DOX, so the IC50 of nanorods is lower than that of the vesicles-DOX.
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    Hinde, E.; Thammasiraphop, K.; Duong, H. T. T.; Yeow, J.; Karagoz, B.; Boyer, C.; Gooding, J. J.; Gaus, K. Pair Correlation Microscopy Reveals the Role of Nanoparticle Shape in Intracellular Transport and Site of Drug Release. Nat. Nanotechnol. 2017, 12 (1), 81– 89,  DOI: 10.1038/nnano.2016.160
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    Pair correlation microscopy reveals the role of nanoparticle shape in intracellular transport and site of drug release
    Hinde, Elizabeth; Thammasiraphop, Kitiphume; Duong, Hien T. T.; Yeow, Jonathan; Karagoz, Bunyamin; Boyer, Cyrille; Gooding, J. Justin; Gaus, Katharina
    Nature Nanotechnology (2017), 12 (1), 81-89CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
    Nanoparticle size, surface charge and material compn. are known to affect the uptake of nanoparticles by cells. However, whether nanoparticle shape affects transport across various barriers inside the cell remains unclear. Here we used pair correlation microscopy to show that polymeric nanoparticles with different shapes but identical surface chemistries moved across the various cellular barriers at different rates, ultimately defining the site of drug release. We measured how micelles, vesicles, rods and worms entered the cell and whether they escaped from the endosomal system and had access to the nucleus via the nuclear pore complex. Rods and worms, but not micelles and vesicles, entered the nucleus by passive diffusion. Improving nuclear access, for example with a nuclear localization signal, resulted in more doxorubicin release inside the nucleus and correlated with greater cytotoxicity. Our results therefore demonstrate that drug delivery across the major cellular barrier, the nuclear envelope, is important for doxorubicin efficiency and can be achieved with appropriately shaped nanoparticles.
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  61. 61
    Noy, J.-M.; Chen, F.; Akhter, D. T.; Houston, Z. H.; Fletcher, N. L.; Thurecht, K. J.; Stenzel, M. H. Direct Comparison of Poly(Ethylene Glycol) and Phosphorylcholine Drug-Loaded Nanoparticles In Vitro and In Vivo. Biomacromolecules 2020, 21 (6), 2320– 2333,  DOI: 10.1021/acs.biomac.0c00257
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    61
    Direct Comparison of Poly(ethylene glycol) and Phosphorylcholine Drug-Loaded Nanoparticles In Vitro and In Vivo
    Noy, Janina-Miriam; Chen, Fan; Akhter, Dewan T.; Houston, Zachary H.; Fletcher, Nicholas L.; Thurecht, Kristofer J.; Stenzel, Martina H.
    Biomacromolecules (2020), 21 (6), 2320-2333CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
    Phosphorylcholine is known to repel the absorption of proteins onto surfaces, which can prevent the formation of a protein corona on the surface of nanoparticles. This can influence the fate of nanoparticles used for drug delivery. This material could therefore serve as an alternative to poly(ethylene glycol) (PEG). Herein, the synthesis of different particles prepd. by polymn.-induced self-assembly (PISA) coated with either poly(ethylene glycol) (PEG) or zwitterionic 2-methacryloyloxyethyl phosphorylcholine (MPC) and 4-(N-(S-penicillaminylacetyl)amino) phenylarsenonous acid (PENAO) was reported. The anticancer drug 4-(N-(S-penicillaminylacetyl)amino) phenylarsenonous acid (PENAO) was conjugated to the shell-forming block. Interactions of the different coated nanoparticles, which present comparable sizes and size distributions (76-85 nm, PDI = 0.067-0.094), with two-dimensional (2D) and three-dimensional (3D) cultured cells were studied, and their cytotoxicities, cellular uptakes, spheroid penetration, and cell localization profiles were analyzed. While only a minimal difference in behavior was obsd. for nanoparticles assessed using in vitro expt. (with PEG-co- PENAO-coated micelles showing slightly higher cytotoxicity and better spheroid penetration and cell localization ability), the effect of the different physicochem. properties between nanoparticles had a more dramatic effect on in vivo biodistribution. After 1 h of injection, the majority of the MPC-co-PENAO-coated nanoparticles were found to accumulate in the liver, making this particle system unfeasible for future biol. studies.
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  62. 62
    Zhang, W.-J.; Hong, C.-Y.; Pan, C.-Y. Polymerization-Induced Self-Assembly of Functionalized Block Copolymer Nanoparticles and Their Application in Drug Delivery. Macromol. Rapid Commun. 2019, 40 (2), 1800279,  DOI: 10.1002/marc.201800279
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    Canton, I.; Warren, N. J.; Chahal, A.; Amps, K.; Wood, A.; Weightman, R.; Wang, E.; Moore, H.; Armes, S. P. Mucin-Inspired Thermoresponsive Synthetic Hydrogels Induce Stasis in Human Pluripotent Stem Cells and Human Embryos. ACS Cent. Sci. 2016, 2 (2), 65– 74,  DOI: 10.1021/acscentsci.5b00370
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    63
    Mucin-Inspired Thermoresponsive Synthetic Hydrogels Induce Stasis in Human Pluripotent Stem Cells and Human Embryos
    Canton, Irene; Warren, Nicholas J.; Chahal, Aman; Amps, Katherine; Wood, Andrew; Weightman, Richard; Wang, Eugenia; Moore, Harry; Armes, Steven P.
    ACS Central Science (2016), 2 (2), 65-74CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
    Human pluripotent stem cells (hPSCs; both embryonic and induced pluripotent) rapidly proliferate in adherent culture to maintain their undifferentiated state. However, for mammals exhibiting delayed gestation (diapause), mucin-coated embryos can remain dormant for days or months in utero, with their constituent PSCs remaining pluripotent under these conditions. Here we report cellular stasis for both hPSC colonies and preimplantation embryos immersed in a wholly synthetic thermoresponsive gel comprising poly(glycerol monomethacrylate)-poly(2-hydroxypropyl methacrylate) [PGMA55-PHPMA135] diblock copolymer worms. This hydroxyl-rich mucin-mimicking nonadherent 3D gel maintained PSC viability and pluripotency in the quiescent G0 state without passaging for at least 14 days. Similarly, gel-coated human embryos remain in a state of suspended animation (diapause) for up to 8 days. The discovery of a cryptic cell arrest mechanism for both hPSCs and embryos suggests an important connection between the cellular mechanisms that evoke embryonic diapause and pluripotency. Moreover, such synthetic worm gels offer considerable utility for the short-term (weeks) storage of either pluripotent stem cells or human embryos without cryopreservation.
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  64. 64
    Binch, A. L. A.; Ratcliffe, L. P. D.; Milani, A. H.; Saunders, B. R.; Armes, S. P.; Hoyland, J. A. Site-Directed Differentiation of Human Adipose-Derived Mesenchymal Stem Cells to Nucleus Pulposus Cells Using an Injectable Hydroxyl-Functional Diblock Copolymer Worm Gel. Biomacromolecules 2021, 22 (2), 837– 845,  DOI: 10.1021/acs.biomac.0c01556
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    64
    Site-Directed Differentiation of Human Adipose-Derived Mesenchymal Stem Cells to Nucleus Pulposus Cells Using an Injectable Hydroxyl-Functional Diblock Copolymer Worm Gel
    Binch, Abbie L. A.; Ratcliffe, Liam P. D.; Milani, Amir H.; Saunders, Brian R.; Armes, Steven P.; Hoyland, Judith A.
    Biomacromolecules (2021), 22 (2), 837-845CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
    Adipose-derived mesenchymal stem cells (ASCs) have been identified for their promising therapeutic potential to regenerate and repopulate the degenerate intervertebral disk (IVD), which is a major cause of lower back pain. The optimal cell delivery system remains elusive but encapsulation of cells within scaffolds is likely to offer a decisive advantage over the delivery of cells in soln. by ensuring successful retention within the tissue. Herein, we evaluate the use of a fully synthetic, thermoresponsive poly(glycerol monomethacrylate)-poly(2-hydroxypropyl methacrylate) (PGMA-PHPMA) diblock copolymer worm gel that mimics the structure of hydrophilic glycosaminoglycans. The objective was to use this gel to direct differentiation of human ASCs toward a nucleus pulposus (NP) phenotype, with or without the addn. of discogenic growth factors TGFβ or GDF6. Accordingly, human ASCs were incorporated into a cold, free-flowing aq. dispersion of the diblock copolymer, gelation induced by warming to 37° and cell culture was conducted for 14 days with or without such growth factors to assess the expression of characteristic NP markers compared to those produced when using collagen gels. In principle, the shear-thinning nature of the biocompatible worm gel enables encapsulated human ASCs to be injected into the IVD using a 21G needle. Moreover, we find significantly higher gene expression levels of ACAN, SOX-9, KRT8, and KR18 for ASCs encapsulated within worm gels compared to collagen scaffolds, regardless of the growth factors employed. In summary, such wholly synthetic worm gels offer considerable potential as an injectable cell delivery scaffold for the treatment of degenerate disk disease by promoting the transition of ASCs toward an NP-phenotype.
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  65. 65
    Mitchell, D. E.; Lovett, J. R.; Armes, S. P.; Gibson, M. I. Combining Biomimetic Block Copolymer Worms with an Ice-Inhibiting Polymer for the Solvent-Free Cryopreservation of Red Blood Cells. Angew. Chem., Int. Ed. 2016, 55 (8), 2801– 2804,  DOI: 10.1002/anie.201511454
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    65
    Combining Biomimetic Block Copolymer Worms with an Ice-Inhibiting Polymer for the Solvent-Free Cryopreservation of Red Blood Cells
    Mitchell, Daniel E.; Lovett, Joseph R.; Armes, Steven P.; Gibson, Matthew I.
    Angewandte Chemie, International Edition (2016), 55 (8), 2801-2804CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The first fully synthetic polymer-based approach for red-blood-cell cryopreservation without the need for any (toxic) org. solvents is reported. Highly hydroxylated block copolymer worms are shown to be a suitable replacement for hydroxyethyl starch as a extracellular matrix for red blood cells. When used alone, the worms are not a particularly effective preservative. However, when combined with poly(vinyl alc.), a known ice-recrystn. inhibitor, a remarkable additive cryopreservative effect is obsd. that matches the performance of hydroxyethyl starch. Moreover, these block copolymer worms enable post-thaw gelation by simply warming to 20 °C. This approach offers a new soln. for both the storage and transport of red blood cells and also a convenient matrix for subsequent 3D cell cultures.
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  66. 66
    Blackman, L. D.; Varlas, S.; Arno, M. C.; Fayter, A.; Gibson, M. I.; O’Reilly, R. K. Permeable Protein-Loaded Polymersome Cascade Nanoreactors by Polymerization-Induced Self-Assembly. ACS Macro Lett. 2017, 6 (11), 1263– 1267,  DOI: 10.1021/acsmacrolett.7b00725
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    66
    Permeable Protein-Loaded Polymersome Cascade Nanoreactors by Polymerization-Induced Self-Assembly
    Blackman, Lewis D.; Varlas, Spyridon; Arno, Maria C.; Fayter, Alice; Gibson, Matthew I.; OReilly, Rachel K.
    ACS Macro Letters (2017), 6 (11), 1263-1267CODEN: AMLCCD; ISSN:2161-1653. (American Chemical Society)
    Enzyme loading of polymersomes requires permeability to enable them to interact with the external environment, typically requiring addn. of complex functionality to enable porosity. Herein, we describe a synthetic route toward intrinsically permeable polymersomes loaded with functional proteins using initiator-free visible light-mediated polymn.-induced self-assembly (photo-PISA) under mild, aq. conditions using a com. monomer. Compartmentalization and retention of protein functionality was demonstrated using green fluorescent protein as a macromol. chromophore. Catalytic enzyme-loaded vesicles using horseradish peroxidase and glucose oxidase were also prepd. and the permeability of the membrane toward their small mol. substrates was revealed for the first time. Finally, the interaction of the compartmentalized enzymes between sep. vesicles was validated by means of an enzymic cascade reaction. These findings have a broad scope as the methodol. could be applied for the encapsulation of a large range of macromols. for advancements in the fields of nanotechnol., biomimicry and nanomedicine.
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  67. 67
    Blackman, L. D.; Varlas, S.; Arno, M. C.; Houston, Z. H.; Fletcher, N. L.; Thurecht, K. J.; Hasan, M.; Gibson, M. I.; O’Reilly, R. K. Confinement of Therapeutic Enzymes in Selectively Permeable Polymer Vesicles by Polymerization-Induced Self-Assembly (PISA) Reduces Antibody Binding and Proteolytic Susceptibility. ACS Cent. Sci. 2018, 4 (6), 718– 723,  DOI: 10.1021/acscentsci.8b00168
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    67
    Confinement of Therapeutic Enzymes in Selectively Permeable Polymer Vesicles by Polymerization-Induced Self-Assembly (PISA) Reduces Antibody Binding and Proteolytic Susceptibility
    Blackman, Lewis D.; Varlas, Spyridon; Arno, Maria C.; Houston, Zachary H.; Fletcher, Nicholas L.; Thurecht, Kristofer J.; Hasan, Muhammad; Gibson, Matthew I.; O'Reilly, Rachel K.
    ACS Central Science (2018), 4 (6), 718-723CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
    Covalent PEGylation of biologics has been widely employed to reduce immunogenicity, while improving stability and half-life in vivo. This approach requires covalent protein modification, creating a new entity. An alternative approach is stabilization by encapsulation into polymersomes; however this typically requires multiple steps, and the segregation requires the vesicles to be permeable to retain function. Herein, we demonstrate the one-pot synthesis of therapeutic enzyme-loaded vesicles with size-selective permeability using polymn.-induced self-assembly (PISA) enabling the encapsulated enzyme to function from within a confined domain. This strategy increased the proteolytic stability and reduced antibody recognition compared to the free protein or a PEGylated conjugate, thereby reducing potential dose frequency and the risk of immune response. Finally, the efficacy of encapsulated L-asparaginase (clin. used for leukemia treatment) against a cancer line was demonstrated, and its biodistribution and circulation behavior in vivo was compared to the free enzyme, highlighting this methodol. as an attractive alternative to the covalent PEGylation of enzymes.
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    Varlas, S.; Foster, J. C.; Georgiou, P. G.; Keogh, R.; Husband, J. T.; Williams, D. S.; O’Reilly, R. K. Tuning the Membrane Permeability of Polymersome Nanoreactors Developed by Aqueous Emulsion Polymerization-Induced Self-Assembly. Nanoscale 2019, 11 (26), 12643– 12654,  DOI: 10.1039/C9NR02507C
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    Tuning the membrane permeability of polymersome nanoreactors developed by aqueous emulsion polymerization-induced self-assembly
    Varlas, Spyridon; Foster, Jeffrey C.; Georgiou, Panagiotis G.; Keogh, Robert; Husband, Jonathan T.; Williams, David S.; O'Reilly, Rachel K.
    Nanoscale (2019), 11 (26), 12643-12654CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
    Polymeric vesicles (or polymersomes) are hollow bilayer structures consisting of an inner aq. compartment enclosed by a hydrophobic membrane. Research into polymersomes is motivated primarily by the fact that hydrophilic cargo such as drug mols., DNA, or enzymes can be encapsulated and protected from the often harsh conditions of the surrounding environment. A key factor governing the capability of vesicles to retain and protect their cargo is the permeability of their hydrophobic membrane. Herein, we demonstrate that membrane permeability of enzyme-loaded epoxy-functionalized polymersomes synthesized by aq. emulsion PISA can be modulated via epoxide ring-opening with various diamine crosslinkers and hydrophobic primary amines. In general, membrane crosslinking or amine conjugation resulted in increased polymersome membrane thickness. Membrane modification was also found to decrease permeability in all cases, as measured by enzymically-catalyzed oxidn. of an externally administered substrate. Functionalization with hydrophobic amines resulted in the largest redn. in enzyme activity, suggesting significant blocking of substrate diffusion into the central aq. compartment. This procedurally facile strategy yields meaningful insight into how the chem. structure of the membrane influences permeability and thus could be generally applied to the formulation of polymeric vesicles for therapeutic applications.
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    Cheng, G.; Pérez-Mercader, J. Polymerization-Induced Self-Assembly for Artificial Biology: Opportunities and Challenges. Macromol. Rapid Commun. 2019, 40 (2), 1970006,  DOI: 10.1002/marc.201970006
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    Canning, S. L.; Smith, G. N.; Armes, S. P. A Critical Appraisal of RAFT-Mediated Polymerization-Induced Self-Assembly. Macromolecules 2016, 49, 1985– 2001,  DOI: 10.1021/acs.macromol.5b02602
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    A Critical Appraisal of RAFT-Mediated Polymerization-Induced Self-Assembly
    Canning, Sarah L.; Smith, Gregory N.; Armes, Steven P.
    Macromolecules (Washington, DC, United States) (2016), 49 (6), 1985-2001CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    Recently, polymn.-induced self-assembly (PISA) has become widely recognized as a robust and efficient route to produce block copolymer nanoparticles of controlled size, morphol., and surface chem. Several reviews of this field have been published since 2012, but a substantial no. of new papers have been published in the last three years. In this Perspective, we provide a crit. appraisal of the various advantages offered by this approach, while also pointing out some of its current drawbacks. Promising future research directions as well as remaining tech. challenges and unresolved problems are briefly highlighted.
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    Khor, S. Y.; Quinn, J. F.; Whittaker, M. R.; Truong, N. P.; Davis, T. P. Controlling Nanomaterial Size and Shape for Biomedical Applications via Polymerization-Induced Self-Assembly. Macromol. Rapid Commun. 2019, 40 (2), 1800438,  DOI: 10.1002/marc.201800438
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    D’Agosto, F.; Rieger, J.; Lansalot, M. RAFT-Mediated Polymerization-Induced Self-Assembly. Angew. Chem., Int. Ed. 2020, 59 (22), 8368– 8392,  DOI: 10.1002/anie.201911758
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    RAFT-Mediated Polymerization-Induced Self-Assembly
    D'Agosto, Franck; Rieger, Jutta; Lansalot, Muriel
    Angewandte Chemie, International Edition (2020), 59 (22), 8368-8392CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. After a brief history that positions polymn.-induced self-assembly (PISA) in the field of polymer chem., this Review will cover the fundamentals of the PISA mechanism. Furthermore, this Review will also give an overview of some of the features and limitations of RAFT-mediated PISA in terms of the choice of the components involved, the nature of the nanoobjects that can be obtained and how the syntheses can be controlled, as well as some potential applications.
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    Penfold, N. J. W.; Yeow, J.; Boyer, C.; Armes, S. P. Emerging Trends in Polymerization-Induced Self-Assembly. ACS Macro Lett. 2019, 8 (8), 1029– 1054,  DOI: 10.1021/acsmacrolett.9b00464
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    Emerging Trends in Polymerization-Induced Self-Assembly
    Penfold, Nicholas J. W.; Yeow, Jonathan; Boyer, Cyrille; Armes, Steven P.
    ACS Macro Letters (2019), 8 (8), 1029-1054CODEN: AMLCCD; ISSN:2161-1653. (American Chemical Society)
    A review. In this Perspective, we summarize recent progress in polymn.-induced self-assembly (PISA) for the rational synthesis of block copolymer nanoparticles with various morphologies. Much of the PISA literature has been based on thermally initiated reversible addn.-fragmentation chain transfer (RAFT) polymn. Herein, we pay particular attention to alternative PISA protocols, which allow the prepn. of nanoparticles with improved control over copolymer morphol. and functionality. For example, initiation based on visible light, redox chem., or enzymes enables the incorporation of sensitive monomers and fragile biomols. into block copolymer nanoparticles. Furthermore, PISA syntheses and postfunctionalization of the resulting nanoparticles (e.g., crosslinking) can be conducted sequentially without intermediate purifn. by using various external stimuli. Finally, PISA formulations have been optimized via high-throughput polymn. and recently evaluated within flow reactors for facile scale-up syntheses.
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    Georgiou, P. G.; Kontopoulou, I.; Congdon, T. R.; Gibson, M. I. Ice Recrystallisation Inhibiting Polymer Nano-Objects: Via Saline-Tolerant Polymerisation-Induced Self-Assembly. Mater. Horiz. 2020, 7 (7), 1883– 1887,  DOI: 10.1039/D0MH00354A
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    74
    Ice recrystallisation inhibiting polymer nano-objects via saline-tolerant polymerisation-induced self-assembly
    Georgiou, Panagiotis G.; Kontopoulou, Ioanna; Congdon, Thomas R.; Gibson, Matthew I.
    Materials Horizons (2020), 7 (7), 1883-1887CODEN: MHAOBM; ISSN:2051-6355. (Royal Society of Chemistry)
    Chem. tools to modulate ice formation/growth have great (bio)technol. value, with ice binding/antifreeze proteins being exciting targets for biomimetic materials. Here we introduce polymer nanomaterials that are potent inhibitors of ice recrystn. using polymn.-induced self-assembly (PISA), employing a poly(vinyl alc.) graft macromol. chain transfer agent (macro-CTA). Crucially, engineering the core-forming block with diacetone acrylamide enabled PISA to be conducted in saline, whereas poly(2-hydroxypropyl methacrylate) cores led to coagulation. The most active particles inhibited ice growth as low as 0.5 mg mL-1, and were more active than the PVA stabilizer block alone, showing that the dense packing of this nanoparticle format enhanced activity. This provides a unique route towards colloids capable of modulating ice growth.
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    Warren, N. J.; Mykhaylyk, O. O.; Mahmood, D.; Ryan, A. J.; Armes, S. P. RAFT Aqueous Dispersion Polymerization Yields Poly(Ethylene Glycol)-Based Diblock Copolymer Nano-Objects with Predictable Single Phase Morphologies. J. Am. Chem. Soc. 2014, 136 (3), 1023– 1033,  DOI: 10.1021/ja410593n
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    75
    RAFT Aqueous Dispersion Polymerization Yields Poly(ethylene glycol)-Based Diblock Copolymer Nano-Objects with Predictable Single Phase Morphologies
    Warren, Nicholas J.; Mykhaylyk, Oleksandr O.; Mahmood, Daniel; Ryan, Anthony J.; Armes, Steven P.
    Journal of the American Chemical Society (2014), 136 (3), 1023-1033CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A poly(ethylene glycol) (PEG) macromol. chain transfer agent (macro-CTA) is prepd. in high yield (>95%) with 97% dithiobenzoate chain-end functionality in a three-step synthesis starting from a monohydroxy PEG113 precursor. This PEG113-dithiobenzoate is then used for the reversible addn.-fragmentation chain transfer (RAFT) aq. dispersion polymn. of 2-hydroxypropyl methacrylate (HPMA). Polymns. conducted under optimized conditions at 50 °C led to high conversions as judged by 1H NMR spectroscopy and relatively low diblock copolymer polydispersities (Mw/Mn < 1.25) as judged by GPC. The latter technique also indicated good blocking efficiencies, since there was minimal PEG113 macro-CTA contamination. Systematic variation of the mean d.p. of the core-forming PHPMA block allowed PEG113-PHPMAx diblock copolymer spheres, worms, or vesicles to be prepd. at up to 17.5% wt./wt. solids, as judged by dynamic light scattering and transmission electron microscopy studies. Small-angle X-ray scattering (SAXS) anal. revealed that more exotic oligolamellar vesicles were obsd. at 20% wt./wt. solids when targeting highly asym. diblock compns. Detailed anal. of SAXS curves indicated that the mean no. of membranes per oligolamellar vesicle is approx. three. A PEG113-PHPMAx phase diagram was constructed to enable the reproducible targeting of pure phases, as opposed to mixed morphologies (e.g., spheres plus worms or worms plus vesicles). This new RAFT PISA formulation is expected to be important for the rational and efficient synthesis of a wide range of biocompatible, thermo-responsive PEGylated diblock copolymer nano-objects for various biomedical applications.
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    Yoshida, E. Perforated Vesicles Composed of Amphiphilic Diblock Copolymer: New Artificial Biomembrane Model of Nuclear Envelope. Soft Matter 2019, 15 (48), 9849– 9857,  DOI: 10.1039/C9SM01832H
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    76
    Perforated vesicles composed of amphiphilic diblock copolymer: new artificial biomembrane model of nuclear envelope
    Yoshida, Eri
    Soft Matter (2019), 15 (48), 9849-9857CODEN: SMOABF; ISSN:1744-6848. (Royal Society of Chemistry)
    With the aim of creating a new artificial model of a biomembrane for the nuclear envelope, perforated vesicles were prepd. employing an amphiphilic diblock copolymer of poly(methacrylic acid)-block-poly(Me methacrylate-random-methacrylic acid-random-2,2,6,6-tetramethyl-4-piperidyl methacrylate), PMAA-b-P(MMA-r-MAA-r-TPMA), by polymn.-induced self-assembly through photo nitroxide-mediated controlled/living radical polymn. (photo NMP). The photo NMP in an aq. methanol soln. produced spherical vesicles perforated with various holes and pores in the surface. The perforation of the vesicles was prevented by trifluoroacetic acid based on the disturbance of the MAA-TPMA interaction in the hydrophobic block chain. The investigation of the morphol. changes by the polymn. progress revealed that the perforated spherical vesicles were produced within the membrane of contorted huge vesicles that were formed during the early stage of the polymn. due to the extension of the hydrophobic block chain. The perforated vesicles were found to show a reversible thermo-responsive behavior in the range of 25-50°C based on dynamic light scattering and transmittance measurements. The vesicles were fused and divided into much smaller vesicles at high temp., but were restored by cooling. However, the restored vesicles only had a few holes and no pores in the surface. The rearrangement of the MAA-TPMA interaction at high temp. produced more morphol. stable non-perforated vesicles.
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    Yoshida, E. Fission of Giant Vesicles Accompanied by Hydrophobic Chain Growth through Polymerization-Induced Self-Assembly. Colloid Polym. Sci. 2014, 292 (6), 1463– 1468,  DOI: 10.1007/s00396-014-3216-x
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    Fission of giant vesicles accompanied by hydrophobic chain growth through polymerization-induced self-assembly
    Yoshida, Eri
    Colloid and Polymer Science (2014), 292 (6), 1463-1468CODEN: CPMSB6; ISSN:0303-402X. (Springer)
    To clarify the formation mechanisms of micrometer-sized spherical vesicles through the polymn.-induced self-assembly of amphiphilic poly(methacrylic acid)-block-poly(Me methacrylate-random-methacrylic acid), PMAA-b-P(MMA-r-MAA), the nitroxide-mediated photocontrolled/living radical polymn. initiated by a PMAA end-capped with 4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl was performed in an aq. MeOH soln. The polymn. proceeded in a living manner during the self-assembly. The vesicles produced during the early stage of the polymn. were not completely spherical and had dents and very small holes on their surface. As the hydrophobic P(MMA-r-MAA) block chains grew by the polymn., the contorted vesicles were changed into half-sized elliptical vesicles accompanied by enlargement of the dents and holes. The vesicles were finally transformed into much smaller spherical vesicles by further growth of the hydrophobic chains. The mechanisms of the vesicles by fission involved the outside sepn. by the expansion of the dents and holes on the surface and the inside sepn. by budding.
