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Endogenously Triggerable Ultrasmall-in-Nano Architectures: Targeting Assessment on 3D Pancreatic Carcinoma Spheroids

  • Ana Katrina Mapanao
    Ana Katrina Mapanao
    Center for Nanotechnology Innovation, NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro, 12, 56126 Pisa, Italy
    NEST—Scuola Normale Superiore, Piazza San Silvestro, 12, 56126 Pisa, Italy
    More by Ana Katrina Mapanao
  • , 
  • Melissa Santi
    Melissa Santi
    Center for Nanotechnology Innovation, NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro, 12, 56126 Pisa, Italy
    More by Melissa Santi
  • , 
  • Paolo Faraci
    Paolo Faraci
    NEST—Scuola Normale Superiore, Piazza San Silvestro, 12, 56126 Pisa, Italy
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  • , 
  • Valentina Cappello
    Valentina Cappello
    Center for Nanotechnology Innovation, NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro, 12, 56126 Pisa, Italy
    More by Valentina Cappello
  • , 
  • Domenico Cassano
    Domenico Cassano
    Center for Nanotechnology Innovation, NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro, 12, 56126 Pisa, Italy
    NEST—Scuola Normale Superiore, Piazza San Silvestro, 12, 56126 Pisa, Italy
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  • , and 
  • Valerio Voliani*
    Valerio Voliani
    Center for Nanotechnology Innovation, NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro, 12, 56126 Pisa, Italy
    *E-mail: [email protected]
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    Orcidhttp://orcid.org/0000-0003-1311-3349
Cite this: ACS Omega 2018, 3, 9, 11796–11801
Publication Date (Web):September 24, 2018
https://doi.org/10.1021/acsomega.8b01719

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Abstract

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Several nanomaterials rely on the passive accumulation in the neoplasm target because of enhanced permeability and retention effect. On the other hand, directing nanomaterials to the target by employing the targeting agents may lead to a pivotal improvement in the efficacy of the treatment for a number of cancers. However, targeting moieties often lose their functionality upon injection in the bloodstream, leaving questions on their efficiency. Here, we assessed using a significant in vitro 3D model of pancreatic carcinoma the targeting efficiency of passion fruit-like nanoarchitectures (NAs) incorporated with a peptide that can recognize transferrin directly in the medium, thereby modulating protein solvation. NAs are biodegradable ultrasmall-in-nano platforms that combine the most appealing behaviors of noble metal nanomaterials with organism excretion of the building blocks by the renal pathway. Although the confocal images did not illustrate the significant differences in the targeting efficiency of the peptide-modified NAs, an improved internalization was quantitatively observed by inductively coupled plasma-mass spectrometry analysis. Our findings demonstrate that the peptide conjugation of NAs might be considered to enhance their theranostic potentials for this type of neoplasm.