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    Scheutz, G. M.; Touve, M. A.; Carlini, A. S.; Garrison, J. B.; Gnanasekaran, K.; Sumerlin, B. S.; Gianneschi, N. C. Probing Thermoresponsive Polymerization-Induced Self-Assembly with Variable-Temperature Liquid-Cell Transmission Electron Microscopy. Matter 2021, 4 (2), 722– 736,  DOI: 10.1016/j.matt.2020.11.017
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    Probing Thermoresponsive Polymerization-Induced Self-Assembly with Variable-Temperature Liquid-Cell Transmission Electron Microscopy
    Scheutz, Georg M.; Touve, Mollie A.; Carlini, Andrea S.; Garrison, John B.; Gnanasekaran, Karthikeyan; Sumerlin, Brent S.; Gianneschi, Nathan C.
    Matter (2021), 4 (2), 722-736CODEN: MATTCG; ISSN:2590-2385. (Elsevier Inc.)
    We directly initiate and visualize the formation of polymeric nanomaterials via variable-temp. liq.-cell transmission electron microscopy. With temp. control in the liq. cell, reversible addn.-fragmentation chain transfer polymn. was thermally initiated, leading to the formation of amphiphilic block copolymers that assemble upon dispersion polymn.-induced self-assembly (PISA). In combination with traditional ex-situ analyses, VT-LCTEM enabled not only the characterization of the nanoparticles in situ but also the observation of a thermal phase transition. Critically, because these assemblies form from thermoresponsive components, any temp. changes during sample prepn. and anal. can alter morphologies, necessitating direct in situ characterization of reaction progression. We believe that the findings and the technique described herein will lead to unprecedented possibilities for the development and characterization of self-organizing soft matter.
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    Byard, S. J.; Williams, M.; McKenzie, B. E.; Blanazs, A.; Armes, S. P. Preparation and Cross-Linking of All-Acrylamide Diblock Copolymer Nano-Objects via Polymerization-Induced Self-Assembly in Aqueous Solution. Macromolecules 2017, 50 (4), 1482– 1493,  DOI: 10.1021/acs.macromol.6b02643
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    Preparation and Cross-Linking of All-Acrylamide Diblock Copolymer Nano-Objects via Polymerization-Induced Self-Assembly in Aqueous Solution
    Byard, Sarah J.; Williams, Mark; McKenzie, Beulah E.; Blanazs, Adam; Armes, Steven P.
    Macromolecules (Washington, DC, United States) (2017), 50 (4), 1482-1493CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    Various carboxylic acid-functionalized poly(N,N-dimethylacrylamide) (PDMAC) macromol. chain transfer agents (macro-CTAs) were chain-extended with diacetone acrylamide (DAAM) by reversible addn.-fragmentation chain transfer (RAFT) aq. dispersion polymn. at 70 °C and 20% wt./wt. solids to produce a series of PDMAC-PDAAM diblock copolymer nano-objects via polymn.-induced self-assembly (PISA). TEM studies indicate that a PDMAC macro-CTA with a mean d.p. (DP) of 68 or higher results in the formation of well-defined spherical nanoparticles with mean diams. ranging from 40 to 150 nm. In contrast, either highly anisotropic worms or polydisperse vesicles are formed when relatively short macro-CTAs (DP = 40-58) are used. A phase diagram was constructed to enable accurate targeting of pure copolymer morphologies. Dynamic light scattering (DLS) and aq. electrophoresis studies indicated that in most cases these PDMAC-PDAAM nano-objects are surprisingly resistant to changes in either soln. pH or temp. However, PDMAC40-PDAAM99 worms do undergo partial dissocn. to form a mixt. of relatively short worms and spheres on adjusting the soln. pH from pH 2-3 to around pH 9 at 20 °C. Moreover, a change in copolymer morphol. from worms to a mixt. of short worms and vesicles was obsd. by DLS and TEM on heating this worm dispersion to 50 °C. Postpolymn. crosslinking of concd. aq. dispersions of PDMAC-PDAAM spheres, worms, or vesicles was performed at ambient temp. using adipic acid dihydrazide (ADH), which reacts with the hydrophobic ketone-functionalized PDAAM chains. The formation of hydrazone groups was monitored by FT-IR spectroscopy and afforded covalently stabilized nano-objects that remained intact on exposure to methanol, which is a good solvent for both blocks. Rheol. studies indicated that the cross-linked worms formed a stronger gel compared to linear precursor worms.
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    Wang, X.; Zhou, J.; Lv, X.; Zhang, B.; An, Z. Temperature-Induced Morphological Transitions of Poly(Dimethylacrylamide)–Poly(Diacetone Acrylamide) Block Copolymer Lamellae Synthesized via Aqueous Polymerization-Induced Self-Assembly. Macromolecules 2017, 50 (18), 7222– 7232,  DOI: 10.1021/acs.macromol.7b01644
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    Temperature-Induced Morphological Transitions of Poly(dimethylacrylamide)-Poly(diacetone acrylamide) Block Copolymer Lamellae Synthesized via Aqueous Polymerization-Induced Self-Assembly
    Wang, Xiao; Zhou, Jiamin; Lv, Xiaoqing; Zhang, Baohua; An, Zesheng
    Macromolecules (Washington, DC, United States) (2017), 50 (18), 7222-7232CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    Aq. dispersion polymn. of diacetone acrylamide (DAAM) by chain extension from a hydrophilic poly(N,N-dimethylacrylamide) (PDMA30) macromol. chain transfer agent (macro-CTA) to produce PDMA30-PDAAMx block copolymer nano-objects was investigated in detail by systematically varying solids content and d.p. of the core-forming PDAAM, leading to the formation of pure lamellae, mixed lamellae/vesicles, and pure vesicles as revealed by dynamic light scattering (DLS), transmission electron microscopy (TEM), at. force microscopy (AFM), and SEM (SEM). PDMA30-PDAAMx lamellae were found to span an unprecedented wide space in the morphol. phase diagram. Moreover, in situ crosslinking of lamellae via statistical copolymn. of DAAM with an asym. crosslinker allyl acrylamide and the effect of crosslinking d. on the colloidal and morphol. stabilities were studied, representing the first report on in situ crosslinking of lamellae during polymn.-induced self-assembly (PISA). Finally, reversible, temp.-induced morphol. transitions from lamellae to worms/spheres on cooling were investigated by DLS, TEM, 1H NMR spectroscopy, and rheol. The kinetics of the temp.-dependent morphol. transitions and the rheol. properties could be tuned by the crosslinking d.
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    Knight, C. A.; Hallett, J.; DeVries, A. L. Solute Effects on Ice Recrystallization: An Assessment Technique. Cryobiology 1988, 25 (1), 55– 60,  DOI: 10.1016/0011-2240(88)90020-X
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    Solute effects on ice recrystallization: an assessment technique
    Knight C A; Hallett J; DeVries A L
    Cryobiology (1988), 25 (1), 55-60 ISSN:0011-2240.
    Reliable assessment of the effect of a solute upon ice recrystallization is accomplished with "splat cooling," the impaction of a small solution droplet onto a very cold metal plate. The ice disc has extremely small crystals, and recrystallization can be followed without confusing effects caused by grain nucleation. This method confirms the exceptionally strong recrystallization inhibition effect of antifreeze protein from Antarctic fish and shows that grain growth rate is a sensitive function of both grain size and solute concentration.
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    Byard, S. J.; Blanazs, A.; Miller, J. F.; Armes, S. P. Cationic Sterically Stabilized Diblock Copolymer Nanoparticles Exhibit Exceptional Tolerance toward Added Salt. Langmuir 2019, 35 (44), 14348– 14357,  DOI: 10.1021/acs.langmuir.9b02789
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    Cationic Sterically Stabilized Diblock Copolymer Nanoparticles Exhibit Exceptional Tolerance toward Added Salt
    Byard, Sarah J.; Blanazs, Adam; Miller, John F.; Armes, Steven P.
    Langmuir (2019), 35 (44), 14348-14357CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
    For certain com. applications such as enhanced oil recovery, sterically stabilized colloidal dispersions that exhibit high tolerance toward added salt are desirable. Herein, we report a series of new cationic diblock copolymer nanoparticles that display excellent colloidal stability in concd. aq. salt solns. More specifically, poly(2-(acryloyloxy)ethyltrimethylammonium chloride) (PATAC) has been chain-extended by reversible addn.-fragmentation chain transfer aq. dispersion polymn. of diacetone acrylamide (DAAM) at 70 °C to produce PATAC100-PDAAMx diblock copolymer spheres at 20% wt./wt. solids via polymn.-induced self-assembly. Transmission electron microscopy and dynamic light scattering (DLS) anal. confirm that the mean sphere diam. can be adjusted by systematic variation of the mean d.p. of the PDAAM block. Remarkably, DLS studies confirm that highly cationic PATAC100-PDAAM1500 spheres retain their colloidal stability in the presence of either 4.0 M KCl or 3.0 M ammonium sulfate for at least 115 days at 20 °C. The mole fraction of PATAC chains within the stabilizer shell was systematically varied by the chain extension of various binary mixts. of non-ionic poly(N,N-dimethylacrylamide) (PDMAC) and cationic PATAC with DAAM to produce ([n] PATAC100 + [1 - n] PDMAC67)-PDAAMz diblock copolymer spheres at 20% wt./wt. DLS studies confirmed that a relatively high mole fraction of cationic PATAC stabilizer chains (n ≥ 0.75) is required for the dispersions to remain colloidally stable in 4.0 M KCl. Cationic worms and vesicles could also be synthesized using a binary mixt. of PATAC and PDMAC precursors, where n = 0.10. However, the vesicles only remained colloidally stable up to 1.0 M KCl, whereas the worms proved to be stable up to 2.0 M KCl. Such block copolymer nanoparticles are expected to be useful model systems for understanding the behavior of aq. colloidal dispersions in extremely salty media. Finally, zeta potentials detd. using electrophoretic light scattering are presented for such nanoparticles dispersed in highly salty media.
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    Foster, J. C.; Varlas, S.; Couturaud, B.; Jones, J. R.; Keogh, R.; Mathers, R. T.; O’Reilly, R. K. Predicting Monomers for Use in Polymerization-Induced Self-Assembly. Angew. Chem., Int. Ed. 2018, 57 (48), 15733– 15737,  DOI: 10.1002/anie.201809614
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    Predicting Monomers for Use in Polymerization-Induced Self-Assembly
    Foster, Jeffrey C.; Varlas, Spyridon; Couturaud, Benoit; Jones, Joseph R.; Keogh, Robert; Mathers, Robert T.; O'Reilly, Rachel K.
    Angewandte Chemie, International Edition (2018), 57 (48), 15733-15737CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    We report an in silico method to predict monomers suitable for use in polymn.-induced self-assembly (PISA). By calcg. the dependence of LogPoct /surface area (SA) on the length of the growing polymer chain, the change in hydrophobicity during polymn. was detd. This allowed for evaluation of the capability of a monomer to polymerize to form self-assembled structures during chain extension. Using this method, we identified five new monomers for use in aq. PISA via reversible addn.-fragmentation chain transfer (RAFT) polymn., and confirmed that these all successfully underwent PISA to produce nanostructures of various morphologies. The results obtained using this method correlated well with and predicted the differences in morphol. obtained from the PISA of block copolymers of similar mol. wt. but different chem. structures. Thus, we propose this method can be utilized for the discovery of new monomers for PISA and also the prediction of their self-assembly behavior.
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    Yamago, S.; Nakamura, Y. Recent Progress in the Use of Photoirradiation in Living Radical Polymerization. Polymer 2013, 54 (3), 981– 994,  DOI: 10.1016/j.polymer.2012.11.046
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    Recent progress in the use of photoirradiation in living radical polymerization
    Yamago, Shigeru; Nakamura, Yasuyuki
    Polymer (2013), 54 (3), 981-994CODEN: POLMAG; ISSN:0032-3861. (Elsevier Ltd.)
    A review. The effects of photoirradn. in controlled and living radical polymn. (LRP), namely nitroxide-mediated polymn. (NMP), atom-transfer radical polymn. (ATRP), cobalt-mediated radical polymn. (CMRP), reversible addn.-fragmentation chain transfer polymn. (RAFT), organoiodine-mediated radical polymn. (IRP), and organotellurium-mediated radical polymn. (TERP), are summarized. As in the conventional radical polymn., photoirradn. has been used for generating radicals under mild conditions in LRP methods. In addn. to this use, photoirradn. is also used to overcome the difficulties characteristic to each method, such as activation of catalysis, generation of controlling agents, and increasing the polymer-end structure. The most-recent developments in the use of photochem. in LRP are summarized in this review.
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    McKenzie, T. G.; Fu, Q.; Uchiyama, M.; Satoh, K.; Xu, J.; Boyer, C.; Kamigaito, M.; Qiao, G. G. Beyond Traditional RAFT: Alternative Activation of Thiocarbonylthio Compounds for Controlled Polymerization. Adv. Sci. 2016, 3 (9), 1500394,  DOI: 10.1002/advs.201670047
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    Beyond Traditional RAFT: Alternative Activation of Thiocarbonylthio Compounds for Controlled Polymerization
    McKenzie Thomas G; Fu Qiang; Qiao Greg G; Uchiyama Mineto; Kamigaito Masami; Satoh Kotaro; Xu Jiangtao; Boyer Cyrille
    Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2016), 3 (9), 1500394 ISSN:2198-3844.
    Recent developments in polymerization reactions utilizing thiocarbonylthio compounds have highlighted the surprising versatility of these unique molecules. The increasing popularity of reversible addition-fragmentation chain transfer (RAFT) radical polymerization as a means of producing well-defined, 'controlled' synthetic polymers is largely due to its simplicity of implementation and the availability of a wide range of compatible reagents. However, novel modes of thiocarbonylthio activation can expand the technique beyond the traditional system (i.e., employing a free radical initiator) pushing the applicability and use of thiocarbonylthio compounds even further than previously assumed. The primary advances seen in recent years are a revival in the direct photoactivation of thiocarbonylthio compounds, their activation via photoredox catalysis, and their use in cationic polymerizations. These synthetic approaches and their implications for the synthesis of controlled polymers represent a significant advance in polymer science, with potentially unforeseen benefits and possibilities for further developments still ahead. This Research News aims to highlight key works in this area while also clarifying the differences and similarities of each system.
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    Binauld, S.; Delafresnaye, L.; Charleux, B.; D’Agosto, F.; Lansalot, M. Emulsion Polymerization of Vinyl Acetate in the Presence of Different Hydrophilic Polymers Obtained by RAFT/MADIX. Macromolecules 2014, 47 (10), 3461– 3472,  DOI: 10.1021/ma402549x
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    Emulsion Polymerization of Vinyl Acetate in the Presence of Different Hydrophilic Polymers Obtained by RAFT/MADIX
    Binauld, Sandra; Delafresnaye, Laura; Charleux, Bernadette; D'Agosto, Franck; Lansalot, Muriel
    Macromolecules (Washington, DC, United States) (2014), 47 (10), 3461-3472CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    The surfactant-free emulsion polymn. of vinyl acetate (VAc) was achieved using RAFT/MADIX-mediated polymn.-induced self-assembly (PISA) process in water. First, well-defined hydrophilic macromol. RAFT agents (macroRAFT) bearing a xanthate chain end were synthesized by RAFT/MADIX polymn. of N-vinylpyrrolidone (NVP) and N-acryloylmorpholine (NAM) or by post-modification of com. poly(ethylene glycol). Chain extension of the macroRAFT with VAc in water led to the block copolymer nanoscale organization and the subsequent formation of stable and isodisperse PVAc latex nanoparticles with high solids content (35-37 wt. %). The influence of various parameters, including the nature and functionality of the macroRAFT agent precursor, on the polymn. kinetics and particle morphol. was also studied.
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    Pound, G.; Eksteen, Z.; Pfukwa, R.; McKenzie, J. M.; Lange, R. F. M.; Klumperman, B. Unexpected Reactions Associated with the Xanthate-Mediated Polymerization of N-Vinylpyrrolidone. J. Polym. Sci., Part A: Polym. Chem. 2008, 46 (19), 6575– 6593,  DOI: 10.1002/pola.22968
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    Unexpected reactions associated with the xanthate-mediated polymerization of N-vinylpyrrolidone
    Pound, Gwenaelle; Eksteen, Zaskia; Pfukwa, Rueben; McKenzie, Jean M.; Lange, Ronald F. M.; Klumperman, Bert
    Journal of Polymer Science, Part A: Polymer Chemistry (2008), 46 (19), 6575-6593CODEN: JPACEC; ISSN:0887-624X. (John Wiley & Sons, Inc.)
    The monomer N-vinylpyrrolidone (NVP) undergoes side reactions in the presence of R group functional xanthates and impurities. The fate of the monomer NVP and a selection of six O-Et xanthates during xanthate-mediated polymn. were studied via NMR spectroscopy. A high no. of byproducts were identified. Significant side reactions affecting NVP include the formation of an unsatd. dimer and hydration products in bulk or in soln. in C6D6. In addn., the xanthate adjacent to a NVP unit was found to undergo elimination at moderate temp. (60-70°), resulting in unsatd. species and the formation of new xanthate species. The presence of the chlorinated compd. α-chlorophenyl acetic acid, Et ester, a precursor in the synthesis of the xanthate S-(2-Et phenylacetate) O-Et xanthate, resulted in a dramatic increase in the rate of side reactions such as unsatd. dimer formation and a high ratio of unsatd. chain ends. The conditions for the occurrence of such side reactions are discussed in this article, with relevance to increasing the control over the polymn. kinetics, endgroup functionality, and control over the molar mass distribution.
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    Guinaudeau, A.; Coutelier, O.; Sandeau, A.; Mazières, S.; Nguyen Thi, H. D.; Le Drogo, V.; Wilson, D. J.; Destarac, M. Facile Access to Poly(N-Vinylpyrrolidone)-Based Double Hydrophilic Block Copolymers by Aqueous Ambient RAFT/MADIX Polymerization. Macromolecules 2014, 47 (1), 41– 50,  DOI: 10.1021/ma4017899
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    Facile Access to Poly(N-vinylpyrrolidone)-Based Double Hydrophilic Block Copolymers by Aqueous Ambient RAFT/MADIX Polymerization
    Guinaudeau, Aymeric; Coutelier, Olivier; Sandeau, Aurelie; Mazieres, Stephane; Nguyen, Thi Hong Diep; Le Drogo, Viviane; Wilson, David James; Destarac, Mathias
    Macromolecules (Washington, DC, United States) (2014), 47 (1), 41-50CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    A new redox initiator pair employing sodium sulfite as reducing agent was proposed to perform aq. ambient RAFT/MADIX polymn. of N-vinylpyrrolidone (NVP) in the presence of a xanthate chain transfer agent. An efficient control of the polymn. with no formation of monomer byproducts was obtained regardless of the concn. of water in the medium. This system was applied to the aq. synthesis of PVP-based double hydrophilic block copolymers through the polymn. of NVP at room temp. with several hydrophilic macro-chain-transfer agents based on poly(acrylamide), poly(acrylic acid), poly(sodium 2-acrylamido-2-methylpropanesulfonate), and poly(3-acrylamidopropyltrimethylammonium chloride). The diblock nature of the copolymers was established by DOSY NMR in all cases when satisfactory SEC anal. conditions could not be established due to the strong adsorption properties of the copolymers.
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    Wan, D.; Satoh, K.; Kamigaito, M.; Okamoto, Y. Xanthate-Mediated Radical Polymerization of N -Vinylpyrrolidone in Fluoroalcohols for Simultaneous Control of Molecular Weight and Tacticity. Macromolecules 2005, 38 (25), 10397– 10405,  DOI: 10.1021/ma0515230
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    Xanthate-Mediated Radical Polymerization of N-Vinylpyrrolidone in Fluoroalcohols for Simultaneous Control of Molecular Weight and Tacticity
    Wan, Decheng; Satoh, Kotaro; Kamigaito, Masami; Okamoto, Yoshio
    Macromolecules (2005), 38 (25), 10397-10405CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    The simultaneous control of the tacticity and mol. wt. of poly(N-vinylpyrrolidone) during radical polymn. is reported for the first time. For mol. wt. control, xanthates of (O-ethylxanthylmethyl)benzene and [1-(O-ethylxanthyl)ethyl]benzene were used as RAFT/MADIX chain transfer agents (CTAs) for the radical polymn. of N-vinylpyrrolidone (NVP). Both led to a controlled/living radical polymn., and the latter showed higher chain transfer ability under the optimal conditions; the mol. wt. distribution was 1.36 when the mol. wt. was up to 26 700. The polymn. was studied between 20 and 120° and at various concns. of CTA. All the polymns. showed an induction period and rate retardation dependent on both the concn. of CTA and temp. For tacticity control, the polymn. was carried out in fluoroalcs. via a conventional radical process without CTAs to give syndiotactic polymers. The polymer tacticity was dependent on the amt. of the fluoroalc., and a more acidic and bulkier fluoroalc. led to a higher syndiotacticity. Esp. with (CF3)3COH, the r dyad increased to 62.6% from 53.5% for the atactic poly(NVP) obtained in the usual solvents. The 1H NMR anal. of the mixt. of NVP and the fluoroalcs. indicated that a 1:1 hydrogen-bonding complex was formed, suggesting that the complex was responsible for the tacticity control of the polymer. When the CTA was used in the fluoroalcs., the living and syndiospecific polymn. proceeded to enable the simultaneous control of the mol. wt. and the tacticity.
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    Kang, H. U.; Yu, Y. C.; Shin, S. J.; Kim, J.; Youk, J. H. One-Pot Synthesis of Poly(N-Vinylpyrrolidone)-b-Poly(ε-Caprolactone) Block Copolymers Using a Dual Initiator for RAFT Polymerization and ROP. Macromolecules 2013, 46 (4), 1291– 1295,  DOI: 10.1021/ma302372h
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    One-Pot Synthesis of Poly(N-vinylpyrrolidone)-b-poly(ε-caprolactone) Block Copolymers Using a Dual Initiator for RAFT Polymerization and ROP
    Kang, Hyun Uk; Yu, Young Chang; Shin, Sang Jin; Kim, Jinsang; Youk, Ji Ho
    Macromolecules (Washington, DC, United States) (2013), 46 (4), 1291-1295CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
    Well-defined amphiphilic poly(N-vinylpyrrolidone)-b-poly(ε-caprolactone) (PVP-b-PCL) block copolymers were synthesized at 30° using a hydroxyl-functionalized xanthate reversible addn.-fragmentation chain transfer (RAFT) agent, 2-hydroxyethyl 2-(ethoxycarbonothioylthio)propanoate, as a dual initiator for RAFT polymn. and ring-opening polymn. (ROP) in a one-pot procedure. Hydrophilic PCL blocks were first synthesized via the ROP of ε-caprolactone (CL) using di-Ph phosphate as a catalyst followed by the RAFT polymn. of N-vinylpyrrolidone (VP) by the addn. of VP and 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70) to the reaction mixt. VP quenched the ROP of CL, and V-70 initiated the RAFT polymn. of VP. The resulting PVP-b-PCL block copolymers showed very narrow mol. wt. distributions, indicating that the ROP and RAFT polymn. proceeded independently in a controlled manner. To the best of our knowledge, this one-pot process is the most convenient method for the synthesis of PVP-b-PCL block copolymers. The PVP-b-PCL block copolymers could be labeled fluorescently through a reaction with rhodamine B isothiocyanate in the same pot.
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    Zhou, W.; Qu, Q.; Xu, Y.; An, Z. Aqueous Polymerization-Induced Self-Assembly for the Synthesis of Ketone-Functionalized Nano-Objects with Low Polydispersity. ACS Macro Lett. 2015, 4 (5), 495– 499,  DOI: 10.1021/acsmacrolett.5b00225
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    Aqueous Polymerization-Induced Self-Assembly for the Synthesis of Ketone-Functionalized Nano-Objects with Low Polydispersity
    Zhou, Wei; Qu, Qingwu; Xu, Yuanyuan; An, Zesheng
    ACS Macro Letters (2015), 4 (5), 495-499CODEN: AMLCCD; ISSN:2161-1653. (American Chemical Society)
    Efficient synthesis of functionalized, uniform polymer nano-objects in water with controlled morphologies in one step and at high concns. is extremely attractive, from perspectives of both materials applications and industrial scale-up. Herein, we report a novel formulation for aq. reversible addn.-fragmentation chain transfer (RAFT) dispersion polymn. based on polymn.-induced self-assembly (PISA) to synthesize ketone-functionalized nanospheres and vesicles. Significantly, the core-forming block was composed entirely of a ketone-contg. polymer from a commodity monomer diacetone acrylamide (DAAM), resulting in a high d. of ketone functionality in the nano-objects. Producing uniform vesicles represents another challenge both in PISA and in the traditional self-assembly process. Aiming at producing uniform nano-objects, esp. vesicles, in such a highly efficient aq. PISA process, we devised strategies to allow sufficient time for the in situ generated polymers to relax and reorganize into vesicles with a remarkably low polydispersity. Specifically, both reducing the radical initiator concn. and lowering the polymn. temp. were effective for improving the uniformity of vesicles. Such an efficient, aq. PISA to produce functionalized and uniform nano-objects with controlled morphologies at solid contents up to 20% represents important progress in the field.
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    Parkinson, S.; Hondow, N. S.; Conteh, J. S.; Bourne, R. A.; Warren, N. J. All-Aqueous Continuous-Flow RAFT Dispersion Polymerisation for Efficient Preparation of Diblock Copolymer Spheres Worms and Vesicles. React. Chem. Eng. 2019, 4 (5), 852– 861,  DOI: 10.1039/C8RE00211H
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    All-aqueous continuous-flow RAFT dispersion polymerisation for efficient preparation of diblock copolymer spheres, worms and vesicles
    Parkinson, Sam; Hondow, Nicole S.; Conteh, John S.; Bourne, Richard A.; Warren, Nicholas J.