Introduction

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Accurate delivery of therapeutics to the site of interest is pivotal for the treatment of a number of diseases, among which are neoplasms, in order to enhance the efficacy while decreasing the adverse side effects. (1,2) On the one hand, nanomaterials have commonly demonstrated an intrinsic ability to passively accumulate in a number of neoplasms because of the enhanced permeability and retention (EPR) effect. (1,2) On the other hand, an increasing number of investigations have shed light on the fact that the EPR is a complex phenomenon that may not accurately represent the biological dynamics in humans. (2,3) Thus, despite some drawbacks such as complex postprocessing procedures, additional production cost, and uncertain efficiency, a number of targeting agents have been developed and conjugated to nanomaterials. (4,5) An elegant approach to enhance the targeting efficacy of nanomaterials is through modulation of their protein corona composition, which leads to an endogenously triggered selectivity. (6) Meanwhile, besides localized accumulation of nanomaterials to the target, other concerns have hampered the translation to clinical practice of almost all the candidates developed in the last 30 years. (7,8) This is especially true for noble metal nanoparticles (NPs), which still remain confined to the bench-side because of the concerns on undefined persistence, despite a number of appealing features for theranostics. (9−12) The combination of the behaviors of NPs with the metal excretion from the renal pathway was recently demonstrated by the platforms developed within the ultrasmall-in-nano approach. (12) Passion fruit-like nanoarchitectures (NAs) are promising examples of nature-inspired ultrasmall-in-nano platform that may bring again NPs to the forefront of cancer theranostics by overcoming the key question of regulatory agencies regarding the metal persistence after the designed action. (13,14) NAs are biodegradable silica nanocapsules comprising gold ultrasmall NPs (USNPs) embedded in a polymeric functional matrix. (13) In cellular environment, NAs disassemble to biocompatible and renal clearable building blocks in 48 h: silicic acid, polymers, and endogenous glutathione (GSH) coated gold USNP. (14−16) Furthermore, the impressive versatility and robustness of the production protocol was already demonstrated together with some of their potential applications as drug delivery vehicles and dual photoacoustic/ultrasound imaging contrast agents, pointing out that all the components of NAs are intrinsically essential. (14,17,18)
Here, we utilized the straightforwardly modifiable surface of NAs to perform a click chemistry conjugation of the NPs to a customized peptide. The employed peptide (Tf2, sequence: CGGGHKYLRW) binds with transferrin (Kd = 0.90 ± 0.25 μM) and was designed to target cells overexpressing the transferrin receptor. (6) Moreover, Tf2 is capable of endogenously triggering an enhanced accumulation of NAs in neoplasms by the protein corona modulation. The cell targeting and internalization performance of peptide-functionalized NAs were quantitatively assessed on significant in vitro three-dimensional (3D) models of pancreatic carcinoma. We have developed 3D spheroids because of their closer resemblance to in vivo models compared to conventional two-dimensional (2D) monolayer cell cultures. The advantages of using 3D spheroids include the establishment of tumor microenvironment, physiochemical gradients, and cell–cell/cell–matrix interactions. (19) In addition, in vitro 3D models are in agreement with the development and promotion of alternatives to animal experiments according to the “3Rs concept”. (20)

Results and Discussion

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The 3D cultures of MIA PaCa-2 were prepared by a modified hanging method and maintained in an incubator with an orbital shaker. (21) It was worth noticing that the orbital shaking was crucial for the maintenance of the 3D cultures to avoid monolayer proliferation. The 3D cell cultures can be maintained for up to 1 month, and the diameter of the spheroids range from 650 μm to about 1 mm. In order to improve the consistency of our investigation, the 3D spheroids were maintained for 12–14 days, reaching an average diameter of 950 μm. In Figure 1A, the bright-field microscopy image of a typical 3D MIA PaCa-2 spheroid is reported, demonstrating the concentric arrangement of viable and necrotic cells. Moreover, the 3D spheroids were observed to be a composite of spherical cells with an average size of 17.1 ± 2.9 μm (Figure 1B,C). The orthogonal view (Figure S1A) illustrated the spherical construction of the cells more evidently. For comparison, we also cultured MIA PaCa-2 cells in a standard 2D monolayer fashion (Figure 1D,E), demonstrating an epithelial-like growth. The transmission electron microscopy (TEM) ultrastructure analysis confirmed that the morphology of the MIA PaCa-2 cells was similar in both 2D and 3D cultures (Figure S2A,B). Interestingly, cells composing the 3D models were interconnected mostly by an early tight junction (Figure S2C,D). Signs of mild hypoxia were also observed (Figure S2C).

Figure 1

Figure 1. (A) Bright-field microscopy image of the 3D MIA PaCa-2 cell culture prepared through the hanging method (scale bar: 100 μm). Zoomed-in bright-field (B) and confocal (C) microscopy images of the MIA PaCa-2 cultured in 3D (scale bars: 10 μm). Bright field (D) and confocal (E) microscopy images of MIA PaCa-2 cultured in 2D (scale bar: 10 μm). The nuclei (blue) and the cell membranes (green) were stained with Hoechst 33342 and CellMask green plasma membrane stain, respectively.