    Reaction Chemistry & Engineering (2019), 4 (5), 852-861CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)
    We report the scalable, all-aq. synthesis of poly(dimethylacrylamide)-poly(diacetone acrylamide) (PDMAm-PDAAm) diblock copolymer spheres, worms and vesicles by reversible addn.-fragmentation chain transfer (RAFT) aq. dispersion polymn. in a low-cost continuous-flow (CF) reactor. A transient state kinetic profiling method using a 5 mL reactor coil indicated a considerably faster rate than the equiv. batch reaction. Higher throughput was subsequently demonstrated by employing a 20 mL coil reactor for the synthesis of a 135 g, 30% wt./wt. batch of PDMAm113 macromol. chain transfer agent (macro-CTA) at 98% conversion. This was used without further purifn. to polymerise DAAm in a CF reactor. During this polymn., the chains underwent polymn.-induced self-assembly (PISA) producing block copolymer spheres. This reaction also proceeded faster than in batch, and the high resoln. kinetics enabled clear observation of the rate enhancement which is characteristic of PISA systems. GPC studies indicated the formation of a copolymer with low molar mass dispersity and complete blocking efficiency, despite the high conversion achieved during the precursor macro-CTA synthesis. It was subsequently demonstrated that the PDMAm113 macro-CTA could be used to prep. PDMAm113-PDAAmx block copolymer spheres (where x = 50, 100 and 200) with systematically increasing particle diams. Finally, by reducing the PDMAm macro-CTA DP to 50 and increasing total solids to 20% wt./wt., it was possible to prep. worms and vesicles in the tubular reactor by tailoring the residence time to achieve specific degrees of polymn. of the PDAAm block.
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    Tuning Hydrophobicity To Program Block Copolymer Assemblies from the Inside Out
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    Macromolecules (Washington, DC, United States) (2017), 50 (3), 935-943CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
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    Hydration Index-A Better Parameter for Explaining Small Molecule Hydration in Inhibition of Ice Recrystallization
    Tam, Roger Y.; Ferreira, Sandra S.; Czechura, Pawel; Chaytor, Jennifer L.; Ben, Robert N.
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    Several simple mono- and disaccharides have been assessed for their ability to inhibit ice recrystn. Two carbohydrates were found to be effective recrystn. inhibitors. D-Galactose was the best monosaccharide and D-melibiose was the most active disaccharide. The ability of each carbohydrate to inhibit ice growth was correlated to its resp. hydration no. reported in the literature. A hydration no. reflects the no. of tightly bound water mols. to the carbohydrate and is a function of carbohydrate stereochem. It was discovered that using the abs. hydration no. of a carbohydrate does not allow one to accurately predict its ability to inhibit ice recrystn. Consequently, we have defined a hydration index in which the hydration no. is divided by the molar volume of the carbohydrate. This new parameter not only takes into account the no. of water mols. tightly bound to a carbohydrate but also the size or vol. of a particular solute and ultimately the concn. of hydrated water mols. The hydration index of both mono- and disaccharides correlates well with exptl. measured RI activity. C-Linked derivs. of the monosaccharides appear to have RI activity comparable to that of their O-linked saccharides but a more thorough investigation is required. The relationship between carbohydrate concn. and RI activity was shown to be noncolligative and a 0.022 M soln. of D-galactose (1) and C-linked galactose deriv. (10) inhibited recrystn. as well as a 3% DMSO soln. The carbohydrates examd. in this study did not possess any thermal hysteresis activity (selective depression of f.p. relative to m.p.) or dynamic ice shaping. As such, we propose that they are inhibiting recrystn. at the interface between bulk water and the quasi liq. layer (a semiordered interface between ice and bulk water) by disrupting the preordering of water.
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  • Abstract

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    Figure 1

    Figure 1. Synthesis of PEG-corona PISA-derived nanoparticles. (A) Synthesis of PEG45-b-PDAAmn diblock copolymer nanoparticles via aqueous RAFT-mediated PISA using a commercially available PEG45 macro-CTA ([solids] = 10% w/w, [NaCl] = 0.05 M). (B) Normalized SEC RI molecular weight distributions. Mn,SEC and ĐM values were calculated from PMMA standards with DMF + 5 mM NH4BF4 as the eluent. (C) Evolution of Mn (black circles) and ĐM (red circles) values with increasing targeted DPPDAAm. (D) Zeta potential values for PEG45-b-PDAAmn diblock copolymer nanoparticles. (E) Representative dry-state images of PEG45-b-PDAAmn diblock copolymer nanoparticles, stained with 1 wt % uranyl acetate (UA) solution. (F) Intensity-weighted size distributions along with average Dh and PD values (the error shows the standard deviation from five repeat measurements).

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    Figure 2

    Figure 2. Assessment of ice recrystallization inhibition activity for PEG-based nanoparticles. (A) IRI activity summary of PEG45-b-PDAAmn nanoparticles corrected to [PEG]. Error bars are ± SD from a minimum of three repeats (key: S, spherical micelles; W, worm-like micelles; V, vesicles). The percent mean grain size (MGS) was reported relative to saline control ([NaCl] = 0.05 M). (B) Example cryomicrographs of ice wafers from the “splat” assay of PEG45-b-PDAAmn nanoparticles, [PEG] = 10 mg mL–1.

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    Figure 3

    Figure 3. Synthesis, characterization, and ice recrystallization inhibition activity of PEG-coronal nanoparticles using PiBuOMAm- and PDAAm-based cores. (A) PEG45-b-PiBuOMAm100, (B) PEG113-b-PDAAm100 (i), and PEG113-b-PDAAm400 vesicles (ii) synthesized at [solids] = 10% w/w via aqueous RAFT-mediated PISA in the presence of [NaCl] = 0.05 M with commercially available PEG45 and PEG113 macro-RAFT agents. Insets show intensity-weighted size distributions along with average Dh and PD values (the error shows the standard deviation from five repeat measurements) and representative dry-state TEM images stained with 1 wt % uranyl acetate (UA) solution. (C) IRI activity summary corrected to [PEG].

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    Figure 4

    Figure 4. Summary of PISA formulation using non-PEG-based coronas. (A) Synthesis of PVP40-b-PDAAmn diblock copolymer nanoparticles via aqueous RAFT/MADIX-mediated PISA. PVP40 macro-CTA was synthesized by photoinitiated RAFT polymerization ([solids] = 20% w/w, [NaCl] = 0.05 M). (B) Representative dry-state TEM images of PVP40-b-PDAAmn diblock copolymer nanoparticles, stained with 1 wt % uranyl acetate (UA) solution. (C) Normalized intensity-weighted size distributions obtained by DLS. (D) Zeta potential values for PVP40-b-PDAAmn diblock copolymer nanoparticles. (E) Synthesis of PDMAC40-b-PDAAm200 diblock copolymer vesicles via aqueous RAFT-mediated PISA using a PDMAC40 macro-CTA ([solids] = 20% w/w, [NaCl] = 0.05 M). (F) (i) Representative dry state and (ii) cryo-TEM images; (iii) intensity-weighted size distribution along with average Dh and PD values (the error shows the standard deviation from five repeat measurements). Inset: autocorrelation function.

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    Figure 5

    Figure 5. Ice recrystallization inhibition (IRI) activity of PVP and PDMAC-based nanoparticles. (A) PVP40-b-PDAAmn nanoparticles corrected to total PVP concentration in particle format. (B) PVP40-b-PDAAmn nanoparticles at [PVP] = 10 mg.mL–1. (C) PDMAC40-b-PDAAm200 diblock copolymer vesicles and PDMAC40 corrected to [PDMAC]. (D) Comparison of IRI activity for diblock copolymer vesicles of PVP40-b-PDAAm200, PDMAC40-b-PDAAm200, and PEG45-b-PDAAm150. Error bars are ± SD from a minimum of three repeats. The percent mean grain size (MGS) was reported relative to saline control. [PVP] was recalibrated based on chain extended PVP40 present particle format after estimating amount of unconsumed PVP40 macro-CTA based on Table S3 data.

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    Figure 6

    Figure 6. Ice binding and ice nucleation analysis of nanoparticles. (A) Modified “sucrose sandwich” ice shaping assay images for 1 mg mL–1 of PEG45-b-PDAAm100 nanoparticles in 45 wt % sucrose solution; (B) 1 mg mL–1 of PVP40 and (C) 1 mg mL–1 of PVP40-b-PDAAm200. (D) Assessment of ice nucleation activity in microliter droplets showing immersion mode fraction frozen curves as a function of temperature for droplets containing 1 mg mL–1 PEG45-b-PDAAm150, PDMAC40-b-PDAAm200, and PVP40-b-PDAAm200 along with their corresponding macro-CTAs (E) and PVP40-b-PDAAmn (n = 25, 50, 100, 200) nanoparticle series. Example temperature errors bars are included on selected data points on panels D and E.

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    This article references 94 other publications.

    1. 1
      Bar Dolev, M.; Braslavsky, I.; Davies, P. L. Ice-Binding Proteins and Their Function. Annu. Rev. Biochem. 2016, 85 (1), 515– 542,  DOI: 10.1146/annurev-biochem-060815-014546
      1
      Ice-Binding Proteins and Their Function
      Bar Dolev, Maya; Braslavsky, Ido; Davies, Peter L.
      Annual Review of Biochemistry (2016), 85 (), 515-542CODEN: ARBOAW; ISSN:0066-4154. (Annual Reviews)
      A review. Ice-binding proteins (IBPs) are a diverse class of proteins that assist organism survival in the presence of ice in cold climates. They have different origins in many organisms, including bacteria, fungi, algae, diatoms, plants, insects, and fish. This review covers the gamut of IBP structures and functions and the common features they use to bind ice. We discuss mechanisms by which IBPs adsorb to ice and interfere with its growth, evidence for their irreversible assocn. with ice, and methods for enhancing the activity of IBPs. The applications of IBPs in the food industry, in cryopreservation, and in other technologies are vast, and we chart out some possibilities.
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    2. 2
      Guo, S.; Stevens, C. A.; Vance, T. D. R.; Olijve, L. L. C.; Graham, L. A.; Campbell, R. L.; Yazdi, S. R.; Escobedo, C.; Bar-Dolev, M.; Yashunsky, V. Structure of a 1.5-MDa Adhesin That Binds Its Antarctic Bacterium to Diatoms and Ice. Sci. Adv. 2017, 3 (8), e1701440,  DOI: 10.1126/sciadv.1701440
      2
      Structure of a 1.5-MDa adhesin that binds its Antarctic bacterium to diatoms and ice
      Guo, Shuaiqi; Stevens, Corey A.; Vance, Tyler D. R.; Olijve, Luuk L. C.; Graham, Laurie A.; Campbell, Robert L.; Yazdi, Saeed R.; Escobedo, Carlos; Bar-Dolev, Maya; Yashunsky, Victor; Braslavsky, Ido; Langelaan, David N.; Smith, Steven P.; Allingham, John S.; Voets, Ilja K.; Davies, Peter L.
      Science Advances (2017), 3 (8), e1701440/1-e1701440/10CODEN: SACDAF; ISSN:2375-2548. (American Association for the Advancement of Science)
      Bacterial adhesins are modular cell-surface proteins that mediate adherence to other cells, surfaces, and ligands. The Antarctic bacterium Marinomonas primoryensis uses a 1.5-MDa adhesin comprising over 130 domains to position it on ice at the top of the water column for better access to oxygen and nutrients. We have reconstructed this 0.6-mm-long adhesin using a "dissect and build" structural biol. approach and have established complementary roles for its five distinct regions. Domains in region I (RI) tether the adhesin to the type I secretion machinery in the periplasm of the bacterium and pass it through the outer membrane. RII comprises ∼120 identical immunoglobulinlike β-sandwich domains that rigidify on binding Ca2+ to project the adhesion regions RIII and RIV into the medium. RIII contains ligand-binding domains that join diatoms and bacteria together in a mixed-species community on the underside of sea ice where incident light is maximal. RIV is the ice-binding domain, and the terminal RV domain contains several "repeats-in-toxin" motifs and a noncleavable signal sequence that target proteins for export via the type I secretion system. Similar structural architecture is present in the adhesins of many pathogenic bacteria and provides a guide to finding and blocking binding domains to weaken infectivity.
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    3. 3
      Walters, K. R.; Serianni, A. S.; Sformo, T.; Barnes, B. M.; Duman, J. G. A Nonprotein Thermal Hysteresis-Producing Xylomannan Antifreeze in the Freeze-Tolerant Alaskan Beetle Upis Ceramboides. Proc. Natl. Acad. Sci. U. S. A. 2009, 106 (48), 20210– 20215,  DOI: 10.1073/pnas.0909872106
      3
      A nonprotein thermal hysteresis-producing xylomannan antifreeze in the freeze-tolerant Alaskan beetle Upis ceramboides
      Walters, Kent R., Jr.; Serianni, Anthony S.; Sformo, Todd; Barnes, Brian M.; Duman, John G.
      Proceedings of the National Academy of Sciences of the United States of America (2009), 106 (48), 20210-20215CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Thermal hysteresis (TH), a difference between the melting and f.ps. of a soln. that is indicative of the presence of large-mol.-mass antifreezes (e.g., antifreeze proteins), has been described in animals, plants, bacteria, and fungi. Although all previously described TH-producing biomols. are proteins, most thermal hysteresis factors (THFs) have not yet been structurally characterized, and none have been characterized from a freeze-tolerant animal. We isolated a highly active THF from the freeze-tolerant beetle, Upis ceramboides, by means of ice affinity. Amino acid chromatog. anal., PAGE, UV-Vis spectrophotometry, and NMR spectroscopy indicated that the THF contained little or no protein, yet it produced 3.7±0.3° of TH at 5 mg/mL, comparable to that of the most active insect antifreeze proteins. Compositional and structural analyses indicated that this antifreeze contains a β-mannopyranosyl-(1→4) β-xylopyranose backbone and a fatty acid component, although the lipid may not be covalently linked to the saccharide. Consistent with the proposed structure, treatment with endo-β-(1→4)xylanase ablated TH activity. This xylomannan is the first TH-producing antifreeze isolated from a freeze-tolerant animal and the first in a new class of highly active THFs that contain little or no protein.
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    4. 4
      Dreischmeier, K.; Budke, C.; Wiehemeier, L.; Kottke, T.; Koop, T. Boreal Pollen Contain Ice-Nucleating as Well as Ice-Binding ‘Antifreeze’ Polysaccharides. Sci. Rep. 2017, 7, 41890,  DOI: 10.1038/srep41890
      4
      Boreal pollen contain ice-nucleating as well as ice-binding 'antifreeze' polysaccharides
      Dreischmeier, Katharina; Budke, Carsten; Wiehemeier, Lars; Kottke, Tilman; Koop, Thomas
      Scientific Reports (2017), 7 (), 41890CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
      Ice nucleation and growth is an important and widespread environmental process. Accordingly, nature has developed means to either promote or inhibit ice crystal formation, for example ice-nucleating proteins in bacteria or ice-binding antifreeze proteins in polar fish. Recently, it was found that birch pollen release ice-nucleating macromols. when suspended in water. Here we show that birch pollen washing water exhibits also ice-binding properties such as ice shaping and ice recrystn. inhibition, similar to antifreeze proteins. We present spectroscopic evidence that both the ice-nucleating as well as the ice-binding mols. are polysaccharides bearing carboxylate groups. The spectra suggest that both polysaccharides consist of very similar chem. moieties, but centrifugal filtration indicates differences in mol. size: ice nucleation occurs only in the supernatant of a 100 kDa filter, while ice shaping is strongly enhanced in the filtrate. This finding may suggest that the larger ice-nucleating polysaccharides consist of clusters of the smaller ice-binding polysaccharides, or that the latter are fragments of the ice-nucleating polysaccharides. Finally, similar polysaccharides released from pine and alder pollen also display both ice-nucleating as well as ice-binding ability, suggesting a common mechanism of interaction with ice among several boreal pollen with implications for atm. processes and antifreeze protection.
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    5. 5
      Celik, Y.; Graham, L. A.; Mok, Y.-F.; Bar, M.; Davies, P. L.; Braslavsky, I. Superheating of Ice Crystals in Antifreeze Protein Solutions. Proc. Natl. Acad. Sci. U. S. A. 2010, 107 (12), 5423– 5428,  DOI: 10.1073/pnas.0909456107
      5
      Superheating of ice crystals in antifreeze protein solutions
      Celik, Yeliz; Graham, Laurie A.; Mok, Yee-Foong; Bar, Maya; Davies, Peter L.; Braslavky, Ido
      Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (12), 5423-5428, S5423/1-S5423/7CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      It has been argued that for antifreeze proteins (AFPs) to stop ice crystal growth, they must irreversibly bind to the ice surface. Surface-adsorbed AFPs should also prevent ice from melting, but to date this has been demonstrated only in a qual. manner. Here we present the first quant. measurements of superheating of ice in AFP solns. Superheated ice crystals were stable for hours above their equil. m.p., and the max. superheating obtained was 0.44°C. When melting commenced in this superheated regime, rapid melting of the crystals from a point on the surface was obsd. This increase in melting temp. was more appreciable for hyperactive AFPs compared to the AFPs with moderate antifreeze activity. For each of the AFP solns. that exhibited superheating, the enhancement of the melting temp. was far smaller than the depression of the freezing temp. The present findings clearly show that AFPs adsorb to ice surfaces as part of their mechanism of action, and this absorption leads to protection of ice against melting as well as freezing.
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    6. 6
      Fitzner, M.; Sosso, G. C.; Cox, S. J.; Michaelides, A. The Many Faces of Heterogeneous Ice Nucleation: Interplay between Surface Morphology and Hydrophobicity. J. Am. Chem. Soc. 2015, 137 (42), 13658– 13669,  DOI: 10.1021/jacs.5b08748
      6
      The Many Faces of Heterogeneous Ice Nucleation: Interplay Between Surface Morphology and Hydrophobicity
      Fitzner, Martin; Sosso, Gabriele C.; Cox, Stephen J.; Michaelides, Angelos
      Journal of the American Chemical Society (2015), 137 (42), 13658-13669CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      The ability of generic cryst. substrates to promote ice nucleation has been examd. as a function of the hydrophobicity and the morphol. of the surface. Nucleation rates have been obtained by brute-force mol. dynamics simulations of coarse-grained water on top of different surfaces of a model fcc. crystal, varying the water-surface interaction and the surface lattice parameter. It turns out that the lattice mismatch of the surface with respect to ice, customarily regarded as the most important requirement for a good ice nucleating agent, is at most desirable but not a requirement. On the other hand, the balance between the morphol. of the surface and its hydrophobicity can significantly alter the ice nucleation rate and can also lead to the formation of up to three different faces of ice on the same substrate. Three circumstances where heterogeneous ice nucleation can be promoted by the cryst. surface were found: (i) the formation of a water overlayer that acts as an in-plane template; (ii) the emergence of a contact layer buckled in an ice-like manner; and (iii) nucleation on compact surfaces with very high interaction strength.
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    7. 7
      Duman, J. G. Antifreeze and Ice Nucleator Proteins in Terrestrial Arthropods. Annu. Rev. Physiol. 2001, 63 (1), 327– 357,  DOI: 10.1146/annurev.physiol.63.1.327
      7
      Antifreeze and ice nucleator proteins in terrestrial arthropods
      Duman, John G.
      Annual Review of Physiology (2001), 63 (), 327-357CODEN: ARPHAD; ISSN:0066-4278. (Annual Reviews Inc.)
      Terrestrial arthropods survive subzero temps. by becoming either freeze tolerant (survive body fluid freezing) or freeze avoiding (prevent body fluid freezing). Protein ice nucleators (PINs), which limit supercooling and induce freezing, and antifreeze proteins (AFPs), which function to prevent freezing, can have roles in both freeze tolerance and avoidance. Many freeze-tolerant insects produce hemolymph PINs, which induce freezing at high subzero temps. thereby inhibiting lethal intracellular freezing. Some freeze-tolerant species have AFPs that function as cryoprotectants to prevent freeze damage. Although the mechanism of this cryoprotection is not known, it may involve recrystn. inhibition and perhaps stabilization of the cell membrane. Freeze-avoiding species must prevent inoculative freezing initiated by external ice across the cuticle and extend supercooling abilities. Some insects remove PINs in the winter to promote supercooling, whereas others have selected against surfaces with ice-nucleating abilities on an evolutionary time scale. However, many freeze-avoiding species do have proteins with ice-nucleating activity, and these proteins must be masked in winter. In the beetle Dendroides canadensis, AFPs in the hemolymph and gut inhibit ice nucleators. Also, hemolymph AFPs and those assocd. with the layer of epidermal cells under the cuticle inhibit inoculative freezing. Two different insect AFPs have been characterized. One type from the beetles D. canadensis and Tenebrio molitor consists of 12- and 13-mer repeating units with disulfide bridges occurring at least every six residues. The spruce budworm AFP lacks regular repeat units. Both have much higher activities than any known AFPs.
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    8. 8
      Cochet, N.; Widehem, P. Ice Crystallization by Pseudomonas Syringae. Appl. Microbiol. Biotechnol. 2000, 54 (2), 153– 161,  DOI: 10.1007/s002530000377
      8
      Ice crystallization by Pseudomonas syringae
      Cochet, N.; Widehem, P.
      Applied Microbiology and Biotechnology (2000), 54 (2), 153-161CODEN: AMBIDG; ISSN:0175-7598. (Springer-Verlag)
      A review with 89 refs. Several bacterial species can serve as biol. ice nuclei. The best characterized of these is Pseudomonas syringae, a widely distributed bacterial epiphyte of plants. These biol. ice nuclei find various applications in different fields, but an optimized prodn. method was required in order to obtain the highly active cells which may be exploited as ice nucleators. The results presented here show that P. syringae cells reduce supercooling of liq. or solid media and enhance ice crystal formation at sub-zero temps., thus leading to a remarkable control of the crystn. phenomenon and a potential for energy savings. This discussion focuses on recent and future applications of these ice nucleators in freezing operations, spray-ice technol. and biotechnol. processes.
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    9. 9
      Fowler, A.; Toner, M. Cryo-Injury and Biopreservation. Ann. N. Y. Acad. Sci. 2005, 1066, 119– 135,  DOI: 10.1196/annals.1363.010
      9
      Cryo-injury and biopreservation
      Fowler, Alex; Toner, Mehmet
      Annals of the New York Academy of Sciences (2005), 1066 (Cell Injury), 119-135CODEN: ANYAA9; ISSN:0077-8923. (New York Academy of Sciences)
      A review. Mammalian cells appear to be naturally tolerant to cold temps., but the formation of ice when cells are cooled leads to a variety of damaging effects. The study of cryo-injury, therefore, becomes the study of when and how ice is formed both inside and outside the cell during cooling. Protectant chems. are used to control or prevent ice formation in many preservation protocols, but these chem. themselves tend to be damaging. Cooling and warming rates also strongly affect the amt. and location of ice that is formed. Through careful modification of these parameters successful cold preservation techniques for many cell types have been developed, but there are many more cell types that have defied preservation techniques, and the extension of cell-based techniques to tissues and whole organs has been very limited. There are many aspects to the damaging effects of ice in cells that are still poorly understood. In this brief article we review our current understanding of cellular injury and highlight the aspects of cellular injury during cryopreservation that are still poorly understood.
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    10. 10
      Deller, R. C. R. C.; Vatish, M.; Mitchell, D. A. D. A.; Gibson, M. I. M. I. Synthetic Polymers Enable Non-Vitreous Cellular Cryopreservation by Reducing Ice Crystal Growth during Thawing. Nat. Commun. 2014, 5, 3244,  DOI: 10.1038/ncomms4244
      10
      Synthetic polymers enable non-vitreous cellular cryopreservation by reducing ice crystal growth during thawing
      Deller Robert C; Vatish Manu; Mitchell Daniel A; Gibson Matthew I
      Nature communications (2014), 5 (), 3244 ISSN:.
      The cryopreservation of cells, tissue and organs is fundamental to modern biotechnology, transplantation medicine and chemical biology. The current state-of-the-art method of cryopreservation is the addition of large amounts of organic solvents such as glycerol or dimethyl sulfoxide, to promote vitrification and prevent ice formation. Here we employ a synthetic, biomimetic, polymer, which is capable of slowing the growth of ice crystals in a manner similar to antifreeze (glyco)proteins to enhance the cryopreservation of sheep and human red blood cells. We find that only 0.1 wt% of the polymer is required to attain significant cell recovery post freezing, compared with over 20 wt% required for solvent-based strategies. These results demonstrate that synthetic antifreeze (glyco)protein mimics could have a crucial role in modern regenerative medicine to improve the storage and distribution of biological material for transplantation.
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    11. 11
      Matsumura, K.; Hyon, S. H. Polyampholytes as Low Toxic Efficient Cryoprotective Agents with Antifreeze Protein Properties. Biomaterials 2009, 30 (27), 4842– 4849,  DOI: 10.1016/j.biomaterials.2009.05.025
      11
      Polyampholytes as low toxic efficient cryoprotective agents with antifreeze protein properties
      Matsumura, Kazuaki; Hyon, Suong-Hyu
      Biomaterials (2009), 30 (27), 4842-4849CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      DMSO has been used for several decades as the most efficient cryoprotective agent (CPA) for many types of cells and tissues in spite of its cytotoxicity and its effects on differentiation. Here the authors report that polyampholytes with an appropriate ratio of amino and carboxyl groups show higher cryopreservation efficiency and lower cytotoxicity than DMSO. Culture medium solns. of ε-poly-L-lysine (PLL) with more than 50 mol% of amino groups carboxylated showed excellent post-thaw survival efficiency of 95% murine L929 cells, and rat mesenchymal stem cells fully retained the potential for differentiation without serum. The authors also found that carboxylated PLLs showed antifreeze protein properties, such as ice recrystn. inhibition, which may contribute to successful cryopreservation by membrane protection. Thus, these polyampholytes can replace DMSO as new materials for CPAs in various preserving functions and will also be useful in studies elucidating the mechanisms of cryopreservation.
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    12. 12
      Chao, H.; Davies, P. L.; Carpenter, J. F. Effects of Antifreeze Proteins on Red Blood Cell Survival during Cryopreservation. J. Exp. Biol. 1996, 199, 2071– 2076,  DOI: 10.1242/jeb.199.9.2071
      12
      Effects of antifreeze proteins on red blood cell survival during cryopreservation
      Chao, Heman; Davies, Peter L.; Carpenter, John F.
      Journal of Experimental Biology (1996), 199 (9), 2071-2076CODEN: JEBIAM; ISSN:0022-0949. (Company of Biologists)
      Antifreeze protein (AFP) types I, II and III were tested for their ability to protect red blood cells from lysis during warming, after cryopreservation in hydroxyethyl starch. All 3 types reduced hemolysis to 25% of control values at similar micromolar concns. but enhanced lysis as the AFP concn. approached millimolar levels. Site-directed mutants of type III AFP with different thermal hysteresis activities were tested for their ability to protect the cryopreserved cells from lysis. Their relative efficacy in protecting the cells correlated closely with their thermal hysteresis activity. Cryomicroscopy indicated that the protection of red cells by type III AFP and the mutant forms was due to inhibition of ice recrystn.
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      John Morris, G.; Acton, E. Controlled Ice Nucleation in Cryopreservation - A Review. Cryobiology 2013, 66 (2), 85– 92,  DOI: 10.1016/j.cryobiol.2012.11.007
      13
      Controlled ice nucleation in cryopreservation - A review
      John Morris, G.; Acton, Elizabeth
      Cryobiology (2013), 66 (2), 85-92CODEN: CRYBAS; ISSN:0011-2240. (Elsevier Ltd.)
      We review here for the first time, the literature on control of ice nucleation in cryopreservation. Water and aq. solns. have a tendency to undercool before ice nucleation occurs. Control of ice nucleation has been recognized as a crit. step in the cryopreservation of embryos and oocytes but is largely ignored for other cell types. We review the processes of ice nucleation and crystal growth in the soln. around cells and tissues during cryopreservation with an emphasis on non IVF applications. The extent of undercooling that is encountered during the cooling of various cryocontainers is defined and the methods that have been employed to control the nucleation of ice are examd. The effects of controlled ice nucleation on the structure of the sample and the outcome of cryopreservation of a range of cell types and tissues are presented and the phys. events which define the cellular response are discussed.Nucleation of ice is the most significant uncontrolled variable in conventional cryopreservation leading to sample to sample variation in cell recovery, viability and function and should be controlled to allow standardisation of cryopreservation protocols for cells for biobanking, cell based assays or clin. application. This intervention allows a way of increasing viability of cells and reducing variability between samples and should be included as std. operating procedures are developed.
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      Frazier, S. D.; Matar, M. G.; Osio-Norgaard, J.; Aday, A. N.; Delesky, E. A.; Srubar, W. V. Inhibiting Freeze-Thaw Damage in Cement Paste and Concrete by Mimicking Nature’s Antifreeze. Cell Reports Phys. Sci. 2020, 1 (6), 100060,  DOI: 10.1016/j.xcrp.2020.100060
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      Valarezo, W. O.; Lynch, F. T.; McGhee, R. J. Aerodynamic Performance Effects Due to Small Leading-Edge Ice (Roughness) on Wings and Tails. J. Aircr. 1993, 30 (6), 807– 812,  DOI: 10.2514/3.46420
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      Sidebottom, C.; Buckley, S.; Pudney, P.; Twigg, S.; Jarman, C.; Holt, C.; Telford, J.; McArthur, A.; Worrall, D.; Hubbard, R. Heat-Stable Antifreeze Protein from Grass. Nature 2000, 406 (6793), 256,  DOI: 10.1038/35018639
      16
      Phytochemistry: Heat-stable antifreeze protein from grass
      Sidebottom, Chris; Buckley, Sarah; Pudney, Paul; Twigg, Sarah; Jarman, Carl; Holt, Chris; Telford, Julia; McArthur, Andrew; Worrall, Dawn; Hubbard, Rod; Lillford, Peter
      Nature (London) (2000), 406 (6793), 256CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      There is no expanded citation for this reference.
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    17. 17
      Regand, A.; Goff, H. D. Ice Recrystallization Inhibition in Ice Cream as Affected by Ice Structuring Proteins from Winter Wheat Grass. J. Dairy Sci. 2006, 89 (1), 49– 57,  DOI: 10.3168/jds.S0022-0302(06)72068-9
      17
      Ice recrystallization inhibition in ice cream as affected by ice structuring proteins from winter wheat grass
      Regand, A.; Goff, H. D.
      Journal of Dairy Science (2006), 89 (1), 49-57CODEN: JDSCAE; ISSN:0022-0302. (American Dairy Science Association)
      Ice recrystn. in quiescently frozen sucrose solns. that contained some of the ingredients commonly found in ice cream and in ice cream manufd. under com. conditions, with or without ice structuring proteins (ISP) from cold-acclimated winter wheat grass ext. (AWWE), was assessed by bright field microscopy. In sucrose solns., crit. differences in moisture content, viscosity, ionic strength, and other properties derived from the presence of other ingredients (skim milk powder, corn syrup solids, locust bean gum) caused a redn. in ice crystal growth. Significant ISP activity in retarding ice crystal growth was obsd. in all solns. (44% for the most complex mix) contg. 0.13% total protein from AWWE. In heat-shocked ice cream, ice recrystn. rates were significantly reduced 40 and 46% with the addn. of 0.0025 and 0.0037% total protein from AWWE. The ISP activity in ice cream was not hindered by its inclusion in mix prior to pasteurization. A synergistic effect between ISP and stabilizer was obsd., as ISP activity was reduced in the absence of stabilizer in ice cream formulations. A remarkably smoother texture for ice creams contg. ISP after heat-shock storage was evident by sensory evaluation. The efficiency of ISP from AWWE in controlling ice crystal growth in ice cream was demonstrated.
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    18. 18
      Stubbs, C.; Bailey, T. L.; Murray, K.; Gibson, M. I. Polyampholytes as Emerging Macromolecular Cryoprotectants. Biomacromolecules 2020, 21 (7), 7– 17,  DOI: 10.1021/acs.biomac.9b01053
      18
      Polyampholytes as Emerging Macromolecular Cryoprotectants
      Stubbs, Christopher; Bailey, Trisha L.; Murray, Kathryn; Gibson, Matthew I.
      Biomacromolecules (2020), 21 (1), 7-17CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
      A review. Cellular cryopreservation is a platform technol. which underpins cell biol., biochem., biomaterials, diagnostics, and the cold chain for emerging cell-based therapies. This technique relies on effective methods for banking and shipping to avoid the need for continuous cell culture. The most common method to achieve cryopreservation is to use large vols. of org. solvent cryoprotective agents which can promote either a vitreous (ice free) phase or dehydrate and protect the cells. These methods are very successful but are not perfect: not all cell types can be cryopreserved and recovered, and the cells do not always retain their phenotype and function post-thaw. This Perspective Article will introduce polyampholytes as emerging macromol. cryoprotective agents and demonstrate they have the potential to impact a range of fields from cell-based therapies to basic cell biol. and may be able to improve, or replace, current solvent-based cryoprotective agents. Polyampholytes have been shown to be remarkable (mammalian cell) cryopreservation enhancers, but their mechanism of action is unclear, which may include membrane protection, solvent replacement, or a yet unknown protective mechanism, but it seems the modulation of ice growth (recrystn.) may only play a minor role in their function, unlike other macromol. cryoprotectants. This article will discuss their synthesis and summarize the state-of-the-art, including hypotheses of how they function, to introduce this exciting area of biomacromol. science.
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    19. 19
      Graham, B.; Bailey, T. L.; Healey, J. R. J.; Marcellini, M.; Deville, S.; Gibson, M. I. Polyproline as a Minimal Antifreeze Protein Mimic That Enhances the Cryopreservation of Cell Monolayers. Angew. Chem. 2017, 129 (50), 16157– 16160,  DOI: 10.1002/ange.201706703
      There is no corresponding record for this reference.
    20. 20
      Voets, I. K. From Ice-Binding Proteins to Bio-Inspired Antifreeze Materials. Soft Matter 2017, 13 (28), 4808– 4823,  DOI: 10.1039/C6SM02867E
      20
      From ice-binding proteins to bio-inspired antifreeze materials
      Voets, I. K.
      Soft Matter (2017), 13 (28), 4808-4823CODEN: SMOABF; ISSN:1744-6848. (Royal Society of Chemistry)
      Ice-binding proteins (IBP) facilitate survival under extreme conditions in diverse life forms. IBPs in polar fishes block further growth of internalized environmental ice and inhibit ice recrystn. of accumulated internal crystals. Algae use IBPs to structure ice, while ice adhesion is crit. for the Antarctic bacterium Marinomonas primoryensis. Successful translation of this natural cryoprotective ability into man-made materials holds great promise but is still in its infancy. This review covers recent advances in the field of ice-binding proteins and their synthetic analogs, highlighting fundamental insights into IBP functioning as a foundation for the knowledge-based development of cheap, bio-inspired mimics through scalable prodn. routes. Recent advances in the utilization of IBPs and their analogs to e.g. improve cryopreservation, ice-templating strategies, gas hydrate inhibition and other technologies are presented.
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    21. 21
      He, Z.; Liu, K.; Wang, J. Bioinspired Materials for Controlling Ice Nucleation, Growth, and Recrystallization. Acc. Chem. Res. 2018, 51 (5), 1082– 1091,  DOI: 10.1021/acs.accounts.7b00528
      21
      Bioinspired Materials for Controlling Ice Nucleation, Growth, and Recrystallization
      He, Zhiyuan; Liu, Kai; Wang, Jianjun
      Accounts of Chemical Research (2018), 51 (5), 1082-1091CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. Ice formation, mainly consisting of ice nucleation, ice growth, and ice recrystn., is ubiquitous and crucial in wide-ranging fields from cryobiol. to atm. physics. Despite active research for more than a century, the mechanism of ice formation is still far from satisfactory. Meanwhile, nature has unique ways of controlling ice formation and can provide resourceful avenues to unravel the mechanism of ice formation. For instance, antifreeze proteins (AFPs) protect living organisms from freezing damage via controlling ice formation, for example, tuning ice nucleation, shaping ice crystals, and inhibiting ice growth and recrystn. In addn., AFP mimics can have applications in cryopreservation of cells, tissues, and organs, food storage, and anti-icing materials. Therefore, continuous efforts have been made to understand the mechanism of AFPs and design AFP inspired materials.In this Account, the authors first review the authors' recent research progress in understanding the mechanism of AFPs in controlling ice formation. A Janus effect of AFPs on ice nucleation was discovered, which was achieved via selectively tethering the ice-binding face (IBF) or the non-ice-binding face (NIBF) of AFPs to solid surfaces and studying specifically the effect of the other face on ice nucleation. Through mol. dynamics (MD) simulation anal., the authors obsd. ordered hexagonal ice-like water structure atop the IBF and disordered water structure atop the NIBF. Therefore, the interfacial water plays a crit. role in controlling ice formation.Next, the design and fabrication of AFP mimics with capabilities in tuning ice nucleation and controlling ice shape and growth, as well as inhibiting ice recrystn are discussed. For example, the authors tuned ice nucleation via modifying solid surfaces with supercharged unfolded polypeptides (SUPs) and polyelectrolyte brushes (PBs) with different counterions. The authors found graphene oxide (GO) and oxidized quasi-carbon nitride quantum dots (OQCNs) had profound effects in controlling ice shape and inhibiting ice growth. The authors also studied the ion-specific effect on ice recrystn. inhibition (IRI) with a large variety of anions and cations. All functionalities are achieved by tuning the properties of interfacial water on these materials, which reinforces the importance of the interfacial water in controlling ice formation. Finally, the authors review the development of novel application-oriented materials emerging from the authors' enhanced understanding of ice formation, for example, ultralow ice adhesion coatings with aq. lubricating layer, cryopreservation of cells by inhibiting ice recrystn., and two-dimensional (2D) and three-dimensional (3D) porous materials with tunable pore sizes through recrystd. ice crystal templates. This Account sheds new light on the mol. mechanism of ice formation and will inspire the design of unprecedented functional materials based on controlled ice formation.
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    22. 22
      Gibson, M. I. Slowing the Growth of Ice with Synthetic Macromolecules: Beyond Antifreeze(Glyco) Proteins. Polym. Chem. 2010, 1 (8), 1141– 1152,  DOI: 10.1039/c0py00089b
      22
      Slowing the growth of ice with synthetic macromolecules: beyond antifreeze(glyco) proteins
      Gibson, Matthew I.
      Polymer Chemistry (2010), 1 (8), 1141-1152CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
      A review. Biol. antifreezes are a relatively large and diverse class of proteins (and very recently expanded to include lipopolysaccharides) which are capable of interacting with ice crystals in such a manner as to influence and, under the correct conditions, to prevent their growth. These properties allow for the survival of organisms which are either continuously or sporadically exposed to subzero temps. which would otherwise lead to cryo-injury/death. These proteins have been found in a range of organisms, including plants, bacteria, insects and fish, and the proteins themselves have a diverse range of chem. structures ranging from the highly conserved antifreeze glycoproteins (AFGPs) to the more diverse antifreeze proteins AFPs. Their unique abilities to non-colligatively decrease the f.p. of aq. solns., inhibit ice recrystn. and induce dynamic ice shaping suggest they will find many applications from cell/tissue/organ cryostorage, frozen food preservatives, texture enhancers or even as cryosurgery adjuvants. However, these applications have been limited by a lack of available material and also underlying questions regarding their mode of activity. The aim of this review article is to highlight the potential of polymeric materials to act as synthetic mimics of antifreeze(glyco) proteins, as well as to summarize the current general challenges in designing compds. capable of mimicking AF(G)Ps. This will cover the basic properties and modes of action of AF(G)Ps along with the methods commonly used to evaluate their activity. This section is essential to specifically define the 'antifreeze' terminol. in terms of these proteins' unique function and to distinguish them from conventional antifreezes. A detailed evaluation of the processes involved in AF(G)P activity is beyond the scope of this review, but the reader will be pointed towards relevant literature. This will then be placed in the context of modern polymer science, with a focus on the ability of synthetic polymers to display some type of specific antifreeze activity, which will be summarized. Finally, the potential applications of these materials will be highlighted and future avenues for their research and the challenges faced in achieving these goals suggested.
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    23. 23
      Qiu, Y.; Hudait, A.; Molinero, V. How Size and Aggregation of Ice-Binding Proteins Control Their Ice Nucleation Efficiency. J. Am. Chem. Soc. 2019, 141 (18), 7439– 7452,  DOI: 10.1021/jacs.9b01854
      23
      How Size and Aggregation of Ice-Binding Proteins Control Their Ice Nucleation Efficiency
      Qiu, Yuqing; Hudait, Arpa; Molinero, Valeria
      Journal of the American Chemical Society (2019), 141 (18), 7439-7452CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Organisms that thrive at cold temps. produce ice-binding proteins to manage the nucleation and growth of ice. Bacterial ice-nucleating proteins (INP) are typically large and form aggregates in the cell membrane, while insect hyperactive antifreeze proteins (AFP) are sol. and generally small. Expts. indicate that larger ice-binding proteins and their aggregates nucleate ice at warmer temps. Nevertheless, a quant. understanding of how size and aggregation of ice-binding proteins det. the temp. Thet at which proteins nucleate ice is still lacking. Here, we address this question using mol. simulations and nucleation theory. The simulations indicate that the 2.5 nm long antifreeze protein TmAFP nucleates ice at 2 ± 1 °C above the homogeneous nucleation temp., in good agreement with recent expts. We predict that the addn. of ice-binding loops to TmAFP increases Thet, but not enough to compete in efficiency with the bacterial INP. We implement an accurate procedure to det. Thet of surfaces of finite size using classical nucleation theory, and, after validating the theory against Thet of the proteins in mol. simulations, we use it to predict Thet of the INP of Ps. syringae as a function of the length and no. of proteins in the aggregates. We conclude that assemblies with at most 34 INP already reach the Thet = -2 °C characteristic of this bacterium. Interestingly, we find that Thet is a strongly varying nonmonotonic function of the distance between proteins in the aggregates. This indicates that, to achieve max. freezing efficiency, bacteria must exert exquisite, subangstrom control of the distance between INP in their membrane.
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    24. 24
      Biggs, C. I.; Bailey, T. L.; Ben Graham; Stubbs, C.; Fayter, A.; Gibson, M. I. Polymer Mimics of Biomacromolecular Antifreezes. Nat. Commun. 2017, 8 (1), 1546,  DOI: 10.1038/s41467-017-01421-7
      24
      Polymer mimics of biomacromolecular antifreezes
      Biggs Caroline I; Bailey Trisha L; Ben Graham; Stubbs Christopher; Fayter Alice; Gibson Matthew I; Gibson Matthew I
      Nature communications (2017), 8 (1), 1546 ISSN:.
      Antifreeze proteins from polar fish species are remarkable biomacromolecules which prevent the growth of ice crystals. Ice crystal growth is a major problem in cell/tissue cryopreservation for transplantation, transfusion and basic biomedical research, as well as technological applications such as icing of aircraft wings. This review will introduce the rapidly emerging field of synthetic macromolecular (polymer) mimics of antifreeze proteins. Particular focus is placed on designing polymers which have no structural similarities to antifreeze proteins but reproduce the same macroscopic properties, potentially by different molecular-level mechanisms. The application of these polymers to the cryopreservation of donor cells is also introduced.
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    25. 25
      Sun, T.; Lin, F.-H.; Campbell, R. L.; Allingham, J. S.; Davies, P. L. An Antifreeze Protein Folds with an Interior Network of More than 400 Semi-Clathrate Waters. Science 2014, 343 (6172), 795– 798,  DOI: 10.1126/science.1247407
      25
      An Antifreeze Protein Folds with an Interior Network of More Than 400 Semi-Clathrate Waters
      Sun, Tianjun; Lin, Feng-Hsu; Campbell, Robert L.; Allingham, John S.; Davies, Peter L.
      Science (Washington, DC, United States) (2014), 343 (6172), 795-798CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      When polypeptide chains fold into a protein, hydrophobic groups are compacted in the center with exclusion of water. We report the crystal structure of the antifreeze protein (AFP) Maxi, a large isoform of the 3-kD alanine-rich AFP from Pseudopleuronectes americanus, that retains ∼400 waters in its core. The putative ice-binding residues of this dimeric, four-helix bundle protein point inwards and coordinate the interior waters into two intersecting polypentagonal networks. The bundle makes minimal protein contacts between helixes, but is stabilized by anchoring to the semi-clathrate water monolayers through backbone carbonyl groups in the protein interior. The ordered waters extend outwards to the protein surface and likely are involved in ice binding. This protein fold supports both the anchored-clathrate water mechanism of antifreeze protein adsorption to ice and the water-expulsion mechanism of protein folding.
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    26. 26
      Marshall, C. B.; Daley, M. E.; Sykes, B. D.; Davies, P. L. Enhancing the Activity of a β-Helical Antifreeze Protein by the Engineered Addition of Coils. Biochemistry 2004, 43 (37), 11637– 11646,  DOI: 10.1021/bi0488909
      26
      Enhancing the Activity of a β-Helical Antifreeze Protein by the Engineered Addition of Coils
      Marshall, Christopher B.; Daley, Margaret E.; Sykes, Brian D.; Davies, Peter L.
      Biochemistry (2004), 43 (37), 11637-11646CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
      The effectiveness of natural antifreeze proteins in inhibiting the growth of a seed ice crystal seems to vary with protein size. Here we have made use of the extreme regularity of the β-helical antifreeze protein from the beetle Tenebrio molitor to explore systematically the relationship between antifreeze activity and the area of the ice-binding site. Each of the 12-amino acid, disulfide-bonded central coils of the β-helix contains a Thr-Xaa-Thr ice-binding motif. By adding coils to, and deleting coils from, the seven-coil parent antifreeze protein, we have made a series of constructs with 6-11 coils. Misfolded forms of these antifreezes were removed by ice affinity purifn. to accurately compare the specific activity of each construct. There was a 10-100-fold gain in activity upon going from six to nine coils, depending on the concn. that was compared. Activity was maximal for the nine-coil construct, which gave a f.p. depression of 6.5 C° at 0.7 mg/mL, but actually decreased for the 10- and 11-coil constructs. This small loss in activity might result from the accumulation of a slight mismatch between the spacing of the ice-binding threonine residues and the O atoms of the ice lattice.
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    27. 27
      Congdon, T.; Notman, R.; Gibson, M. I. Antifreeze (Glyco)Protein Mimetic Behavior of Poly(Vinyl Alcohol): Detailed Structure Ice Recrystallization Inhibition Activity Study. Biomacromolecules 2013, 14 (5), 1578– 1586,  DOI: 10.1021/bm400217j
      27
      Antifreeze (Glyco)protein Mimetic Behavior of Poly(vinyl alcohol): Detailed Structure Ice Recrystallization Inhibition Activity Study
      Congdon, Thomas; Notman, Rebecca; Gibson, Matthew I.
      Biomacromolecules (2013), 14 (5), 1578-1586CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
      This manuscript reports a detailed study on the ability of poly(vinyl alc.) to act as a biomimetic surrogate for AF(G)Ps ("antifreeze(glyco)proteins"), with a focus on the specific property of ice-recrystn. inhibition (IRI). Despite over 40 years of study, the underlying mechanisms that govern the action of biol. antifreezes are still poorly understood, which is in part due to their limited availability and challenging synthesis. Poly(vinyl alc.) (PVA) has been shown to display remarkable ice recrystn. inhibition activity despite its major structural differences to native antifreeze proteins. Here, controlled radical polymn. is used to synthesize well-defined PVA, which has enabled us to obtain the first quant. structure-activity relationships, to probe the role of mol. wt. and comonomers on IRI activity. Crucially, it was found that IRI activity is "switched on" when the polymer chain length increases from 10 and 20 repeat units. Substitution of the polymer side chains with hydrophilic or hydrophobic units was found to diminish activity. Hydrophobic modifications to the backbone were slightly more tolerated than side chain modifications, which implies an unbroken sequence of hydroxyl units is necessary for activity. These results highlight the idea that although hydrophobic domains are key components of IRI activity, the random inclusion of addnl. hydrophobic units does not guarantee an increase in activity and that the actual polymer conformation is important.
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    28. 28
      Naullage, P. M.; Lupi, L.; Molinero, V. Molecular Recognition of Ice by Fully Flexible Molecules. J. Phys. Chem. C 2017, 121 (48), 26949– 26957,  DOI: 10.1021/acs.jpcc.7b10265
      28
      Molecular Recognition of Ice by Fully Flexible Molecules
      Naullage, Pavithra M.; Lupi, Laura; Molinero, Valeria
      Journal of Physical Chemistry C (2017), 121 (48), 26949-26957CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      Cold-acclimatized organisms produce antifreeze proteins that enable them to prevent ice growth and recrystn. at subfreezing conditions. Flatness and rigidity of the ice-binding sites of antifreeze proteins are considered key for their recognition of ice. However, the most potent synthetic ice recrystn. inhibitor (IRI) found to date is polyvinyl alc. (PVA), a fully flexible mol. The ability to tune the architecture and functionalization of PVA makes it a promising candidate to replace antifreeze proteins in industrial applications ranging from cryopreservation of organs to de-icing of turbine blades. However, an understanding of how PVA recognizes ice remains elusive, hampering the design of more effective IRIs. Here, we used large-scale mol. dynamics simulations to elucidate the mechanism by which PVA recognizes ice. We found that the polymer selectively bound to the prismatic faces of ice through a cooperative zipper mechanism. The binding was driven by H-bonding, facilitated by distance matching between the OH groups in PVA and water at the ice surface. Strong, cooperative binding to ice results from the different scaling of the free energy gains on binding per monomer, and the loss of translational and configurational entropy of the chain. We explained why branching of PVA does not improve its IRI activity, and used the new mol. understanding to propose principles for the design of macromols. that bind efficiently to the basal and prismatic planes of ice, producing hyperactive synthetic antifreeze mols. that could compete with the most effective antifreeze proteins.
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    29. 29
      Whale, T. F.; Rosillo-Lopez, M.; Murray, B. J.; Salzmann, C. G. Ice Nucleation Properties of Oxidized Carbon Nanomaterials. J. Phys. Chem. Lett. 2015, 6 (15), 3012– 3016,  DOI: 10.1021/acs.jpclett.5b01096
      29
      Ice Nucleation Properties of Oxidized Carbon Nanomaterials
      Whale, Thomas F.; Rosillo-Lopez, Martin; Murray, Benjamin J.; Salzmann, Christoph G.
      Journal of Physical Chemistry Letters (2015), 6 (15), 3012-3016CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)
      Heterogeneous ice nucleation is an important process in many fields, particularly atm. science, but is still poorly understood. All known inorg. ice nucleating particles are relatively large in size and tend to be hydrophilic. Hence it is not obvious that carbon nanomaterials should nucleate ice. However, in this paper we show that four different readily water-dispersible carbon nanomaterials are capable of nucleating ice. The tested materials were carboxylated graphene nanoflakes, graphene oxide, oxidized single walled carbon nanotubes and oxidized multiwalled carbon nanotubes. The carboxylated graphene nanoflakes have a diam. of ∼30 nm and are among the smallest entities obsd. so far to nucleate ice. Overall, carbon nanotubes were found to nucleate ice more efficiently than flat graphene species, and less oxidized materials nucleated ice more efficiently than more oxidized species. These well-defined carbon nanomaterials may pave the way to bridging the gap between exptl. and computational studies of ice nucleation.
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    30. 30
      Geng, H.; Liu, X.; Shi, G.; Bai, G.; Ma, J.; Chen, J.; Wu, Z.; Song, Y.; Fang, H.; Wang, J. Graphene Oxide Restricts Growth and Recrystallization of Ice Crystals. Angew. Chem., Int. Ed. 2017, 56 (4), 997– 1001,  DOI: 10.1002/anie.201609230
      30
      Graphene Oxide Restricts Growth and Recrystallization of Ice Crystals
      Geng, Hongya; Liu, Xing; Shi, Guosheng; Bai, Guoying; Ma, Ji; Chen, Jingbo; Wu, Zhuangyuan; Song, Yanlin; Fang, Haiping; Wang, Jianjun
      Angewandte Chemie, International Edition (2017), 56 (4), 997-1001CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The authors show graphene oxide (GO) greatly suppresses the growth and recrystn. of ice crystals, and ice crystals display a hexagonal shape in the GO dispersion. Preferred adsorption of GO on the ice crystal surface in liq. H2O leads to curved ice crystal surface. Therefore, the growth of ice crystal is suppressed owing to the Gibbs-Thompson effect, i.e., the curved surface lowers the freezing temp. Mol. dynamics simulation anal. reveals that oxidized groups on the basal plane of GO form more H bonds with ice in comparison with liq. H2O because of the honeycomb hexagonal scaffold of graphene, giving a mol.-level mechanism for controlling ice formation. Application of GO for cryopreservation shows that addn. of only 0.01% of GO to a culture medium greatly increases the motility (from 24.3% to 71.3 %) of horse sperms. This work reports the control of growth of ice with GO, and opens a new avenue for the application of 2D materials.