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Passion fruit-like NAs were produced by employing the standard protocol. (13) The general synthesis scheme to obtain about 100 nm NAs (Figure S3A) is illustrated in Figure 2A. To track NAs during the cellular investigations, commercial AlexaFluor-647 was covalently linked to the polymer [poly-(l-lysine); 15–30 kDa] prior to its use to synthesize the dye-loaded NAs (NAs-647). (15) As expected, the absorbance spectrum of NAs-647 (Figure 2B) showed the presence of bands because of the dye and the localized surface plasmon resonance (LSPR) of gold USNPs. Only the absorbance due to LSPR was observed on the spectrum of the standard NAs. Furthermore, previous surface-enhanced Raman spectroscopy investigations have demonstrated that the dyes were comprised in the cavity and not on the surface of NAs. (13) The surface modification of NAs-647 was performed employing a 2 kDa silane–poly(ethylene glycol) (PEG)–maleimide linker in order to (i) incorporate a thiol-reactive group on the surface of NAs through a single postprocessing step and (ii) utilize the benefits of PEGylation on nanoparticle-based theranostics. (22) Then, the click chemistry conjugation of Tf2 peptide to NAs was performed through a maleimide–thiol reaction. The potential free-maleimide groups left on the surface of NAs were blocked by employing GSH. The changes in the zeta potential values after each step confirmed the success of the procedure (Figure S3B). Indeed, the zeta potential for NAs-647 was −21.3 ± 0.6 mV and increased to −7.23 ± 0.41 mV for NAs-647–Tf2 because of the presence of the peptide. GSH blocking slightly decreased the zeta potential to −8.09 ± 0.53 mV, confirming the presence of some free-maleimide groups after the reaction with Tf2, to which GSH subsequently reacted with. All cellular experiments were performed using GSH-treated NAs-647–Tf2. Remarkably, the TEM images (Figure 2C) highlighted that the postprocessing steps did not affect the physical structure of the NAs. NAs, NAs-647, and NAs-647–Tf2 maintained the “passion fruit-like arrangement,” and no significant structural modifications were recognized. To further ensure the success of the functionalization procedure, the maleimide–thiol reaction was also performed using a thiol-modified Atto-425 instead of Tf2 (NAs-647–SH-Atto425). The same dye containing a carboxylic acid functional group was employed to serve as the control sample (NAs-647/Atto425-COOH). The confocal images after incubation of 3D MIA PaCa-2 models with both samples (Figure S4) confirmed through Pearson’s coefficient the higher colocalization of NAs-647 and Atto-425 in NAs-647–SH-Atto425 compared to the control NAs-647/Atto425-COOH.

Figure 2

Figure 2. (A) Scheme of the synthesis of NAs-647–Tf2. Gold USNPs were embedded in AlexaFluor-647-modified poly(l-lysine). The polymeric aggregates were employed as templates to form hollow silica nanocapsules (NAs) by a modified Stöber method. The surface of NAs was modified by silane–PEG–maleimide linkers. Finally, NAs were click-chemical functionalized by the peptide Tf2, and GSH was added to block the excess maleimide ends. (B) Background-subtracted UV–vis spectrum of standard NAs (the continuous black line) and NAs-647 (the red dashed line). Measurements were performed in PBS. (C) TEM images of NAs (left), NAs-647 (middle), and GSH-treated NAs-647–Tf2 (right). The Gray matrix is due to a not-completely-dry sample during the imaging. Scale bar: 50 nm.

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NAs-647 and NAs-647–Tf2 were incubated for 2 h with 3D MIA PaCa-2 models, and confocal images were collected from 0 to 72 h postincubation (Figure 3A). At t = 0 h, both NAs attached on the cell membranes resulting in individual dots of similar size (inset of Figure 3A). After 24 h, the signals from both types of NAs appeared more aggregated and more colocalized inside the cells, highlighting an internalization process. Overall, no qualitative differences on the targeting efficiency were distinguished between NAs-647 and NAs-647–Tf2. Interestingly, the intensity of the signals from the dye increased for both samples at 48 and 72 h time points. This can be related to the changes in the structures of NAs-647 and NAs-647–Tf2, implying their biodegradation. Indeed, at time 0 and 24 h, the NAs were intact, and the dye was quenched because of the proximity to the gold USNPs, leading to reduced emission intensity. (14) On the other hand, at later time points, NAs disassembled, allowing the dye to increase the distance from gold USNPs surfaces. This observation was further supported by the decreasing amount of gold quantified through inductively coupled plasma-mass spectrometry (ICP-MS). It is worth noticing that the imaging quality in confocal microscopy is dependent on the sample depth. Cells and NAs located in the inner part of the 3D cell constructs were not clearly imaged. Therefore, analytical instruments, such as ICP-MS, provide complementary data that take into consideration the total gold content of the whole 3D cell construct, for a quantitative analysis of the samples. Furthermore, the collected data can be normalized for both the gold loaded in the nanomaterials and the protein content of the 3D cell constructs, in order to obtain a more accurate comparison of the targeting and internalization efficiencies of nanomaterials. Indeed, the collected amount of gold from both NAs-647 and NAs-647–Tf2 was double-normalized to the total protein content and to the starting amount of gold on each NAs where the 3D spheroids were incubated (Figure 3B). NAs-647–Tf2 resulted to an average of 1.5× higher internalization with respect to NAs-647. Overall, the surface functionalization and peptide conjugation of NAs may not have generated a substantial improvement in the targeting efficiency of NAs but led to an increased particle cell internalization. On the other hand, the significant internalization of nontargeted NAs-647 may be due to the ability of the MIA PaCa-2 cells to uptake materials from the environment even if organized in 3D models. Apart from enhanced internalization, NAs-647–Tf2 also demonstrated intracellular retention. This effect can be related to the transferrin receptor-mediated endocytosis, which may also have a different intracellular fate compared to the nonspecific endocytosis of unfunctionalized particles. (23)

Figure 3

Figure 3. (A) Confocal images of 3D MIA PaCa-2 at four postincubation time points. Cells were incubated for 2 h on NAs-647 or NAs-647–Tf2. The signals for NAs are in red. The nuclei (blue) were stained with Hoechst 33342, and the cell membranes (green) were stained using a CellMask green plasma membrane stain. Inset: zoom-in on a single cell. Scale bars: 20 μm. (B) Quantitative analysis of gold detected by ICP-MS in the 3D MIA PaCa-2 spheroids incubated with NAs-647 (black) and NAs-647–Tf2 (red). The raw data were normalized for (i) the initial gold concentration during the incubation and (ii) the total protein content.

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Conclusions

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In summary, we have evaluated the targeting and internalization efficiency of the peptide-functionalized passion fruit-like NA on 3D pancreatic carcinoma models. The confocal microscopy images confirmed the cell localization and internalization of both targeted and nontargeted NAs after 2 h of incubation. Furthermore, we have quantified an increased cell internalization of the peptide-conjugated NA. Thus, this approach can be considered to improve nanoparticle internalization for this kind of neoplasm, regardless of the concerns with targeting moiety conjugation in terms of additional procedures and cost.

Experimental Section

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Materials

Alexa-647 was purchased from Invitrogen, and silane–PEG–maleimide (2 kDa) was from Nanocs. All other chemicals were purchased from Sigma-Aldrich, unless otherwise specified. All chemicals were used as received.

Synthesis of Passion Fruit-Like NAs

Synthesis of Dye-Modified Poly(l-lysine)

Poly(l-lysine) hydrobromide (15–30 kDa) was dissolved in Milli-Q water to a final concentration of 20 mg/mL. From this stock solution, 150 μL was added with AlexaFluor-647-NHS ester (200 μg) in phosphate-buffered saline (PBS) (200 μL). The solution was stirred overnight at room temperature and used without further purification.