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    31. 31
      Biggs, C. I.; Packer, C.; Hindmarsh, S.; Walker, M.; Wilson, N. R.; Rourke, J. P.; Gibson, M. I. Impact of Sequential Surface-Modification of Graphene Oxide on Ice Nucleation. Phys. Chem. Chem. Phys. 2017, 19 (33), 21929– 21932,  DOI: 10.1039/C7CP03219F
      31
      Impact of sequential surface-modification of graphene oxide on ice nucleation
      Biggs, Caroline I.; Packer, Christopher; Hindmarsh, Steven; Walker, Marc; Wilson, Neil R.; Rourke, Jonathan P.; Gibson, Matthew I.
      Physical Chemistry Chemical Physics (2017), 19 (33), 21929-21932CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
      Base-washed graphene-oxide which has been sequentially-modified by thiol-epoxy chem., results in materials with ice-nucleation activity. The role of hydrophilic and hydrophobic grafts and polymers was evaluated with the most potent functioning at just 0.25 wt.%. These 2D hybrid materials may find use in cryopreservation and fundamental studies on ice formation.
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    32. 32
      Drori, R.; Li, C.; Hu, C.; Raiteri, P.; Rohl, A. L.; Ward, M. D.; Kahr, B. A Supramolecular Ice Growth Inhibitor. J. Am. Chem. Soc. 2016, 138 (40), 13396– 13401,  DOI: 10.1021/jacs.6b08267
      32
      A Supramolecular Ice Growth Inhibitor
      Drori, Ran; Li, Chao; Hu, Chunhua; Raiteri, Paolo; Rohl, Andrew L.; Ward, Michael D.; Kahr, Bart
      Journal of the American Chemical Society (2016), 138 (40), 13396-13401CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Safranine O, a synthetic dye, was found to inhibit growth of ice at mM concns. with an activity comparable to that of highly evolved antifreeze glycoproteins. Safranine inhibits growth of ice crystals along the crystallog. a-axis, resulting in bipyramidal needles extended along the <0001> directions as well as and plane-specific thermal hysteresis (TH) activity. The interaction of safranine with ice is reversible, distinct from the previously reported behavior of antifreeze proteins. Spectroscopy and mol. dynamics indicate that safranine forms aggregates in aq. soln. at μM concns. Metadynamics simulations and aggregation theory suggested that as many as 30 safranine mols. were preorganized in stacks at the concns. where ice growth inhibition was obsd. The simulations and single-crystal x-ray structure of safranine revealed regularly spaced amino and Me substituents in the aggregates, akin to the ice-binding site of antifreeze proteins. Collectively, these observations suggest an unusual link between supramol. assemblies of small mols. and functional proteins.
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    33. 33
      Fayter, A.; Huband, S.; Gibson, M. I. X-Ray Diffraction to Probe the Kinetics of Ice Recrystallization Inhibition. Analyst 2020, 145, 3666– 3677,  DOI: 10.1039/C9AN02141H
      33
      X-ray diffraction to probe the kinetics of ice recrystallization inhibition
      Fayter, Alice; Huband, Steven; Gibson, Matthew I.
      Analyst (Cambridge, United Kingdom) (2020), 145 (10), 3666-3677CODEN: ANALAO; ISSN:0003-2654. (Royal Society of Chemistry)
      Understanding the nucleation and growth of ice is crucial in fields ranging from infrastructure maintenance, to the environment, and to preserving biologics in the cold chain. Ice binding and antifreeze proteins are potent ice recrystn. inhibitors (IRI), and synthetic materials that mimic this function have emerged, which may find use in biotechnol. To evaluate IRI activity, optical microscopy tools are typically used to monitor ice grain size either by end-point measurements or as a function of time. However, these methods provide 2-dimensional information and image anal. is required to ext. the data. Here we explore using wide angle X-ray scattering (WAXS/X-ray powder diffraction (XRD)) to interrogate 100's of ice crystals in 3-dimensions as a function of time. Due to the random organization of the ice crystals in the frozen sample, the no. of orientations measured by XRD is proportional to the no. of ice crystals, which can be measured as a function of time. This method was used to evaluate the activity for a panel of known IRI active compds., and shows strong agreement with results obtained from cryo-microscopy, as well as being advantageous in that time-dependent ice growth is easily extd. Diffraction anal. also confirmed, by comparing the obtained diffraction patterns of both ice binding and non-binding additives, that the obsd. hexagonal ice diffraction patterns obtained cannot be used to det. which crystal faces are being bound. This method may help in the discovery of new IRI active materials as well as enabling kinetic anal. of ice growth.
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    34. 34
      Balcerzak, A. K.; Capicciotti, C. J.; Briard, J. G.; Ben, R. N. Designing Ice Recrystallization Inhibitors: From Antifreeze (Glyco)Proteins to Small Molecules. RSC Adv. 2014, 4 (80), 42682– 42696,  DOI: 10.1039/C4RA06893A
      34
      Designing ice recrystallization inhibitors: from antifreeze (glyco)proteins to small molecules
      Balcerzak, Anna K.; Capicciotti, Chantelle J.; Briard, Jennie G.; Ben, Robert N.
      RSC Advances (2014), 4 (80), 42682-42696CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
      A review. Ice recrystn. occurs during cryopreservation and is correlated with reduced cell viability after thawing. Therefore, ice recrystn. inhibition (IRI) activity is a very desirable property for an effective cryoprotectant. Antifreeze proteins (AFPs) and antifreeze glycoproteins (AFGPs) were the first compds. discovered with this property, however they are poor cryoprotectants due to their unique ability to bind to ice and alter habits of ice crystals. Consequently, AFGP analogs with "custom-tailored" antifreeze activity have been developed which exhibit potent IRI activity but do not bind to ice. Subsequent to this, it was reported that simple mono- and disaccharides exhibit moderate IRI activity and this has ultimately facilitated the discovery of several small carbohydrate-based ice recrystn. inhibitors with IRI activity similar to that of native AFGP-8. This represents a major advancement in the field of ice recrystn. inhibitors (IRIs). The recent developments of IRIs will be reviewed, focusing on novel small mols. that have great potential for use as cryoprotectants.
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    35. 35
      Capicciotti, C. J.; Leclere, M.; Perras, F. A.; Bryce, D. L.; Paulin, H.; Harden, J.; Liu, Y.; Ben, R. N. Potent Inhibition of Ice Recrystallization by Low Molecular Weight Carbohydrate-Based Surfactants and Hydrogelators. Chem. Sci. 2012, 3 (5), 1408– 1416,  DOI: 10.1039/c2sc00885h
      35
      Potent inhibition of ice recrystallization by low molecular weight carbohydrate-based surfactants and hydrogelators
      Capicciotti, Chantelle J.; Leclere, Mathieu; Perras, Frederic A.; Bryce, David L.; Paulin, Hilary; Harden, James; Liu, Yun; Ben, Robert N.
      Chemical Science (2012), 3 (5), 1408-1416CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      Ice recrystn. inhibition (IRI) activity is a very desirable property for an effective cryoprotectant. This property was first obsd. in biol. antifreezes (BAs), which cannot be utilized in cryopreservation due to their ability to bind to ice. To date, potent IRI active compds. have been limited to BAs or synthetic C-linked AFGP analogs (1 and 2), all of which are large peptide-based mols. This paper describes the first example of low mol. wt. carbohydrate-based derivs. that exhibit potent IRI activity. Non-ionic surfactant n-octyl-β-d-galactopyranoside (4) exhibited potent IRI activity at a concn. of 22 mM, whereas hydrogelator N-octyl-d-gluconamide (5) exhibited potent IRI activity at a low concn. of 0.5 mM. Thermal hysteresis measurements and solid-state NMR expts. indicated that these derivs. are not exhibiting IRI activity by binding to ice. For non-ionic surfactant derivs. (3 and 4), we demonstrated that carbohydrate hydration is important for IRI activity and that the formation of micelles in soln. is not a prerequisite for IRI activity. Furthermore, using solid-state NMR and rheol. we demonstrated that the ability of hydrogelators 5 and 6 to form a hydrogel is not relevant to IRI activity. Structure-function studies indicated that the amide bond in 5 is an essential structural feature required for potent IRI activity.
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    36. 36
      Gruneberg, A. K.; Graham, L. A.; Eves, R.; Agrawal, P.; Oleschuk, R. D.; Davies, P. L. Ice Recrystallization Inhibition Activity Varies with Ice-Binding Protein Type and Does Not Correlate with Thermal Hysteresis. Cryobiology 2021, 99, 28– 39,  DOI: 10.1016/j.cryobiol.2021.01.017
      36
      Ice recrystallization inhibition activity varies with ice-binding protein type and does not correlate with thermal hysteresis
      Gruneberg, Audrey K.; Graham, Laurie A.; Eves, Robert; Agrawal, Prashant; Oleschuk, Richard D.; Davies, Peter L.
      Cryobiology (2021), 99 (), 28-39CODEN: CRYBAS; ISSN:0011-2240. (Elsevier Ltd.)
      Ice-binding proteins (IBPs) inhibit the growth of ice through surface adsorption. In some freeze-resistant fishes and insects, circulating IBPs serve as antifreeze proteins to stop ice growth by lowering the f.p. Plants are less able to avoid freezing and some use IBPs to minimize the damage caused in the frozen state by ice recrystn., which is the growth of large ice grains at the expense of small ones. Here we have accurately and reproducibly measured the ice recrystn. inhibition (IRI) activity of over a dozen naturally occurring IBPs from fishes, insects, plants, and microorganisms using a modified on serial dilns. of IBPs whose concns. were detd. by amino acid anal. The endpoint of IRI, which was scored as the lowest protein concn. at which no recrystn. was obsd., varied for the different IBPs over two orders of magnitude from 1000 nM to 5 nM. Moreover, there was no apparent correlation between their IRI levels and reported antifreeze activities. IBPs from insects and fishes had similar IRI activity, even though the insect IBPs are typically 10x more active in f.p. depression. Plant IBPs had weak antifreeze activity but were more effective at IRI. Bacterial IBPs involved in ice adhesion showed both strong f.p. depression and IRI. Two trends did emerge, including that basal plane binding IBPs correlated with stronger IRI activity and larger IBPs had higher IRI activity.
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    37. 37
      Olijve, L. L. C.; Meister, K.; DeVries, A. L.; Duman, J. G.; Guo, S.; Bakker, H. J.; Voets, I. K. Blocking Rapid Ice Crystal Growth through Nonbasal Plane Adsorption of Antifreeze Proteins. Proc. Natl. Acad. Sci. U. S. A. 2016, 113 (14), 3740– 3745,  DOI: 10.1073/pnas.1524109113
      37
      Blocking rapid ice crystal growth through nonbasal plane adsorption of antifreeze proteins
      Olijve, Luuk L. C.; Meister, Konrad; DeVries, Arthur L.; Duman, John G.; Guo, Shuaiqi; Bakker, Huib J.; Voets, Ilja K.
      Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (14), 3740-3745CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Antifreeze proteins (AFPs) are a unique class of proteins that bind to growing ice crystal surfaces and arrest further ice growth. AFPs have gained a large interest for their use in antifreeze formulations for water-based materials, such as foods, waterborne paints, and organ transplants. Instead of commonly used colligative antifreezes such as salts and alcs., the advantage of using AFPs as an additive is that they do not alter the physicochem. properties of the water-based material. Here, the authors report the 1st comprehensive evaluation of thermal hysteresis (TH) and ice recrystn. inhibition (IRI) activity of all major classes of AFPs using cryoscopy, sonocrystn., and recrystn. assays. The results showed that TH activities detd. by cryoscopy and sonocrystn. differed markedly, and that TH and IRI activities were not correlated. The absence of a distinct correlation in antifreeze activity pointed to a mechanistic difference in ice growth inhibition by the different classes of AFPs: blocking fast ice growth requires rapid nonbasal plane adsorption, whereas basal plane adsorption is only relevant at long annealing times and at small undercooling. These findings clearly demonstrated that biomimetic analogs of antifreeze (glyco)proteins should be tailored to the specific requirements of the targeted application.
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    38. 38
      Biggs, C. I.; Stubbs, C.; Graham, B.; Fayter, A. E. R.; Hasan, M.; Gibson, M. I. Mimicking the Ice Recrystallization Activity of Biological Antifreezes. When Is a New Polymer “Active”?. Macromol. Biosci. 2019, 19 (7), 1900082,  DOI: 10.1002/mabi.201900082
      There is no corresponding record for this reference.
    39. 39
      Mitchell, D. E.; Clarkson, G.; Fox, D. J.; Vipond, R. A.; Scott, P.; Gibson, M. I. Antifreeze Protein Mimetic Metallohelices with Potent Ice Recrystallization Inhibition Activity. J. Am. Chem. Soc. 2017, 139 (29), 9835– 9838,  DOI: 10.1021/jacs.7b05822
      39
      Antifreeze Protein Mimetic Metallohelices with Potent Ice Recrystallization Inhibition Activity
      Mitchell, Daniel E.; Clarkson, Guy; Fox, David J.; Vipond, Rebecca A.; Scott, Peter; Gibson, Matthew I.
      Journal of the American Chemical Society (2017), 139 (29), 9835-9838CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Antifreeze proteins are produced by extremophile species to control ice formation and growth, and they have potential applications in many fields. There are few examples of synthetic materials which can reproduce their potent ice recrystn. inhibition property. We report that self-assembled enantiomerically pure, amphipathic metallohelicies inhibited ice growth at just 20 μM. Structure-property relationships and calcns. support the hypothesis that amphipathicity is the key motif for activity. This opens up a new field of metallo-org. antifreeze protein mimetics and provides insight into the origins of ice-growth inhibition.
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    40. 40
      Graham, B.; Fayter, A. E. R.; Houston, J. E.; Evans, R. C.; Gibson, M. I. Facially Amphipathic Glycopolymers Inhibit Ice Recrystallization. J. Am. Chem. Soc. 2018, 140 (17), 5682– 5685,  DOI: 10.1021/jacs.8b02066
      40
      Facially amphipathic glycopolymers inhibit ice recrystallization
      Graham, Ben; Fayter, Alice E. R.; Houston, Judith E.; Evans, Rachel C.; Gibson, Matthew I.
      Journal of the American Chemical Society (2018), 140 (17), 5682-5685CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Antifreeze glycoproteins (AFGPs) from polar fish are the most potent ice recrystn. (growth) inhibitors known, and synthetic mimics are required for low-temp. applications such as cell cryopreservation. Here we introduce facially amphipathic glycopolymers that mimic the three-dimensional structure of AFGPs. Glycopolymers featuring segregated hydrophilic and hydrophobic faces were prepd. by ring-opening metathesis polymn., and their rigid conformation was confirmed by small-angle neutron scattering. Ice recrystn. inhibition (IRI) activity was reduced when a hydrophilic oxo-ether was installed on the glycan-opposing face, but significant activity was restored by incorporating a hydrophobic dimethylfulvene residue. This biomimetic strategy demonstrates that segregated domains of distinct hydrophilicity/hydrophobicity are a crucial motif to introduce IRI activity, which increases our understanding of the complex ice crystal inhibition processes.
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    41. 41
      Li, T.; Zhao, Y.; Zhong, Q.; Wu, T. Inhibiting Ice Recrystallization by Nanocelluloses. Biomacromolecules 2019, 20 (4), 1667– 1674,  DOI: 10.1021/acs.biomac.9b00027
      41
      Inhibiting Ice Recrystallization by Nanocelluloses
      Li, Teng; Zhao, Ying; Zhong, Qixin; Wu, Tao
      Biomacromolecules (2019), 20 (4), 1667-1674CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
      Biocompatible materials with ice recrystn. inhibition (IRI) activity have potential applications in several fields. Emerging studies have assocd. the IRI activity of antifreeze proteins/glycoproteins and several mimics of synthetic materials with a facially amphipathic structure. Nanocelluloses are a new family of renewable materials that demonstrate amphiphilicity. Herein the IRI activity of cellulose nanocrystals (CNCs) and 2,2,6,6-tetramethylpiperidine-1-oxyl oxidized cellulose nanofibrils (TEMPO-CNFs) is reported. In 0.01 M NaCl, ice recrystn. was effectively inhibited by 5.0 mg/mL CNCs or 2.0 mg/mL TEMPO-CNFs. In phosphate-buffered saline, observable IRI activity was found with 30.0 mg/mL CNCs. IRI assays in sucrose solns. showed that the decreased IRI activity of nanocelluloses in saline was caused by the aggregation of nanocelluloses due to charge screening. Neither thermal hysteresis nor dynamic ice shaping activity was obsd. in nanocelluloses. These findings may lead to the use of nanocelluloses as novel ice recrystn. inhibitors.
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    42. 42
      Balcerzak, A. K.; Febbraro, M.; Ben, R. N. The Importance of Hydrophobic Moieties in Ice Recrystallization Inhibitors. RSC Adv. 2013, 3 (10), 3232– 3236,  DOI: 10.1039/c3ra23220d
      42
      The importance of hydrophobic moieties in ice recrystallization inhibitors
      Balcerzak, Anna K.; Febbraro, Michela; Ben, Robert N.
      RSC Advances (2013), 3 (10), 3232-3236CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
      Structurally diverse lysine-based surfactants/gelators and anti-ice nucleating agents (anti-INAs) were investigated as ice recrystn. inhibitors (IRIs). The results indicate that long alkyl chains are important for potent IRI activity and that the position of these alkyl chains is essential. Addnl., no correlation was found between IRI activity and crit. micelle concns., gelation or anti-ice nucleation activity, although the counterion of some lysine surfactants did affect IRI activity.
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    43. 43
      Budke, C.; Dreyer, A.; Jaeger, J.; Gimpel, K.; Berkemeier, T.; Bonin, A. S.; Nagel, L.; Plattner, C.; Devries, A. L.; Sewald, N. Quantitative Efficacy Classification of Ice Recrystallization Inhibition Agents. Cryst. Growth Des. 2014, 14 (9), 4285– 4294,  DOI: 10.1021/cg5003308
      43
      Quantitative Efficacy Classification of Ice Recrystallization Inhibition Agents
      Budke, Carsten; Dreyer, Axel; Jaeger, Jasmin; Gimpel, Kerstin; Berkemeier, Thomas; Bonin, Anna S.; Nagel, Lilly; Plattner, Carolin; DeVries, Arthur L.; Sewald, Norbert; Koop, Thomas
      Crystal Growth & Design (2014), 14 (9), 4285-4294CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
      Exptl. investigations of ice recrystn. inhibition (IRI) efficacy have been performed for a large no. of different substances, including natural antifreeze proteins (AFP) and antifreeze glycoproteins (AFGP), several synthetic AFGP analogs, as well as synthetic polymers. Here we define IRI efficacy as that concn. at which the ice recrystn. rate is dominated by the IRI compd. The investigated 39 compds. show IRI efficacies from about 2 mmol L-1 for the least effective compd. still showing activity to about 1 nmol L-1, which corresponds to the highest efficacy found for natural AFGP samples. Hence, the assay employed allows for a quant. comparison of IRI efficacy over a range of at least 6 orders of magnitude, thereby enabling studies of distinguishing effects induced by even subtle structural variations in AFGP analogs that were synthesized. Our results show that AFGP are by far the most effective IRI agents in our assay, and we surmise that this particular efficacy may be due to their disaccharide moieties. This supposition is supported by the fact that IRI efficacy is strongly reduced for monosaccharide AFGP analogs, as well as for AFGP analogs with acetyl-protected monosaccharide moieties.
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    44. 44
      Adam, M. K.; Jarrett-Wilkins, C.; Beards, M.; Staykov, E.; MacFarlane, L. R.; Bell, T. D. M.; Matthews, J. M.; Manners, I.; Faul, C. F. J.; Moens, P. D. J. 1D Self-Assembly and Ice Recrystallization Inhibition Activity of Antifreeze Glycopeptide-Functionalized Perylene Bisimides. Chem. - Eur. J. 2018, 24 (31), 7834– 7839,  DOI: 10.1002/chem.201800857
      44
      1D Self-Assembly and Ice Recrystallization Inhibition Activity of Antifreeze Glycopeptide-Functionalized Perylene Bisimides
      Adam, Madeleine K.; Jarrett-Wilkins, Charles; Beards, Michael; Staykov, Emiliyan; MacFarlane, Liam R.; Bell, Toby D. M.; Matthews, Jacqueline M.; Manners, Ian; Faul, Charl F. J.; Moens, Pierre D. J.; Ben, Robert N.; Wilkinson, Brendan L.
      Chemistry - A European Journal (2018), 24 (31), 7834-7839CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Antifreeze glycoproteins (AFGPs) are polymeric natural products that have drawn considerable interest in diverse research fields owing to their potent ice recrystn. inhibition (IRI) activity. Self-assembled materials have emerged as a promising class of biomimetic ice growth inhibitor, yet the development of AFGP-based supramol. materials that emulate the aggregative behavior of AFGPs have not yet been reported. This work reports the first example of the 1D self-assembly and IRI activity of AFGP-functionalized perylene bisimides (AFGP-PBIs). Glycopeptide-functionalized PBIs underwent 1D self-assembly in water and showed modest IRI activity, which could be tuned through substitution of the PBI core. This work presents essential proof-of-principle for the development of novel IRIs as potential supramol. cryoprotectants and glycoprotein mimics.
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    45. 45
      Olijve, L. L. C.; Hendrix, M. M. R. M.; Voets, I. K. Influence of Polymer Chain Architecture of Poly(Vinyl Alcohol) on the Inhibition of Ice Recrystallization. Macromol. Chem. Phys. 2016, 217 (8), 951– 958,  DOI: 10.1002/macp.201500497
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      Influence of Polymer Chain Architecture of Poly(vinyl alcohol) on the Inhibition of Ice Recrystallization
      Olijve, Luuk L. C.; Hendrix, Marco M. R. M.; Voets, Ilja K.
      Macromolecular Chemistry and Physics (2016), 217 (8), 951-958CODEN: MCHPES; ISSN:1022-1352. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Poly(vinyl alc.) (PVA) is a water-sol. synthetic polymer well-known to effectively block the recrystn. of ice. The effect of polymer chain architecture on the ice recrystn. inhibition (IRI) by PVA remains unexplored. In this work, the synthesis of PVA mol. bottlebrushes is described via a combination of atom-transfer radical polymn. and reversible addn.-fragmentation chain-transfer polymn. The facile prepn. of the PVA bottlebrushes is performed via the selective hydrolysis of the chloroacetate esters of the poly(vinyl chloroacetate) (PVClAc) side chains of a PVClAc precursor bottlebrush. The IRI efficacy of the PVA bottlebrush is quant. compared to linear PVA. The results show that even if the PVA chains are densely grafted onto a rigid polymer backbone, the IRI activity of PVA is maintained, demonstrating the flexibility in PVA polymer chain architecture for the design of synthetic PVA-based ice growth inhibitors.
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    46. 46
      Sproncken, C. C. M.; Surís-Valls, R.; Cingil, H. E.; Detrembleur, C.; Voets, I. K. Complex Coacervate Core Micelles Containing Poly(Vinyl Alcohol) Inhibit Ice Recrystallization. Macromol. Rapid Commun. 2018, 39, 1700814,  DOI: 10.1002/marc.201700814
      There is no corresponding record for this reference.
    47. 47
      Stubbs, C.; Wilkins, L. E.; Fayter, A. E. R.; Walker, M.; Gibson, M. I. Multivalent Presentation of Ice Recrystallization Inhibiting Polymers on Nanoparticles Retains Activity. Langmuir 2019, 35 (23), 7347– 7353,  DOI: 10.1021/acs.langmuir.8b01952
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      Multivalent Presentation of Ice Recrystallization Inhibiting Polymers on Nanoparticles Retains Activity
      Stubbs, Christopher; Wilkins, Laura E.; Fayter, Alice E. R.; Walker, Marc; Gibson, Matthew I.
      Langmuir (2019), 35 (23), 7347-7353CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      Poly(vinyl alc.) (PVA) has emerged as the most potent mimic of antifreeze (glyco)proteins ice recrystn. inhibition (IRI) activity, despite its lack of structural similarities and flexible, rather than rigid, backbone. The precise spacing of hydroxyl groups is hypothesized to enable PVA to recognize the prism planes of ice but not the basal plane, due to hydroxyl pattern matching of the ice surface giving rise to the macroscopic activity. Here, well-defined PVA derived from reversible addn.-fragmentation chain-transfer (RAFT) polymn. is immobilized onto gold nanoparticles to enable the impact of nanoscale assembly and confinement on the obsd. IRI activity. Unlike previous reports using star-branched or bottle-brush PVAs, the nanoparticle-PVA retains all IRI activity compared to polymers in soln. Evidence is presented to show that this is due to the low grafting densities on the particle surface meaning the chains are free to explore the ice faces, rather than being constrained as in star-branched polymers. These results demonstrate a route to develop more functional IRI's and inclusion of metallic particle cores for imaging and assocd. applications in cryobiol.
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    48. 48
      Stevens, C. A.; Drori, R.; Zalis, S.; Braslavsky, I.; Davies, P. L. Dendrimer-Linked Antifreeze Proteins Have Superior Activity and Thermal Recovery. Bioconjugate Chem. 2015, 26 (9), 1908– 1915,  DOI: 10.1021/acs.bioconjchem.5b00290
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      Dendrimer-Linked Antifreeze Proteins Have Superior Activity and Thermal Recovery
      Stevens, Corey A.; Drori, Ran; Zalis, Shiran; Braslavsky, Ido; Davies, Peter L.
      Bioconjugate Chemistry (2015), 26 (9), 1908-1915CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      By binding to ice, antifreeze proteins (AFPs) depress the f.p. of a soln. and inhibit ice recrystn. if freezing does occur. Previous work showed that the activity of an AFP was incrementally increased by fusing it to another protein. Even larger increases in activity were achieved by doubling the no. of ice-binding sites by dimerization. Here, the authors have combined the two strategies by linking multiple outward-facing AFPs to a dendrimer to significantly increase both the size of the mol. and the no. of ice-binding sites. Using a heterobifunctional crosslinker, the authors attached between 6 and 11 type III AFPs to a second-generation polyamidoamine (G2-PAMAM) dendrimer with 16 reactive termini. This heterogeneous sample of dendrimer-linked type III constructs showed a >4-fold increase in f.p. depression over that of monomeric type III AFP. This multimerized AFP was particularly effective at ice recrystn. inhibition activity, likely because it can simultaneously bind multiple ice surfaces. Addnl., attachment to the dendrimer has afforded the AFP superior recovery from heat denaturation. Linking AFPs together via polymers can generate novel reagents for controlling ice growth and recrystn.
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    49. 49
      Wilkins, L. E.; Hasan, M.; Fayter, A. E. R.; Biggs, C.; Walker, M.; Gibson, M. I. Site-Specific Conjugation of Antifreeze Proteins onto Polymer-Stabilized Nanoparticles. Polym. Chem. 2019, 10, 2986– 2990,  DOI: 10.1039/C8PY01719K
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      Site-specific conjugation of antifreeze proteins onto polymer-stabilized nanoparticles
      Wilkins, Laura E.; Hasan, Muhammad; Fayter, Alice E. R.; Biggs, Caroline; Walker, Marc; Gibson, Matthew I.
      Polymer Chemistry (2019), 10 (23), 2986-2990CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
      Antifreeze proteins (AFPs) have many potential applications, ranging from cryobiol. to aerospace, if they can be incorporated into materials. Here, a range of engineered AFP mutants were prepd. and site-specifically conjugated onto RAFT polymer-stabilized gold nanoparticles to generate new hybrid multivalent ice growth inhibitors. Only the SNAP-tagged AFPs lead to potent 'antifreeze' active nanomaterials with His-Tag capture resulting in no activity, showing the mode of conjugation is essential. This versatile strategy will enable the development of multivalent AFPs for translational and fundamental studies.
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    50. 50
      Ogawa, S.; Koga, M.; Osanai, S. Anomalous Ice Nucleation Behavior in Aqueous Polyvinyl Alcohol Solutions. Chem. Phys. Lett. 2009, 480 (1), 86– 89,  DOI: 10.1016/j.cplett.2009.08.046
      50
      Anomalous ice nucleation behavior in aqueous polyvinyl alcohol solutions
      Ogawa, S.; Koga, M.; Osanai, S.
      Chemical Physics Letters (2009), 480 (1-3), 86-89CODEN: CHPLBC; ISSN:0009-2614. (Elsevier B.V.)
      The effect of polymers on the ice nucleation temp. (T f) was studied in a W/O emulsion using ∼5 μm diam. droplets by differential scanning calorimetry (DSC). Four types of polymers were used. Among them, only poly(vinyl alc.) (PVA) showed the addnl. effect of increasing the T f of the aq. solns. This increase was logarithmic with the concn. of PVA and the difference in mol. wt. did not have any significant effect on T f for the same wt. concn. It was shown that the no. of the structural unit (CH2CHOH) was the key parameter for the increasing degree of T f.
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    51. 51
      Pummer, B. G.; Budke, C.; Augustin-Bauditz, S.; Niedermeier, D.; Felgitsch, L.; Kampf, C. J.; Huber, R. G.; Liedl, K. R.; Loerting, T.; Moschen, T. Ice Nucleation by Water-Soluble Macromolecules. Atmos. Chem. Phys. 2015, 15 (8), 4077– 4091,  DOI: 10.5194/acp-15-4077-2015
      51
      Ice nucleation by water-soluble macromolecules
      Pummer, B. G.; Budke, C.; Augustin-Bauditz, S.; Niedermeier, D.; Felgitsch, L.; Kampf, C. J.; Huber, R. G.; Liedl, K. R.; Loerting, T.; Moschen, T.; Schauperl, M.; Tollinger, M.; Morris, C. E.; Wex, H.; Grothe, H.; Poeschl, U.; Koop, T.; Froehlich-Nowoisky, J.
      Atmospheric Chemistry and Physics (2015), 15 (8), 4077-4091CODEN: ACPTCE; ISSN:1680-7324. (Copernicus Publications)
      Cloud glaciation is critically important for the global radiation budget (albedo) and for initiation of pptn. But the freezing of pure water droplets requires cooling to temps. as low as 235 K. Freezing at higher temps. requires the presence of an ice nucleator, which serves as a template for arranging water mols. in an ice-like manner. It is often assumed that these ice nucleators have to be insol. particles. We point out that also free macromols. which are dissolved in water can efficiently induce ice nucleation: the size of such ice nucleating macromols. (INMs) is in the range of nanometers, corresponding to the size of the crit. ice embryo. As the latter is temp.-dependent, we see a correlation between the size of INMs and the ice nucleation temp. as predicted by classical nucleation theory. Different types of INMs have been found in a wide range of biol. species and comprise a variety of chem. structures including proteins, saccharides, and lipids. Our investigation of the fungal species Acremonium implicatum, Isaria farinosa, and Mortierella alpina shows that their ice nucleation activity is caused by proteinaceous water-sol. INMs. We combine these new results and literature data on INMs from fungi, bacteria, and pollen with theor. calcns. to develop a chem. interpretation of ice nucleation and water-sol. INMs. This has atm. implications since many of these INMs can be released by fragmentation of the carrier cell and subsequently may be distributed independently. Up to now, this process has not been accounted for in atm. models.
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    52. 52
      Eickhoff, L.; Dreischmeier, K.; Zipori, A.; Sirotinskaya, V.; Adar, C.; Reicher, N.; Braslavsky, I.; Rudich, Y.; Koop, T. Contrasting Behavior of Antifreeze Proteins: Ice Growth Inhibitors and Ice Nucleation Promoters. J. Phys. Chem. Lett. 2019, 10 (5), 966– 972,  DOI: 10.1021/acs.jpclett.8b03719
      52
      Contrasting Behavior of Antifreeze Proteins: Ice Growth Inhibitors and Ice Nucleation Promoters
      Eickhoff, Lukas; Dreischmeier, Katharina; Zipori, Assaf; Sirotinskaya, Vera; Adar, Chen; Reicher, Naama; Braslavsky, Ido; Rudich, Yinon; Koop, Thomas
      Journal of Physical Chemistry Letters (2019), 10 (5), 966-972CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)
      Several types of natural mols. interact specifically with ice crystals. Small antifreeze proteins (AFPs) adsorb to particular facets of ice crystals, thus inhibiting their growth, whereas larger ice-nucleating proteins (INPs) can trigger the formation of new ice crystals at temps. much higher than the homogeneous ice nucleation temp. of pure water. It has been proposed that both types of proteins interact similarly with ice and that, in principle, they may be able to exhibit both functions. Here we investigated two naturally occurring antifreeze proteins, one from fish, type-III AFP, and one from beetles, TmAFP. We show that in addn. to ice growth inhibition, both can also trigger ice nucleation above the homogeneous freezing temp., providing unambiguous exptl. proof for their contrasting behavior. Our anal. suggests that the predominant difference between AFPs and INPs is their mol. size, which is a very good predictor of their ice nucleation temp.
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    53. 53
      Bissoyi, A.; Reicher, N.; Chasnitsky, M.; Arad, S.; Koop, T.; Rudich, Y.; Braslavsky, I. Ice Nucleation Properties of Ice-Binding Proteins from Snow Fleas. Biomolecules 2019, 9 (10), 532,  DOI: 10.3390/biom9100532
      53
      Ice nucleation properties of ice-binding proteins from snow fleas
      Bissoyi, Akalabya; Reicher, Naama; Chasnitsky, Michael; Arad, Sivan; Koop, Thomas; Rudich, Yinon; Braslavsky, Ido
      Biomolecules (2019), 9 (10), 532CODEN: BIOMHC; ISSN:2218-273X. (MDPI AG)
      Ice-binding proteins (IBPs) are found in many organisms, such as fish and hexapods, plants, and bacteria that need to cope with low temps. Ice nucleation and thermal hysteresis are two attributes of IBPs. While ice nucleation is promoted by large proteins, known as ice nucleating proteins, the smaller IBPs, referred to as antifreeze proteins (AFPs), inhibit the growth of ice crystals by up to several degrees below the m.p., resulting in a thermal hysteresis (TH) gap between melting and ice growth. Recently, we showed that the nucleation capacity of two types of IBPs corresponds to their size, in agreement with classical nucleation theory. Here, we expand this finding to addnl. IBPs that we isolated from snow fleas (the arthropod Collembola), collected in northern Israel. Chem. analyses using CD and Fourier-transform IR spectroscopy data suggest that these IBPs have a similar structure to a previously reported snow flea antifreeze protein. Further expts. reveal that the ice-shell purified proteins have hyperactive antifreeze properties, as detd. by nanoliter osmometry, and also exhibit low ice-nucleation activity in accordance with their size.
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    54. 54
      Blanazs, A.; Madsen, J.; Battaglia, G.; Ryan, A. J.; Armes, S. P. Mechanistic Insights for Block Copolymer Morphologies: How Do Worms Form Vesicles?. J. Am. Chem. Soc. 2011, 133 (41), 16581– 16587,  DOI: 10.1021/ja206301a
      54
      Mechanistic Insights for Block Copolymer Morphologies: How Do Worms Form Vesicles?
      Blanazs, Adam; Madsen, Jeppe; Battaglia, Giuseppe; Ryan, Anthony J.; Armes, Steven P.
      Journal of the American Chemical Society (2011), 133 (41), 16581-16587CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Amphiphilic diblock copolymers composed of two covalently linked, chem. distinct chains can be considered to be biol. mimics of cell membrane-forming lipid mols., but with typically more than an order of magnitude increase in mol. wt. These macromol. amphiphiles are known to form a wide range of nanostructures (spheres, worms, vesicles, etc.) in solvents that are selective for one of the blocks. However, such self-assembly is usually limited to dil. copolymer solns. (<1%), which is a significant disadvantage for potential com. applications such as drug delivery and coatings. In principle, this problem can be circumvented by polymn.-induced block copolymer self-assembly. Here the authors detail the synthesis and subsequent in situ self-assembly of amphiphilic AB diblock copolymers in a one pot concd. aq. dispersion polymn. formulation. The authors show that spherical micelles, wormlike micelles, and vesicles can be predictably and efficiently obtained (within 2 h of polymn., >99% monomer conversion) at relatively high solids in purely aq. soln. Furthermore, careful monitoring of the in situ polymn. by transmission electron microscopy reveals various novel intermediate structures (including branched worms, partially coalesced worms, nascent bilayers, "octopi", "jellyfish", and finally pure vesicles) that provide important mechanistic insights regarding the evolution of the particle morphol. during the sphere-to-worm and worm-to-vesicle transitions. This environmentally benign approach (which involves no toxic solvents, is conducted at relatively high solids, and requires no addnl. processing) is readily amenable to industrial scale-up, since it is based on com. available starting materials.
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    55. 55
      Warren, N. J.; Armes, S. P. Polymerization-Induced Self-Assembly of Block Copolymer Nano-Objects via RAFT Aqueous Dispersion Polymerization. J. Am. Chem. Soc. 2014, 136 (29), 10174– 10185,  DOI: 10.1021/ja502843f
      55
      Polymerization-Induced Self-Assembly of Block Copolymer Nano-objects via RAFT Aqueous Dispersion Polymerization
      Warren, Nicholas J.; Armes, Steven P.
      Journal of the American Chemical Society (2014), 136 (29), 10174-10185CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A review. In this Perspective, we discuss the recent development of polymn.-induced self-assembly mediated by reversible addn.-fragmentation chain transfer (RAFT) aq. dispersion polymn. This approach has quickly become a powerful and versatile technique for the synthesis of a wide range of bespoke org. diblock copolymer nano-objects of controllable size, morphol., and surface functionality. Given its potential scalability, such environmentally-friendly formulations are expected to offer many potential applications, such as novel Pickering emulsifiers, efficient microencapsulation vehicles, and sterilizable thermo-responsive hydrogels for the cost-effective long-term storage of mammalian cells.
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    56. 56
      Warren, N. J.; Mykhaylyk, O. O.; Ryan, A. J.; Williams, M.; Doussineau, T.; Dugourd, P.; Antoine, R.; Portale, G.; Armes, S. P. Testing the Vesicular Morphology to Destruction: Birth and Death of Diblock Copolymer Vesicles Prepared via Polymerization-Induced Self-Assembly. J. Am. Chem. Soc. 2015, 137 (5), 1929– 1937,  DOI: 10.1021/ja511423m
      56
      Testing the Vesicular Morphology to Destruction: Birth and Death of Diblock Copolymer Vesicles Prepared via Polymerization-Induced Self-Assembly
      Warren, Nicholas J.; Mykhaylyk, Oleksandr O.; Ryan, Anthony J.; Williams, Mark; Doussineau, Tristan; Dugourd, Philippe; Antoine, Rodolphe; Portale, Giuseppe; Armes, Steven P.
      Journal of the American Chemical Society (2015), 137 (5), 1929-1937CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Small angle X-ray scattering (SAXS), electrospray ionization charge detection mass spectrometry (CD-MS), dynamic light scattering (DLS), and transmission electron microscopy (TEM) are used to characterize poly(glycerol monomethacrylate)55-poly(2-hydroxypropyl methacrylate)x (G55-Hx) vesicles prepd. by polymn.-induced self-assembly (PISA) using a reversible addn.-fragmentation chain transfer (RAFT) aq. dispersion polymn. formulation. A G55 chain transfer agent is utilized to prep. a series of G55-Hx diblock copolymers, where the mean d.p. (DP) of the membrane-forming block (x) is varied from 200 to 2000. TEM confirms that vesicles with progressively thicker membranes are produced for x = 200-1000, while SAXS indicates a gradual redn. in mean aggregation no. for higher x values, which is consistent with CD-MS studies. Both DLS and SAXS studies indicate minimal change in the overall vesicle diam. between x = 400 and 800. Fitting SAXS patterns to a vesicle model enables calcn. of the membrane thickness, degree of hydration of the membrane, and the mean vesicle aggregation no. The membrane thickness increases at higher x values, hence the vesicle lumen must become smaller if the external vesicle dimensions remain const. Geometric considerations indicate that this growth mechanism lowers the total vesicle interfacial area and hence reduces the free energy of the system. However, it also inevitably leads to gradual ingress of the encapsulated water mols. into the vesicle membrane, as confirmed by SAXS anal. Ultimately, the highly plasticized membranes become insufficiently hydrophobic to stabilize the vesicle morphol. when x exceeds 1000, thus this PISA growth mechanism ultimately leads to vesicle "death".
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    57. 57
      Doncom, K. E. B.; Blackman, L. D.; Wright, D. B.; Gibson, M. I.; O’Reilly, R. K. Dispersity Effects in Polymer Self-Assemblies: A Matter of Hierarchical Control. Chem. Soc. Rev. 2017, 46 (14), 4119– 4134,  DOI: 10.1039/C6CS00818F
      57
      Dispersity effects in polymer self-assemblies: a matter of hierarchical control
      Doncom, Kay E. B.; Blackman, Lewis D.; Wright, Daniel B.; Gibson, Matthew I.; O'Reilly, Rachel K.
      Chemical Society Reviews (2017), 46 (14), 4119-4134CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Advanced applications of polymeric self-assembled structures require a stringent degree of control over such aspects as functionality location, morphol. and size of the resulting assemblys. A loss of control in the polymeric building blocks of these assemblys can have drastic effects upon the final morphol. or function of these structures. Gaining precise control over various aspects of the polymers, such as chain lengths and architecture, blocking efficiency and compositional distribution is a challenge and, hence, measuring the intrinsic mass and size dispersity within these areas is an important aspect of such control. It is of great importance that a good handle on how to improve control and accurately measure it is achieved. Addnl. dispersity of the final structure can also play a large part in the suitability for a desired application. In this Tutorial Review, we aim to highlight the different aspects of dispersity that are often overlooked and the effect that a lack of control can have on both the polymer and the final assembled structure.
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    58. 58
      Czajka, A.; Armes, S. P. In Situ SAXS Studies of a Prototypical RAFT Aqueous Dispersion Polymerization Formulation: Monitoring the Evolution in Copolymer Morphology during Polymerization-Induced Self-Assembly. Chem. Sci. 2020, 11 (42), 11443– 11454,  DOI: 10.1039/D0SC03411H
      58
      In situ SAXS studies of a prototypical RAFT aqueous dispersion polymerization formulation: monitoring the evolution in copolymer morphology during polymerization-induced self-assembly
      Czajka, Adam; Armes, Steven P.
      Chemical Science (2020), 11 (42), 11443-11454CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      Small-angle X-ray scattering (SAXS) is used to characterize the in situ formation of diblock copolymer spheres, worms and vesicles during reversible addn.-fragmentation chain transfer (RAFT) aq. dispersion polymn. of 2-hydroxypropyl methacrylate at 70°C using a poly(glycerol monomethacrylate) steric stabilizer. The 1H NMR spectroscopy indicates more than 99% HPMA conversion within 80 min, while transmission electron microscopy and dynamic light scattering studies are consistent with the final morphol. being pure vesicles. Anal. of time-resolved SAXS patterns for this prototypical polymn.-induced self-assembly (PISA) formulation enables the evolution in copolymer morphol., particle diam., mean aggregation no., solvent vol. fraction, surface d. of copolymer chains and their mean inter-chain sepn. distance at the nanoparticle surface to be monitored. Furthermore, the change in vesicle diam. and membrane thickness during the final stages of polymn. supports an 'inward growth' mechanism.
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    59. 59
      Qiu, L.; Xu, C.-R.; Zhong, F.; Hong, C.-Y.; Pan, C.-Y. Fabrication of Functional Nano-Objects through RAFT Dispersion Polymerization and Influences of Morphology on Drug Delivery. ACS Appl. Mater. Interfaces 2016, 8 (28), 18347– 18359,  DOI: 10.1021/acsami.6b04693
      59
      Fabrication of Functional Nano-objects through RAFT Dispersion Polymerization and Influences of Morphology on Drug Delivery
      Qiu, Liang; Xu, Chao-Ran; Zhong, Feng; Hong, Chun-Yan; Pan, Cai-Yuan
      ACS Applied Materials & Interfaces (2016), 8 (28), 18347-18359CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)
      To study the influence of self-assembled morphologies on drug delivery, four different nano-objects, spheres, nanorods, nanowires, and vesicles having aldehyde-based polymer as core, were successfully prepd. via alc. RAFT dispersion polymn. of p-(methacryloxyethoxy)benzaldehyde (MAEBA) using poly((N,N'-dimethylamino)ethyl methacrylate) (PDMAEMA) as a macro chain transfer agent (macro-CTA) for the first time. The morphologies and sizes of the four nano-objects were characterized by TEM and DLS, and the spheres with av. diam. (D) of 70 nm, the nanorods with D of 19 nm and length of 140 nm, and the vesicles with D of 137 nm were used in the subsequent cellular internalization, in vitro release, and intracellular release of the drug. The anticancer drug doxorubicin (DOX) was conjugated onto the core polymers of nano-objects through condensation reaction between aldehyde groups of the PMAEBA with primary amine groups in the DOX. Because the arom. imine is stable under neutral conditions, but is decompd. in a weakly acidic soln., in vitro release of the DOX from the DOX-loaded nano-objects was investigated in the different acidic solns. All of the block copolymer nano-objects show very low cytotoxicity to HeLa cells up to the concn. of 1.2 mg/mL, but the DOX-loaded nano-objects reveal different cell viability and their IC50s increase as the following order: nanorods-DOX < vesicles-DOX < spheres-DOX. The IC50 of nanowires-DOX is the biggest among the four nano-objects owing to their too large size to be internalized. Endocytosis tests demonstrate that the internalization of vesicles-DOX by the HeLa cells is faster than that of the nanorods-DOX, and the spheres-DOX are the slowest to internalize among the studied nano-objects. Relatively more nanorods localized in the acidic organelles of the HeLa cells lead to faster intracellular release of the DOX, so the IC50 of nanorods is lower than that of the vesicles-DOX.
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    60. 60
      Hinde, E.; Thammasiraphop, K.; Duong, H. T. T.; Yeow, J.; Karagoz, B.; Boyer, C.; Gooding, J. J.; Gaus, K. Pair Correlation Microscopy Reveals the Role of Nanoparticle Shape in Intracellular Transport and Site of Drug Release. Nat. Nanotechnol. 2017, 12 (1), 81– 89,  DOI: 10.1038/nnano.2016.160
      60
      Pair correlation microscopy reveals the role of nanoparticle shape in intracellular transport and site of drug release
      Hinde, Elizabeth; Thammasiraphop, Kitiphume; Duong, Hien T. T.; Yeow, Jonathan; Karagoz, Bunyamin; Boyer, Cyrille; Gooding, J. Justin; Gaus, Katharina
      Nature Nanotechnology (2017), 12 (1), 81-89CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
      Nanoparticle size, surface charge and material compn. are known to affect the uptake of nanoparticles by cells. However, whether nanoparticle shape affects transport across various barriers inside the cell remains unclear. Here we used pair correlation microscopy to show that polymeric nanoparticles with different shapes but identical surface chemistries moved across the various cellular barriers at different rates, ultimately defining the site of drug release. We measured how micelles, vesicles, rods and worms entered the cell and whether they escaped from the endosomal system and had access to the nucleus via the nuclear pore complex. Rods and worms, but not micelles and vesicles, entered the nucleus by passive diffusion. Improving nuclear access, for example with a nuclear localization signal, resulted in more doxorubicin release inside the nucleus and correlated with greater cytotoxicity. Our results therefore demonstrate that drug delivery across the major cellular barrier, the nuclear envelope, is important for doxorubicin efficiency and can be achieved with appropriately shaped nanoparticles.
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    61. 61
      Noy, J.-M.; Chen, F.; Akhter, D. T.; Houston, Z. H.; Fletcher, N. L.; Thurecht, K. J.; Stenzel, M. H. Direct Comparison of Poly(Ethylene Glycol) and Phosphorylcholine Drug-Loaded Nanoparticles In Vitro and In Vivo. Biomacromolecules 2020, 21 (6), 2320– 2333,  DOI: 10.1021/acs.biomac.0c00257
      61
      Direct Comparison of Poly(ethylene glycol) and Phosphorylcholine Drug-Loaded Nanoparticles In Vitro and In Vivo
      Noy, Janina-Miriam; Chen, Fan; Akhter, Dewan T.; Houston, Zachary H.; Fletcher, Nicholas L.; Thurecht, Kristofer J.; Stenzel, Martina H.
      Biomacromolecules (2020), 21 (6), 2320-2333CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
      Phosphorylcholine is known to repel the absorption of proteins onto surfaces, which can prevent the formation of a protein corona on the surface of nanoparticles. This can influence the fate of nanoparticles used for drug delivery. This material could therefore serve as an alternative to poly(ethylene glycol) (PEG). Herein, the synthesis of different particles prepd. by polymn.-induced self-assembly (PISA) coated with either poly(ethylene glycol) (PEG) or zwitterionic 2-methacryloyloxyethyl phosphorylcholine (MPC) and 4-(N-(S-penicillaminylacetyl)amino) phenylarsenonous acid (PENAO) was reported. The anticancer drug 4-(N-(S-penicillaminylacetyl)amino) phenylarsenonous acid (PENAO) was conjugated to the shell-forming block. Interactions of the different coated nanoparticles, which present comparable sizes and size distributions (76-85 nm, PDI = 0.067-0.094), with two-dimensional (2D) and three-dimensional (3D) cultured cells were studied, and their cytotoxicities, cellular uptakes, spheroid penetration, and cell localization profiles were analyzed. While only a minimal difference in behavior was obsd. for nanoparticles assessed using in vitro expt. (with PEG-co- PENAO-coated micelles showing slightly higher cytotoxicity and better spheroid penetration and cell localization ability), the effect of the different physicochem. properties between nanoparticles had a more dramatic effect on in vivo biodistribution. After 1 h of injection, the majority of the MPC-co-PENAO-coated nanoparticles were found to accumulate in the liver, making this particle system unfeasible for future biol. studies.
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    62. 62
      Zhang, W.-J.; Hong, C.-Y.; Pan, C.-Y. Polymerization-Induced Self-Assembly of Functionalized Block Copolymer Nanoparticles and Their Application in Drug Delivery. Macromol. Rapid Commun. 2019, 40 (2), 1800279,  DOI: 10.1002/marc.201800279
      There is no corresponding record for this reference.
    63. 63
      Canton, I.; Warren, N. J.; Chahal, A.; Amps, K.; Wood, A.; Weightman, R.; Wang, E.; Moore, H.; Armes, S. P. Mucin-Inspired Thermoresponsive Synthetic Hydrogels Induce Stasis in Human Pluripotent Stem Cells and Human Embryos. ACS Cent. Sci. 2016, 2 (2), 65– 74,  DOI: 10.1021/acscentsci.5b00370
      63
      Mucin-Inspired Thermoresponsive Synthetic Hydrogels Induce Stasis in Human Pluripotent Stem Cells and Human Embryos
      Canton, Irene; Warren, Nicholas J.; Chahal, Aman; Amps, Katherine; Wood, Andrew; Weightman, Richard; Wang, Eugenia; Moore, Harry; Armes, Steven P.
      ACS Central Science (2016), 2 (2), 65-74CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
      Human pluripotent stem cells (hPSCs; both embryonic and induced pluripotent) rapidly proliferate in adherent culture to maintain their undifferentiated state. However, for mammals exhibiting delayed gestation (diapause), mucin-coated embryos can remain dormant for days or months in utero, with their constituent PSCs remaining pluripotent under these conditions. Here we report cellular stasis for both hPSC colonies and preimplantation embryos immersed in a wholly synthetic thermoresponsive gel comprising poly(glycerol monomethacrylate)-poly(2-hydroxypropyl methacrylate) [PGMA55-PHPMA135] diblock copolymer worms. This hydroxyl-rich mucin-mimicking nonadherent 3D gel maintained PSC viability and pluripotency in the quiescent G0 state without passaging for at least 14 days. Similarly, gel-coated human embryos remain in a state of suspended animation (diapause) for up to 8 days. The discovery of a cryptic cell arrest mechanism for both hPSCs and embryos suggests an important connection between the cellular mechanisms that evoke embryonic diapause and pluripotency. Moreover, such synthetic worm gels offer considerable utility for the short-term (weeks) storage of either pluripotent stem cells or human embryos without cryopreservation.
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    64. 64
      Binch, A. L. A.; Ratcliffe, L. P. D.; Milani, A. H.; Saunders, B. R.; Armes, S. P.; Hoyland, J. A. Site-Directed Differentiation of Human Adipose-Derived Mesenchymal Stem Cells to Nucleus Pulposus Cells Using an Injectable Hydroxyl-Functional Diblock Copolymer Worm Gel. Biomacromolecules 2021, 22 (2), 837– 845,  DOI: 10.1021/acs.biomac.0c01556
      64
      Site-Directed Differentiation of Human Adipose-Derived Mesenchymal Stem Cells to Nucleus Pulposus Cells Using an Injectable Hydroxyl-Functional Diblock Copolymer Worm Gel
      Binch, Abbie L. A.; Ratcliffe, Liam P. D.; Milani, Amir H.; Saunders, Brian R.; Armes, Steven P.; Hoyland, Judith A.
      Biomacromolecules (2021), 22 (2), 837-845CODEN: BOMAF6; ISSN:1525-7797. (American Chemical Society)
      Adipose-derived mesenchymal stem cells (ASCs) have been identified for their promising therapeutic potential to regenerate and repopulate the degenerate intervertebral disk (IVD), which is a major cause of lower back pain. The optimal cell delivery system remains elusive but encapsulation of cells within scaffolds is likely to offer a decisive advantage over the delivery of cells in soln. by ensuring successful retention within the tissue. Herein, we evaluate the use of a fully synthetic, thermoresponsive poly(glycerol monomethacrylate)-poly(2-hydroxypropyl methacrylate) (PGMA-PHPMA) diblock copolymer worm gel that mimics the structure of hydrophilic glycosaminoglycans. The objective was to use this gel to direct differentiation of human ASCs toward a nucleus pulposus (NP) phenotype, with or without the addn. of discogenic growth factors TGFβ or GDF6. Accordingly, human ASCs were incorporated into a cold, free-flowing aq. dispersion of the diblock copolymer, gelation induced by warming to 37° and cell culture was conducted for 14 days with or without such growth factors to assess the expression of characteristic NP markers compared to those produced when using collagen gels. In principle, the shear-thinning nature of the biocompatible worm gel enables encapsulated human ASCs to be injected into the IVD using a 21G needle. Moreover, we find significantly higher gene expression levels of ACAN, SOX-9, KRT8, and KR18 for ASCs encapsulated within worm gels compared to collagen scaffolds, regardless of the growth factors employed. In summary, such wholly synthetic worm gels offer considerable potential as an injectable cell delivery scaffold for the treatment of degenerate disk disease by promoting the transition of ASCs toward an NP-phenotype.
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    65. 65
      Mitchell, D. E.; Lovett, J. R.; Armes, S. P.; Gibson, M. I. Combining Biomimetic Block Copolymer Worms with an Ice-Inhibiting Polymer for the Solvent-Free Cryopreservation of Red Blood Cells. Angew. Chem., Int. Ed. 2016, 55 (8), 2801– 2804,  DOI: 10.1002/anie.201511454
      65
      Combining Biomimetic Block Copolymer Worms with an Ice-Inhibiting Polymer for the Solvent-Free Cryopreservation of Red Blood Cells
      Mitchell, Daniel E.; Lovett, Joseph R.; Armes, Steven P.; Gibson, Matthew I.
      Angewandte Chemie, International Edition (2016), 55 (8), 2801-2804CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The first fully synthetic polymer-based approach for red-blood-cell cryopreservation without the need for any (toxic) org. solvents is reported. Highly hydroxylated block copolymer worms are shown to be a suitable replacement for hydroxyethyl starch as a extracellular matrix for red blood cells. When used alone, the worms are not a particularly effective preservative. However, when combined with poly(vinyl alc.), a known ice-recrystn. inhibitor, a remarkable additive cryopreservative effect is obsd. that matches the performance of hydroxyethyl starch. Moreover, these block copolymer worms enable post-thaw gelation by simply warming to 20 °C. This approach offers a new soln. for both the storage and transport of red blood cells and also a convenient matrix for subsequent 3D cell cultures.
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    66. 66
      Blackman, L. D.; Varlas, S.; Arno, M. C.; Fayter, A.; Gibson, M. I.; O’Reilly, R. K. Permeable Protein-Loaded Polymersome Cascade Nanoreactors by Polymerization-Induced Self-Assembly. ACS Macro Lett. 2017, 6 (11), 1263– 1267,  DOI: 10.1021/acsmacrolett.7b00725
      66
      Permeable Protein-Loaded Polymersome Cascade Nanoreactors by Polymerization-Induced Self-Assembly
      Blackman, Lewis D.; Varlas, Spyridon; Arno, Maria C.; Fayter, Alice; Gibson, Matthew I.; OReilly, Rachel K.
      ACS Macro Letters (2017), 6 (11), 1263-1267CODEN: AMLCCD; ISSN:2161-1653. (American Chemical Society)
      Enzyme loading of polymersomes requires permeability to enable them to interact with the external environment, typically requiring addn. of complex functionality to enable porosity. Herein, we describe a synthetic route toward intrinsically permeable polymersomes loaded with functional proteins using initiator-free visible light-mediated polymn.-induced self-assembly (photo-PISA) under mild, aq. conditions using a com. monomer. Compartmentalization and retention of protein functionality was demonstrated using green fluorescent protein as a macromol. chromophore. Catalytic enzyme-loaded vesicles using horseradish peroxidase and glucose oxidase were also prepd. and the permeability of the membrane toward their small mol. substrates was revealed for the first time. Finally, the interaction of the compartmentalized enzymes between sep. vesicles was validated by means of an enzymic cascade reaction. These findings have a broad scope as the methodol. could be applied for the encapsulation of a large range of macromols. for advancements in the fields of nanotechnol., biomimicry and nanomedicine.
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    67. 67
      Blackman, L. D.; Varlas, S.; Arno, M. C.; Houston, Z. H.; Fletcher, N. L.; Thurecht, K. J.; Hasan, M.; Gibson, M. I.; O’Reilly, R. K. Confinement of Therapeutic Enzymes in Selectively Permeable Polymer Vesicles by Polymerization-Induced Self-Assembly (PISA) Reduces Antibody Binding and Proteolytic Susceptibility. ACS Cent. Sci. 2018, 4 (6), 718– 723,  DOI: 10.1021/acscentsci.8b00168
      67
      Confinement of Therapeutic Enzymes in Selectively Permeable Polymer Vesicles by Polymerization-Induced Self-Assembly (PISA) Reduces Antibody Binding and Proteolytic Susceptibility
      Blackman, Lewis D.; Varlas, Spyridon; Arno, Maria C.; Houston, Zachary H.; Fletcher, Nicholas L.; Thurecht, Kristofer J.; Hasan, Muhammad; Gibson, Matthew I.; O'Reilly, Rachel K.
      ACS Central Science (2018), 4 (6), 718-723CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
      Covalent PEGylation of biologics has been widely employed to reduce immunogenicity, while improving stability and half-life in vivo. This approach requires covalent protein modification, creating a new entity. An alternative approach is stabilization by encapsulation into polymersomes; however this typically requires multiple steps, and the segregation requires the vesicles to be permeable to retain function. Herein, we demonstrate the one-pot synthesis of therapeutic enzyme-loaded vesicles with size-selective permeability using polymn.-induced self-assembly (PISA) enabling the encapsulated enzyme to function from within a confined domain. This strategy increased the proteolytic stability and reduced antibody recognition compared to the free protein or a PEGylated conjugate, thereby reducing potential dose frequency and the risk of immune response. Finally, the efficacy of encapsulated L-asparaginase (clin. used for leukemia treatment) against a cancer line was demonstrated, and its biodistribution and circulation behavior in vivo was compared to the free enzyme, highlighting this methodol. as an attractive alternative to the covalent PEGylation of enzymes.
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    68. 68
      Varlas, S.; Foster, J. C.; Georgiou, P. G.; Keogh, R.; Husband, J. T.; Williams, D. S.; O’Reilly, R. K. Tuning the Membrane Permeability of Polymersome Nanoreactors Developed by Aqueous Emulsion Polymerization-Induced Self-Assembly. Nanoscale 2019, 11 (26), 12643– 12654,  DOI: 10.1039/C9NR02507C
      68
      Tuning the membrane permeability of polymersome nanoreactors developed by aqueous emulsion polymerization-induced self-assembly
      Varlas, Spyridon; Foster, Jeffrey C.; Georgiou, Panagiotis G.; Keogh, Robert; Husband, Jonathan T.; Williams, David S.; O'Reilly, Rachel K.
      Nanoscale (2019), 11 (26), 12643-12654CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      Polymeric vesicles (or polymersomes) are hollow bilayer structures consisting of an inner aq. compartment enclosed by a hydrophobic membrane. Research into polymersomes is motivated primarily by the fact that hydrophilic cargo such as drug mols., DNA, or enzymes can be encapsulated and protected from the often harsh conditions of the surrounding environment. A key factor governing the capability of vesicles to retain and protect their cargo is the permeability of their hydrophobic membrane. Herein, we demonstrate that membrane permeability of enzyme-loaded epoxy-functionalized polymersomes synthesized by aq. emulsion PISA can be modulated via epoxide ring-opening with various diamine crosslinkers and hydrophobic primary amines. In general, membrane crosslinking or amine conjugation resulted in increased polymersome membrane thickness. Membrane modification was also found to decrease permeability in all cases, as measured by enzymically-catalyzed oxidn. of an externally administered substrate. Functionalization with hydrophobic amines resulted in the largest redn. in enzyme activity, suggesting significant blocking of substrate diffusion into the central aq. compartment. This procedurally facile strategy yields meaningful insight into how the chem. structure of the membrane influences permeability and thus could be generally applied to the formulation of polymeric vesicles for therapeutic applications.
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    69. 69
      Cheng, G.; Pérez-Mercader, J. Polymerization-Induced Self-Assembly for Artificial Biology: Opportunities and Challenges. Macromol. Rapid Commun. 2019, 40 (2), 1970006,  DOI: 10.1002/marc.201970006
      There is no corresponding record for this reference.
    70. 70
      Canning, S. L.; Smith, G. N.; Armes, S. P. A Critical Appraisal of RAFT-Mediated Polymerization-Induced Self-Assembly. Macromolecules 2016, 49, 1985– 2001,  DOI: 10.1021/acs.macromol.5b02602
      70
      A Critical Appraisal of RAFT-Mediated Polymerization-Induced Self-Assembly
      Canning, Sarah L.; Smith, Gregory N.; Armes, Steven P.
      Macromolecules (Washington, DC, United States) (2016), 49 (6), 1985-2001CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      Recently, polymn.-induced self-assembly (PISA) has become widely recognized as a robust and efficient route to produce block copolymer nanoparticles of controlled size, morphol., and surface chem. Several reviews of this field have been published since 2012, but a substantial no. of new papers have been published in the last three years. In this Perspective, we provide a crit. appraisal of the various advantages offered by this approach, while also pointing out some of its current drawbacks. Promising future research directions as well as remaining tech. challenges and unresolved problems are briefly highlighted.
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    71. 71
      Khor, S. Y.; Quinn, J. F.; Whittaker, M. R.; Truong, N. P.; Davis, T. P. Controlling Nanomaterial Size and Shape for Biomedical Applications via Polymerization-Induced Self-Assembly. Macromol. Rapid Commun. 2019, 40 (2), 1800438,  DOI: 10.1002/marc.201800438
      There is no corresponding record for this reference.
    72. 72
      D’Agosto, F.; Rieger, J.; Lansalot, M. RAFT-Mediated Polymerization-Induced Self-Assembly. Angew. Chem., Int. Ed. 2020, 59 (22), 8368– 8392,  DOI: 10.1002/anie.201911758
      72
      RAFT-Mediated Polymerization-Induced Self-Assembly
      D'Agosto, Franck; Rieger, Jutta; Lansalot, Muriel
      Angewandte Chemie, International Edition (2020), 59 (22), 8368-8392CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. After a brief history that positions polymn.-induced self-assembly (PISA) in the field of polymer chem., this Review will cover the fundamentals of the PISA mechanism. Furthermore, this Review will also give an overview of some of the features and limitations of RAFT-mediated PISA in terms of the choice of the components involved, the nature of the nanoobjects that can be obtained and how the syntheses can be controlled, as well as some potential applications.
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    73. 73
      Penfold, N. J. W.; Yeow, J.; Boyer, C.; Armes, S. P. Emerging Trends in Polymerization-Induced Self-Assembly. ACS Macro Lett. 2019, 8 (8), 1029– 1054,  DOI: 10.1021/acsmacrolett.9b00464
      73
      Emerging Trends in Polymerization-Induced Self-Assembly
      Penfold, Nicholas J. W.; Yeow, Jonathan; Boyer, Cyrille; Armes, Steven P.
      ACS Macro Letters (2019), 8 (8), 1029-1054CODEN: AMLCCD; ISSN:2161-1653. (American Chemical Society)
      A review. In this Perspective, we summarize recent progress in polymn.-induced self-assembly (PISA) for the rational synthesis of block copolymer nanoparticles with various morphologies. Much of the PISA literature has been based on thermally initiated reversible addn.-fragmentation chain transfer (RAFT) polymn. Herein, we pay particular attention to alternative PISA protocols, which allow the prepn. of nanoparticles with improved control over copolymer morphol. and functionality. For example, initiation based on visible light, redox chem., or enzymes enables the incorporation of sensitive monomers and fragile biomols. into block copolymer nanoparticles. Furthermore, PISA syntheses and postfunctionalization of the resulting nanoparticles (e.g., crosslinking) can be conducted sequentially without intermediate purifn. by using various external stimuli. Finally, PISA formulations have been optimized via high-throughput polymn. and recently evaluated within flow reactors for facile scale-up syntheses.
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    74. 74
      Georgiou, P. G.; Kontopoulou, I.; Congdon, T. R.; Gibson, M. I. Ice Recrystallisation Inhibiting Polymer Nano-Objects: Via Saline-Tolerant Polymerisation-Induced Self-Assembly. Mater. Horiz. 2020, 7 (7), 1883– 1887,  DOI: 10.1039/D0MH00354A
      74
      Ice recrystallisation inhibiting polymer nano-objects via saline-tolerant polymerisation-induced self-assembly
      Georgiou, Panagiotis G.; Kontopoulou, Ioanna; Congdon, Thomas R.; Gibson, Matthew I.
      Materials Horizons (2020), 7 (7), 1883-1887CODEN: MHAOBM; ISSN:2051-6355. (Royal Society of Chemistry)
      Chem. tools to modulate ice formation/growth have great (bio)technol. value, with ice binding/antifreeze proteins being exciting targets for biomimetic materials. Here we introduce polymer nanomaterials that are potent inhibitors of ice recrystn. using polymn.-induced self-assembly (PISA), employing a poly(vinyl alc.) graft macromol. chain transfer agent (macro-CTA). Crucially, engineering the core-forming block with diacetone acrylamide enabled PISA to be conducted in saline, whereas poly(2-hydroxypropyl methacrylate) cores led to coagulation. The most active particles inhibited ice growth as low as 0.5 mg mL-1, and were more active than the PVA stabilizer block alone, showing that the dense packing of this nanoparticle format enhanced activity. This provides a unique route towards colloids capable of modulating ice growth.
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    75. 75
      Warren, N. J.; Mykhaylyk, O. O.; Mahmood, D.; Ryan, A. J.; Armes, S. P. RAFT Aqueous Dispersion Polymerization Yields Poly(Ethylene Glycol)-Based Diblock Copolymer Nano-Objects with Predictable Single Phase Morphologies. J. Am. Chem. Soc. 2014, 136 (3), 1023– 1033,  DOI: 10.1021/ja410593n
      75
      RAFT Aqueous Dispersion Polymerization Yields Poly(ethylene glycol)-Based Diblock Copolymer Nano-Objects with Predictable Single Phase Morphologies
      Warren, Nicholas J.; Mykhaylyk, Oleksandr O.; Mahmood, Daniel; Ryan, Anthony J.; Armes, Steven P.
      Journal of the American Chemical Society (2014), 136 (3), 1023-1033CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A poly(ethylene glycol) (PEG) macromol. chain transfer agent (macro-CTA) is prepd. in high yield (>95%) with 97% dithiobenzoate chain-end functionality in a three-step synthesis starting from a monohydroxy PEG113 precursor. This PEG113-dithiobenzoate is then used for the reversible addn.-fragmentation chain transfer (RAFT) aq. dispersion polymn. of 2-hydroxypropyl methacrylate (HPMA). Polymns. conducted under optimized conditions at 50 °C led to high conversions as judged by 1H NMR spectroscopy and relatively low diblock copolymer polydispersities (Mw/Mn < 1.25) as judged by GPC. The latter technique also indicated good blocking efficiencies, since there was minimal PEG113 macro-CTA contamination. Systematic variation of the mean d.p. of the core-forming PHPMA block allowed PEG113-PHPMAx diblock copolymer spheres, worms, or vesicles to be prepd. at up to 17.5% wt./wt. solids, as judged by dynamic light scattering and transmission electron microscopy studies. Small-angle X-ray scattering (SAXS) anal. revealed that more exotic oligolamellar vesicles were obsd. at 20% wt./wt. solids when targeting highly asym. diblock compns. Detailed anal. of SAXS curves indicated that the mean no. of membranes per oligolamellar vesicle is approx. three. A PEG113-PHPMAx phase diagram was constructed to enable the reproducible targeting of pure phases, as opposed to mixed morphologies (e.g., spheres plus worms or worms plus vesicles). This new RAFT PISA formulation is expected to be important for the rational and efficient synthesis of a wide range of biocompatible, thermo-responsive PEGylated diblock copolymer nano-objects for various biomedical applications.
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    76. 76
      Yoshida, E. Perforated Vesicles Composed of Amphiphilic Diblock Copolymer: New Artificial Biomembrane Model of Nuclear Envelope. Soft Matter 2019, 15 (48), 9849– 9857,  DOI: 10.1039/C9SM01832H
      76
      Perforated vesicles composed of amphiphilic diblock copolymer: new artificial biomembrane model of nuclear envelope
      Yoshida, Eri
      Soft Matter (2019), 15 (48), 9849-9857CODEN: SMOABF; ISSN:1744-6848. (Royal Society of Chemistry)
      With the aim of creating a new artificial model of a biomembrane for the nuclear envelope, perforated vesicles were prepd. employing an amphiphilic diblock copolymer of poly(methacrylic acid)-block-poly(Me methacrylate-random-methacrylic acid-random-2,2,6,6-tetramethyl-4-piperidyl methacrylate), PMAA-b-P(MMA-r-MAA-r-TPMA), by polymn.-induced self-assembly through photo nitroxide-mediated controlled/living radical polymn. (photo NMP). The photo NMP in an aq. methanol soln. produced spherical vesicles perforated with various holes and pores in the surface. The perforation of the vesicles was prevented by trifluoroacetic acid based on the disturbance of the MAA-TPMA interaction in the hydrophobic block chain. The investigation of the morphol. changes by the polymn. progress revealed that the perforated spherical vesicles were produced within the membrane of contorted huge vesicles that were formed during the early stage of the polymn. due to the extension of the hydrophobic block chain. The perforated vesicles were found to show a reversible thermo-responsive behavior in the range of 25-50°C based on dynamic light scattering and transmittance measurements. The vesicles were fused and divided into much smaller vesicles at high temp., but were restored by cooling. However, the restored vesicles only had a few holes and no pores in the surface. The rearrangement of the MAA-TPMA interaction at high temp. produced more morphol. stable non-perforated vesicles.
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    77. 77
      Yoshida, E. Fission of Giant Vesicles Accompanied by Hydrophobic Chain Growth through Polymerization-Induced Self-Assembly. Colloid Polym. Sci. 2014, 292 (6), 1463– 1468,  DOI: 10.1007/s00396-014-3216-x
      77
      Fission of giant vesicles accompanied by hydrophobic chain growth through polymerization-induced self-assembly
      Yoshida, Eri
      Colloid and Polymer Science (2014), 292 (6), 1463-1468CODEN: CPMSB6; ISSN:0303-402X. (Springer)
      To clarify the formation mechanisms of micrometer-sized spherical vesicles through the polymn.-induced self-assembly of amphiphilic poly(methacrylic acid)-block-poly(Me methacrylate-random-methacrylic acid), PMAA-b-P(MMA-r-MAA), the nitroxide-mediated photocontrolled/living radical polymn. initiated by a PMAA end-capped with 4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl was performed in an aq. MeOH soln. The polymn. proceeded in a living manner during the self-assembly. The vesicles produced during the early stage of the polymn. were not completely spherical and had dents and very small holes on their surface. As the hydrophobic P(MMA-r-MAA) block chains grew by the polymn., the contorted vesicles were changed into half-sized elliptical vesicles accompanied by enlargement of the dents and holes. The vesicles were finally transformed into much smaller spherical vesicles by further growth of the hydrophobic chains. The mechanisms of the vesicles by fission involved the outside sepn. by the expansion of the dents and holes on the surface and the inside sepn. by budding.
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    78. 78
      Scheutz, G. M.; Touve, M. A.; Carlini, A. S.; Garrison, J. B.; Gnanasekaran, K.; Sumerlin, B. S.; Gianneschi, N. C. Probing Thermoresponsive Polymerization-Induced Self-Assembly with Variable-Temperature Liquid-Cell Transmission Electron Microscopy. Matter 2021, 4 (2), 722– 736,  DOI: 10.1016/j.matt.2020.11.017
      78
      Probing Thermoresponsive Polymerization-Induced Self-Assembly with Variable-Temperature Liquid-Cell Transmission Electron Microscopy
      Scheutz, Georg M.; Touve, Mollie A.; Carlini, Andrea S.; Garrison, John B.; Gnanasekaran, Karthikeyan; Sumerlin, Brent S.; Gianneschi, Nathan C.
      Matter (2021), 4 (2), 722-736CODEN: MATTCG; ISSN:2590-2385. (Elsevier Inc.)
      We directly initiate and visualize the formation of polymeric nanomaterials via variable-temp. liq.-cell transmission electron microscopy. With temp. control in the liq. cell, reversible addn.-fragmentation chain transfer polymn. was thermally initiated, leading to the formation of amphiphilic block copolymers that assemble upon dispersion polymn.-induced self-assembly (PISA). In combination with traditional ex-situ analyses, VT-LCTEM enabled not only the characterization of the nanoparticles in situ but also the observation of a thermal phase transition. Critically, because these assemblies form from thermoresponsive components, any temp. changes during sample prepn. and anal. can alter morphologies, necessitating direct in situ characterization of reaction progression. We believe that the findings and the technique described herein will lead to unprecedented possibilities for the development and characterization of self-organizing soft matter.
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    79. 79
      Byard, S. J.; Williams, M.; McKenzie, B. E.; Blanazs, A.; Armes, S. P. Preparation and Cross-Linking of All-Acrylamide Diblock Copolymer Nano-Objects via Polymerization-Induced Self-Assembly in Aqueous Solution. Macromolecules 2017, 50 (4), 1482– 1493,  DOI: 10.1021/acs.macromol.6b02643
      79
      Preparation and Cross-Linking of All-Acrylamide Diblock Copolymer Nano-Objects via Polymerization-Induced Self-Assembly in Aqueous Solution
      Byard, Sarah J.; Williams, Mark; McKenzie, Beulah E.; Blanazs, Adam; Armes, Steven P.
      Macromolecules (Washington, DC, United States) (2017), 50 (4), 1482-1493CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      Various carboxylic acid-functionalized poly(N,N-dimethylacrylamide) (PDMAC) macromol. chain transfer agents (macro-CTAs) were chain-extended with diacetone acrylamide (DAAM) by reversible addn.-fragmentation chain transfer (RAFT) aq. dispersion polymn. at 70 °C and 20% wt./wt. solids to produce a series of PDMAC-PDAAM diblock copolymer nano-objects via polymn.-induced self-assembly (PISA). TEM studies indicate that a PDMAC macro-CTA with a mean d.p. (DP) of 68 or higher results in the formation of well-defined spherical nanoparticles with mean diams. ranging from 40 to 150 nm. In contrast, either highly anisotropic worms or polydisperse vesicles are formed when relatively short macro-CTAs (DP = 40-58) are used. A phase diagram was constructed to enable accurate targeting of pure copolymer morphologies. Dynamic light scattering (DLS) and aq. electrophoresis studies indicated that in most cases these PDMAC-PDAAM nano-objects are surprisingly resistant to changes in either soln. pH or temp. However, PDMAC40-PDAAM99 worms do undergo partial dissocn. to form a mixt. of relatively short worms and spheres on adjusting the soln. pH from pH 2-3 to around pH 9 at 20 °C. Moreover, a change in copolymer morphol. from worms to a mixt. of short worms and vesicles was obsd. by DLS and TEM on heating this worm dispersion to 50 °C. Postpolymn. crosslinking of concd. aq. dispersions of PDMAC-PDAAM spheres, worms, or vesicles was performed at ambient temp. using adipic acid dihydrazide (ADH), which reacts with the hydrophobic ketone-functionalized PDAAM chains. The formation of hydrazone groups was monitored by FT-IR spectroscopy and afforded covalently stabilized nano-objects that remained intact on exposure to methanol, which is a good solvent for both blocks. Rheol. studies indicated that the cross-linked worms formed a stronger gel compared to linear precursor worms.
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    80. 80
      Wang, X.; Zhou, J.; Lv, X.; Zhang, B.; An, Z. Temperature-Induced Morphological Transitions of Poly(Dimethylacrylamide)–Poly(Diacetone Acrylamide) Block Copolymer Lamellae Synthesized via Aqueous Polymerization-Induced Self-Assembly. Macromolecules 2017, 50 (18), 7222– 7232,  DOI: 10.1021/acs.macromol.7b01644
      80
      Temperature-Induced Morphological Transitions of Poly(dimethylacrylamide)-Poly(diacetone acrylamide) Block Copolymer Lamellae Synthesized via Aqueous Polymerization-Induced Self-Assembly
      Wang, Xiao; Zhou, Jiamin; Lv, Xiaoqing; Zhang, Baohua; An, Zesheng
      Macromolecules (Washington, DC, United States) (2017), 50 (18), 7222-7232CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      Aq. dispersion polymn. of diacetone acrylamide (DAAM) by chain extension from a hydrophilic poly(N,N-dimethylacrylamide) (PDMA30) macromol. chain transfer agent (macro-CTA) to produce PDMA30-PDAAMx block copolymer nano-objects was investigated in detail by systematically varying solids content and d.p. of the core-forming PDAAM, leading to the formation of pure lamellae, mixed lamellae/vesicles, and pure vesicles as revealed by dynamic light scattering (DLS), transmission electron microscopy (TEM), at. force microscopy (AFM), and SEM (SEM). PDMA30-PDAAMx lamellae were found to span an unprecedented wide space in the morphol. phase diagram. Moreover, in situ crosslinking of lamellae via statistical copolymn. of DAAM with an asym. crosslinker allyl acrylamide and the effect of crosslinking d. on the colloidal and morphol. stabilities were studied, representing the first report on in situ crosslinking of lamellae during polymn.-induced self-assembly (PISA). Finally, reversible, temp.-induced morphol. transitions from lamellae to worms/spheres on cooling were investigated by DLS, TEM, 1H NMR spectroscopy, and rheol. The kinetics of the temp.-dependent morphol. transitions and the rheol. properties could be tuned by the crosslinking d.
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    81. 81
      Knight, C. A.; Hallett, J.; DeVries, A. L. Solute Effects on Ice Recrystallization: An Assessment Technique. Cryobiology 1988, 25 (1), 55– 60,  DOI: 10.1016/0011-2240(88)90020-X
      81
      Solute effects on ice recrystallization: an assessment technique
      Knight C A; Hallett J; DeVries A L
      Cryobiology (1988), 25 (1), 55-60 ISSN:0011-2240.
      Reliable assessment of the effect of a solute upon ice recrystallization is accomplished with "splat cooling," the impaction of a small solution droplet onto a very cold metal plate. The ice disc has extremely small crystals, and recrystallization can be followed without confusing effects caused by grain nucleation. This method confirms the exceptionally strong recrystallization inhibition effect of antifreeze protein from Antarctic fish and shows that grain growth rate is a sensitive function of both grain size and solute concentration.
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    82. 82
      Byard, S. J.; Blanazs, A.; Miller, J. F.; Armes, S. P. Cationic Sterically Stabilized Diblock Copolymer Nanoparticles Exhibit Exceptional Tolerance toward Added Salt. Langmuir 2019, 35 (44), 14348– 14357,  DOI: 10.1021/acs.langmuir.9b02789
      82
      Cationic Sterically Stabilized Diblock Copolymer Nanoparticles Exhibit Exceptional Tolerance toward Added Salt
      Byard, Sarah J.; Blanazs, Adam; Miller, John F.; Armes, Steven P.
      Langmuir (2019), 35 (44), 14348-14357CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      For certain com. applications such as enhanced oil recovery, sterically stabilized colloidal dispersions that exhibit high tolerance toward added salt are desirable. Herein, we report a series of new cationic diblock copolymer nanoparticles that display excellent colloidal stability in concd. aq. salt solns. More specifically, poly(2-(acryloyloxy)ethyltrimethylammonium chloride) (PATAC) has been chain-extended by reversible addn.-fragmentation chain transfer aq. dispersion polymn. of diacetone acrylamide (DAAM) at 70 °C to produce PATAC100-PDAAMx diblock copolymer spheres at 20% wt./wt. solids via polymn.-induced self-assembly. Transmission electron microscopy and dynamic light scattering (DLS) anal. confirm that the mean sphere diam. can be adjusted by systematic variation of the mean d.p. of the PDAAM block. Remarkably, DLS studies confirm that highly cationic PATAC100-PDAAM1500 spheres retain their colloidal stability in the presence of either 4.0 M KCl or 3.0 M ammonium sulfate for at least 115 days at 20 °C. The mole fraction of PATAC chains within the stabilizer shell was systematically varied by the chain extension of various binary mixts. of non-ionic poly(N,N-dimethylacrylamide) (PDMAC) and cationic PATAC with DAAM to produce ([n] PATAC100 + [1 - n] PDMAC67)-PDAAMz diblock copolymer spheres at 20% wt./wt. DLS studies confirmed that a relatively high mole fraction of cationic PATAC stabilizer chains (n ≥ 0.75) is required for the dispersions to remain colloidally stable in 4.0 M KCl. Cationic worms and vesicles could also be synthesized using a binary mixt. of PATAC and PDMAC precursors, where n = 0.10. However, the vesicles only remained colloidally stable up to 1.0 M KCl, whereas the worms proved to be stable up to 2.0 M KCl. Such block copolymer nanoparticles are expected to be useful model systems for understanding the behavior of aq. colloidal dispersions in extremely salty media. Finally, zeta potentials detd. using electrophoretic light scattering are presented for such nanoparticles dispersed in highly salty media.
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    83. 83
      Foster, J. C.; Varlas, S.; Couturaud, B.; Jones, J. R.; Keogh, R.; Mathers, R. T.; O’Reilly, R. K. Predicting Monomers for Use in Polymerization-Induced Self-Assembly. Angew. Chem., Int. Ed. 2018, 57 (48), 15733– 15737,  DOI: 10.1002/anie.201809614
      83
      Predicting Monomers for Use in Polymerization-Induced Self-Assembly
      Foster, Jeffrey C.; Varlas, Spyridon; Couturaud, Benoit; Jones, Joseph R.; Keogh, Robert; Mathers, Robert T.; O'Reilly, Rachel K.
      Angewandte Chemie, International Edition (2018), 57 (48), 15733-15737CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      We report an in silico method to predict monomers suitable for use in polymn.-induced self-assembly (PISA). By calcg. the dependence of LogPoct /surface area (SA) on the length of the growing polymer chain, the change in hydrophobicity during polymn. was detd. This allowed for evaluation of the capability of a monomer to polymerize to form self-assembled structures during chain extension. Using this method, we identified five new monomers for use in aq. PISA via reversible addn.-fragmentation chain transfer (RAFT) polymn., and confirmed that these all successfully underwent PISA to produce nanostructures of various morphologies. The results obtained using this method correlated well with and predicted the differences in morphol. obtained from the PISA of block copolymers of similar mol. wt. but different chem. structures. Thus, we propose this method can be utilized for the discovery of new monomers for PISA and also the prediction of their self-assembly behavior.
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    84. 84
      Yamago, S.; Nakamura, Y. Recent Progress in the Use of Photoirradiation in Living Radical Polymerization. Polymer 2013, 54 (3), 981– 994,  DOI: 10.1016/j.polymer.2012.11.046
      84
      Recent progress in the use of photoirradiation in living radical polymerization
      Yamago, Shigeru; Nakamura, Yasuyuki
      Polymer (2013), 54 (3), 981-994CODEN: POLMAG; ISSN:0032-3861. (Elsevier Ltd.)
      A review. The effects of photoirradn. in controlled and living radical polymn. (LRP), namely nitroxide-mediated polymn. (NMP), atom-transfer radical polymn. (ATRP), cobalt-mediated radical polymn. (CMRP), reversible addn.-fragmentation chain transfer polymn. (RAFT), organoiodine-mediated radical polymn. (IRP), and organotellurium-mediated radical polymn. (TERP), are summarized. As in the conventional radical polymn., photoirradn. has been used for generating radicals under mild conditions in LRP methods. In addn. to this use, photoirradn. is also used to overcome the difficulties characteristic to each method, such as activation of catalysis, generation of controlling agents, and increasing the polymer-end structure. The most-recent developments in the use of photochem. in LRP are summarized in this review.
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    85. 85
      McKenzie, T. G.; Fu, Q.; Uchiyama, M.; Satoh, K.; Xu, J.; Boyer, C.; Kamigaito, M.; Qiao, G. G. Beyond Traditional RAFT: Alternative Activation of Thiocarbonylthio Compounds for Controlled Polymerization. Adv. Sci. 2016, 3 (9), 1500394,  DOI: 10.1002/advs.201670047
      85
      Beyond Traditional RAFT: Alternative Activation of Thiocarbonylthio Compounds for Controlled Polymerization
      McKenzie Thomas G; Fu Qiang; Qiao Greg G; Uchiyama Mineto; Kamigaito Masami; Satoh Kotaro; Xu Jiangtao; Boyer Cyrille
      Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2016), 3 (9), 1500394 ISSN:2198-3844.
      Recent developments in polymerization reactions utilizing thiocarbonylthio compounds have highlighted the surprising versatility of these unique molecules. The increasing popularity of reversible addition-fragmentation chain transfer (RAFT) radical polymerization as a means of producing well-defined, 'controlled' synthetic polymers is largely due to its simplicity of implementation and the availability of a wide range of compatible reagents. However, novel modes of thiocarbonylthio activation can expand the technique beyond the traditional system (i.e., employing a free radical initiator) pushing the applicability and use of thiocarbonylthio compounds even further than previously assumed. The primary advances seen in recent years are a revival in the direct photoactivation of thiocarbonylthio compounds, their activation via photoredox catalysis, and their use in cationic polymerizations. These synthetic approaches and their implications for the synthesis of controlled polymers represent a significant advance in polymer science, with potentially unforeseen benefits and possibilities for further developments still ahead. This Research News aims to highlight key works in this area while also clarifying the differences and similarities of each system.
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    86. 86
      Binauld, S.; Delafresnaye, L.; Charleux, B.; D’Agosto, F.; Lansalot, M. Emulsion Polymerization of Vinyl Acetate in the Presence of Different Hydrophilic Polymers Obtained by RAFT/MADIX. Macromolecules 2014, 47 (10), 3461– 3472,  DOI: 10.1021/ma402549x
      86
      Emulsion Polymerization of Vinyl Acetate in the Presence of Different Hydrophilic Polymers Obtained by RAFT/MADIX
      Binauld, Sandra; Delafresnaye, Laura; Charleux, Bernadette; D'Agosto, Franck; Lansalot, Muriel
      Macromolecules (Washington, DC, United States) (2014), 47 (10), 3461-3472CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      The surfactant-free emulsion polymn. of vinyl acetate (VAc) was achieved using RAFT/MADIX-mediated polymn.-induced self-assembly (PISA) process in water. First, well-defined hydrophilic macromol. RAFT agents (macroRAFT) bearing a xanthate chain end were synthesized by RAFT/MADIX polymn. of N-vinylpyrrolidone (NVP) and N-acryloylmorpholine (NAM) or by post-modification of com. poly(ethylene glycol). Chain extension of the macroRAFT with VAc in water led to the block copolymer nanoscale organization and the subsequent formation of stable and isodisperse PVAc latex nanoparticles with high solids content (35-37 wt. %). The influence of various parameters, including the nature and functionality of the macroRAFT agent precursor, on the polymn. kinetics and particle morphol. was also studied.
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    87. 87
      Pound, G.; Eksteen, Z.; Pfukwa, R.; McKenzie, J. M.; Lange, R. F. M.; Klumperman, B. Unexpected Reactions Associated with the Xanthate-Mediated Polymerization of N-Vinylpyrrolidone. J. Polym. Sci., Part A: Polym. Chem. 2008, 46 (19), 6575– 6593,  DOI: 10.1002/pola.22968
      87
      Unexpected reactions associated with the xanthate-mediated polymerization of N-vinylpyrrolidone
      Pound, Gwenaelle; Eksteen, Zaskia; Pfukwa, Rueben; McKenzie, Jean M.; Lange, Ronald F. M.; Klumperman, Bert
      Journal of Polymer Science, Part A: Polymer Chemistry (2008), 46 (19), 6575-6593CODEN: JPACEC; ISSN:0887-624X. (John Wiley & Sons, Inc.)
      The monomer N-vinylpyrrolidone (NVP) undergoes side reactions in the presence of R group functional xanthates and impurities. The fate of the monomer NVP and a selection of six O-Et xanthates during xanthate-mediated polymn. were studied via NMR spectroscopy. A high no. of byproducts were identified. Significant side reactions affecting NVP include the formation of an unsatd. dimer and hydration products in bulk or in soln. in C6D6. In addn., the xanthate adjacent to a NVP unit was found to undergo elimination at moderate temp. (60-70°), resulting in unsatd. species and the formation of new xanthate species. The presence of the chlorinated compd. α-chlorophenyl acetic acid, Et ester, a precursor in the synthesis of the xanthate S-(2-Et phenylacetate) O-Et xanthate, resulted in a dramatic increase in the rate of side reactions such as unsatd. dimer formation and a high ratio of unsatd. chain ends. The conditions for the occurrence of such side reactions are discussed in this article, with relevance to increasing the control over the polymn. kinetics, endgroup functionality, and control over the molar mass distribution.
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    88. 88
      Guinaudeau, A.; Coutelier, O.; Sandeau, A.; Mazières, S.; Nguyen Thi, H. D.; Le Drogo, V.; Wilson, D. J.; Destarac, M. Facile Access to Poly(N-Vinylpyrrolidone)-Based Double Hydrophilic Block Copolymers by Aqueous Ambient RAFT/MADIX Polymerization. Macromolecules 2014, 47 (1), 41– 50,  DOI: 10.1021/ma4017899
      88
      Facile Access to Poly(N-vinylpyrrolidone)-Based Double Hydrophilic Block Copolymers by Aqueous Ambient RAFT/MADIX Polymerization
      Guinaudeau, Aymeric; Coutelier, Olivier; Sandeau, Aurelie; Mazieres, Stephane; Nguyen, Thi Hong Diep; Le Drogo, Viviane; Wilson, David James; Destarac, Mathias
      Macromolecules (Washington, DC, United States) (2014), 47 (1), 41-50CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      A new redox initiator pair employing sodium sulfite as reducing agent was proposed to perform aq. ambient RAFT/MADIX polymn. of N-vinylpyrrolidone (NVP) in the presence of a xanthate chain transfer agent. An efficient control of the polymn. with no formation of monomer byproducts was obtained regardless of the concn. of water in the medium. This system was applied to the aq. synthesis of PVP-based double hydrophilic block copolymers through the polymn. of NVP at room temp. with several hydrophilic macro-chain-transfer agents based on poly(acrylamide), poly(acrylic acid), poly(sodium 2-acrylamido-2-methylpropanesulfonate), and poly(3-acrylamidopropyltrimethylammonium chloride). The diblock nature of the copolymers was established by DOSY NMR in all cases when satisfactory SEC anal. conditions could not be established due to the strong adsorption properties of the copolymers.
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    89. 89
      Wan, D.; Satoh, K.; Kamigaito, M.; Okamoto, Y. Xanthate-Mediated Radical Polymerization of N -Vinylpyrrolidone in Fluoroalcohols for Simultaneous Control of Molecular Weight and Tacticity. Macromolecules 2005, 38 (25), 10397– 10405,  DOI: 10.1021/ma0515230
      89
      Xanthate-Mediated Radical Polymerization of N-Vinylpyrrolidone in Fluoroalcohols for Simultaneous Control of Molecular Weight and Tacticity
      Wan, Decheng; Satoh, Kotaro; Kamigaito, Masami; Okamoto, Yoshio
      Macromolecules (2005), 38 (25), 10397-10405CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      The simultaneous control of the tacticity and mol. wt. of poly(N-vinylpyrrolidone) during radical polymn. is reported for the first time. For mol. wt. control, xanthates of (O-ethylxanthylmethyl)benzene and [1-(O-ethylxanthyl)ethyl]benzene were used as RAFT/MADIX chain transfer agents (CTAs) for the radical polymn. of N-vinylpyrrolidone (NVP). Both led to a controlled/living radical polymn., and the latter showed higher chain transfer ability under the optimal conditions; the mol. wt. distribution was 1.36 when the mol. wt. was up to 26 700. The polymn. was studied between 20 and 120° and at various concns. of CTA. All the polymns. showed an induction period and rate retardation dependent on both the concn. of CTA and temp. For tacticity control, the polymn. was carried out in fluoroalcs. via a conventional radical process without CTAs to give syndiotactic polymers. The polymer tacticity was dependent on the amt. of the fluoroalc., and a more acidic and bulkier fluoroalc. led to a higher syndiotacticity. Esp. with (CF3)3COH, the r dyad increased to 62.6% from 53.5% for the atactic poly(NVP) obtained in the usual solvents. The 1H NMR anal. of the mixt. of NVP and the fluoroalcs. indicated that a 1:1 hydrogen-bonding complex was formed, suggesting that the complex was responsible for the tacticity control of the polymer. When the CTA was used in the fluoroalcs., the living and syndiospecific polymn. proceeded to enable the simultaneous control of the mol. wt. and the tacticity.
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    90. 90
      Kang, H. U.; Yu, Y. C.; Shin, S. J.; Kim, J.; Youk, J. H. One-Pot Synthesis of Poly(N-Vinylpyrrolidone)-b-Poly(ε-Caprolactone) Block Copolymers Using a Dual Initiator for RAFT Polymerization and ROP. Macromolecules 2013, 46 (4), 1291– 1295,  DOI: 10.1021/ma302372h
      90
      One-Pot Synthesis of Poly(N-vinylpyrrolidone)-b-poly(ε-caprolactone) Block Copolymers Using a Dual Initiator for RAFT Polymerization and ROP
      Kang, Hyun Uk; Yu, Young Chang; Shin, Sang Jin; Kim, Jinsang; Youk, Ji Ho
      Macromolecules (Washington, DC, United States) (2013), 46 (4), 1291-1295CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      Well-defined amphiphilic poly(N-vinylpyrrolidone)-b-poly(ε-caprolactone) (PVP-b-PCL) block copolymers were synthesized at 30° using a hydroxyl-functionalized xanthate reversible addn.-fragmentation chain transfer (RAFT) agent, 2-hydroxyethyl 2-(ethoxycarbonothioylthio)propanoate, as a dual initiator for RAFT polymn. and ring-opening polymn. (ROP) in a one-pot procedure. Hydrophilic PCL blocks were first synthesized via the ROP of ε-caprolactone (CL) using di-Ph phosphate as a catalyst followed by the RAFT polymn. of N-vinylpyrrolidone (VP) by the addn. of VP and 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70) to the reaction mixt. VP quenched the ROP of CL, and V-70 initiated the RAFT polymn. of VP. The resulting PVP-b-PCL block copolymers showed very narrow mol. wt. distributions, indicating that the ROP and RAFT polymn. proceeded independently in a controlled manner. To the best of our knowledge, this one-pot process is the most convenient method for the synthesis of PVP-b-PCL block copolymers. The PVP-b-PCL block copolymers could be labeled fluorescently through a reaction with rhodamine B isothiocyanate in the same pot.
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    91. 91
      Zhou, W.; Qu, Q.; Xu, Y.; An, Z. Aqueous Polymerization-Induced Self-Assembly for the Synthesis of Ketone-Functionalized Nano-Objects with Low Polydispersity. ACS Macro Lett. 2015, 4 (5), 495– 499,  DOI: 10.1021/acsmacrolett.5b00225
      91
      Aqueous Polymerization-Induced Self-Assembly for the Synthesis of Ketone-Functionalized Nano-Objects with Low Polydispersity
      Zhou, Wei; Qu, Qingwu; Xu, Yuanyuan; An, Zesheng
      ACS Macro Letters (2015), 4 (5), 495-499CODEN: AMLCCD; ISSN:2161-1653. (American Chemical Society)
      Efficient synthesis of functionalized, uniform polymer nano-objects in water with controlled morphologies in one step and at high concns. is extremely attractive, from perspectives of both materials applications and industrial scale-up. Herein, we report a novel formulation for aq. reversible addn.-fragmentation chain transfer (RAFT) dispersion polymn. based on polymn.-induced self-assembly (PISA) to synthesize ketone-functionalized nanospheres and vesicles. Significantly, the core-forming block was composed entirely of a ketone-contg. polymer from a commodity monomer diacetone acrylamide (DAAM), resulting in a high d. of ketone functionality in the nano-objects. Producing uniform vesicles represents another challenge both in PISA and in the traditional self-assembly process. Aiming at producing uniform nano-objects, esp. vesicles, in such a highly efficient aq. PISA process, we devised strategies to allow sufficient time for the in situ generated polymers to relax and reorganize into vesicles with a remarkably low polydispersity. Specifically, both reducing the radical initiator concn. and lowering the polymn. temp. were effective for improving the uniformity of vesicles. Such an efficient, aq. PISA to produce functionalized and uniform nano-objects with controlled morphologies at solid contents up to 20% represents important progress in the field.
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    92. 92
      Parkinson, S.; Hondow, N. S.; Conteh, J. S.; Bourne, R. A.; Warren, N. J. All-Aqueous Continuous-Flow RAFT Dispersion Polymerisation for Efficient Preparation of Diblock Copolymer Spheres Worms and Vesicles. React. Chem. Eng. 2019, 4 (5), 852– 861,  DOI: 10.1039/C8RE00211H
      92
      All-aqueous continuous-flow RAFT dispersion polymerisation for efficient preparation of diblock copolymer spheres, worms and vesicles
      Parkinson, Sam; Hondow, Nicole S.; Conteh, John S.; Bourne, Richard A.; Warren, Nicholas J.
      Reaction Chemistry & Engineering (2019), 4 (5), 852-861CODEN: RCEEBW; ISSN:2058-9883. (Royal Society of Chemistry)
      We report the scalable, all-aq. synthesis of poly(dimethylacrylamide)-poly(diacetone acrylamide) (PDMAm-PDAAm) diblock copolymer spheres, worms and vesicles by reversible addn.-fragmentation chain transfer (RAFT) aq. dispersion polymn. in a low-cost continuous-flow (CF) reactor. A transient state kinetic profiling method using a 5 mL reactor coil indicated a considerably faster rate than the equiv. batch reaction. Higher throughput was subsequently demonstrated by employing a 20 mL coil reactor for the synthesis of a 135 g, 30% wt./wt. batch of PDMAm113 macromol. chain transfer agent (macro-CTA) at 98% conversion. This was used without further purifn. to polymerise DAAm in a CF reactor. During this polymn., the chains underwent polymn.-induced self-assembly (PISA) producing block copolymer spheres. This reaction also proceeded faster than in batch, and the high resoln. kinetics enabled clear observation of the rate enhancement which is characteristic of PISA systems. GPC studies indicated the formation of a copolymer with low molar mass dispersity and complete blocking efficiency, despite the high conversion achieved during the precursor macro-CTA synthesis. It was subsequently demonstrated that the PDMAm113 macro-CTA could be used to prep. PDMAm113-PDAAmx block copolymer spheres (where x = 50, 100 and 200) with systematically increasing particle diams. Finally, by reducing the PDMAm macro-CTA DP to 50 and increasing total solids to 20% wt./wt., it was possible to prep. worms and vesicles in the tubular reactor by tailoring the residence time to achieve specific degrees of polymn. of the PDAAm block.
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    93. 93
      Figg, C. A.; Carmean, R. N.; Bentz, K. C.; Mukherjee, S.; Savin, D. A.; Sumerlin, B. S. Tuning Hydrophobicity To Program Block Copolymer Assemblies from the Inside Out. Macromolecules 2017, 50 (3), 935– 943,  DOI: 10.1021/acs.macromol.6b02754
      93
      Tuning Hydrophobicity To Program Block Copolymer Assemblies from the Inside Out
      Figg, C. Adrian; Carmean, R. Nicholas; Bentz, Kyle C.; Mukherjee, Soma; Savin, Daniel A.; Sumerlin, Brent S.
      Macromolecules (Washington, DC, United States) (2017), 50 (3), 935-943CODEN: MAMOBX; ISSN:0024-9297. (American Chemical Society)
      Hydrophobicity inherently affects a solutes behavior in water, yet how polymer chain hydrophobicity impacts aggregate morphol. during soln. self-assembly and reorganization is largely overlooked. As polymer and nanoparticle syntheses are easily achieved, the resultant nanoparticle architectures are usually attributed to chain topol. and overall d.p., bypassing how the chains may interact with water during/after self-assembly to elicit morphol. changes. Herein, we demonstrate how block copolymer hydrophobicity allows control over aggregate morphol. in water and leads to remarkable control over the length of polymeric nanoparticle worms. Polymn.-induced self-assembly facilitated nanoparticle synthesis through simultaneous polymn., self-assembly, and chain reorganization during a block copolymer chain extension from a hydrophilic poly(N,N-dimethylacrylamide) macro chain transfer agent with diacetone acrylamide and N,N-dimethylacrylamide. Slight variations in the monomer feed ratio dictated the block copolymer chain compn. and were proposed to alter aggregate thermodn. Micelles, worms, and vesicles were synthesized, and the highest level of control over worm elongation attained during a polymn. is reported, simply due to the polymer chain hydrophobicity.
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    94. 94
      Tam, R. Y.; Ferreira, S. S.; Czechura, P.; Ben, R. N.; Chaytor, J. L. Hydration Index-a Better Parameter for Explaining Small Molecule Hydration in Inhibition of Ice Recrystallization. J. Am. Chem. Soc. 2008, 130 (7), 17494– 17501,  DOI: 10.1021/ja806284x
      94
      Hydration Index-A Better Parameter for Explaining Small Molecule Hydration in Inhibition of Ice Recrystallization
      Tam, Roger Y.; Ferreira, Sandra S.; Czechura, Pawel; Chaytor, Jennifer L.; Ben, Robert N.
      Journal of the American Chemical Society (2008), 130 (51), 17494-17501CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Several simple mono- and disaccharides have been assessed for their ability to inhibit ice recrystn. Two carbohydrates were found to be effective recrystn. inhibitors. D-Galactose was the best monosaccharide and D-melibiose was the most active disaccharide. The ability of each carbohydrate to inhibit ice growth was correlated to its resp. hydration no. reported in the literature. A hydration no. reflects the no. of tightly bound water mols. to the carbohydrate and is a function of carbohydrate stereochem. It was discovered that using the abs. hydration no. of a carbohydrate does not allow one to accurately predict its ability to inhibit ice recrystn. Consequently, we have defined a hydration index in which the hydration no. is divided by the molar volume of the carbohydrate. This new parameter not only takes into account the no. of water mols. tightly bound to a carbohydrate but also the size or vol. of a particular solute and ultimately the concn. of hydrated water mols. The hydration index of both mono- and disaccharides correlates well with exptl. measured RI activity. C-Linked derivs. of the monosaccharides appear to have RI activity comparable to that of their O-linked saccharides but a more thorough investigation is required. The relationship between carbohydrate concn. and RI activity was shown to be noncolligative and a 0.022 M soln. of D-galactose (1) and C-linked galactose deriv. (10) inhibited recrystn. as well as a 3% DMSO soln. The carbohydrates examd. in this study did not possess any thermal hysteresis activity (selective depression of f.p. relative to m.p.) or dynamic ice shaping. As such, we propose that they are inhibiting recrystn. at the interface between bulk water and the quasi liq. layer (a semiordered interface between ice and bulk water) by disrupting the preordering of water.
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