Synthesis of Gold USNPs

Gold USNPs with a diameter of approximately 3 nm were prepared by mixing Milli-Q water (20 mL), poly(sodium 4-styrene sulfonate) (70 kDa, 30% aqueous solution), and HAuCl4 solution (10 mg/mL in Milli-Q). The solution was stirred vigorously while adding 200 μL of 8 mg/mL NaBH4. The solution was allowed to further mix for 2 min and aged for another 10 min.

Synthesis of Gold Nanoparticle Arrays

Poly(l-lysine) (200 μL), plain or dye-modified, was added to the solution containing the gold USNPs. The solution was stirred for 20 min. The gold aggregates were collected through centrifugation at 13 400 rpm for 3 min. The product was resuspended in Milli-Q water (2 mL) and sonicated for a maximum of 4 min.

Synthesis of NAs or NAs-647

The synthesized gold nanoparticle arrays (2 mL in Milli-Q) were added to a solution containing absolute ethanol (70 mL), ammonium hydroxide solution (2.4 mL, 30% in water), and tetraethyl orthosilicate (40 μL, 98%). The solution was allowed to gently shake for 3 h. The products, NAs or NAs-647, were collected by centrifugation at 4000 rpm for 30 min. Particles were washed twice with ethanol to remove unreacted precursors. A short-spin centrifugation was done to separate particles with the diameter greater than 200 nm. The supernatant was then collected and centrifuged again at 13 400 rpm for 2.5 min. The final product was stored in 1 mL of ethanol.

Surface Modification and Functionalization of NAs-647

NAs-647 was added to ethanol (5 mL) with a silane–PEG–maleimide linker (1 mL, 400 μg/mL). The volume was adjusted to 10 mL using ethanol, and the solution was stirred vigorously for 15 min. The particles were recovered by centrifugation at 13 400 rpm for 5 min and washed with ethanol twice. Then, the particles were resuspended in N-(2-hydroxyethyl)piperazine-N′-ethanesulfonic acid (HEPES) buffer (1.25 mL, 20 mM, pH 7.2) and sonicated. The Tf2 peptide was prepared as reported elsewhere. (6) The peptide (250 μL, 400 μg/mL in HEPES buffer) was added, and the solution was stirred for 2 h. l-GSH (500 μL, 200 μg/mL in HEPES buffer) was then added to the solution to react with the excess of maleimide groups. The reaction was stirred for another hour. NAs-647–Tf2 was recovered by centrifugation at 13 400 rpm for 3 min. Particles were washed twice in ethanol. The final product was stored in ethanol to maintain sterility and sonicated for 5 min.

UV–Vis Spectrophotometry

The absorption spectra were obtained using a double-beam Jasco V-550 spectrophotometer. The samples in PBS (1×) were placed in quartz cuvettes with a 1.5 mm path length.

Electron Microscopy

The TEM observations of particles and cells were performed in ZEISS Libra 120 and operated at an accelerating voltage of 120 kV. The colloidal solutions of the NPs (5 μL) were deposited to a 300-mesh of carbon-coated copper grids.

Ultrastructure Analysis of 3D MIA PaCa-2

The MIA PaCa-2 3D spheroids in the suspension have been fixed in 2% glutaraldehyde in sodium cacodylate buffer (0.1 M pH 7.4) for 1 h at room temperature and then treated for resin embedding as previously reported. (24) Briefly, the recovered spheroids were kept in a new fixative solution (overnight at 4 °C), then the cells were postfixed 1 h (2% OsO4 in sodium cacodylate buffer; 0.1 M pH 7.4), and stained with 3% solution of uranyl acetate in 20% ethanol. Finally, they were dehydrated and embedded in epoxy resin (Epon 812, Electron Microscopy Science, Hatfield, PA, USA). Polymerization has been performed for 48 h at 60 °C. In order to perform ultrastructural analysis, 90 nm sections of the treated samples were cut by using UC7 (Leica Microsystems, Vienna, Austria).

Zeta Potential Measurement

The zeta potential measurements were performed on Malvern Zetasizer nano ZS90 using a DTS 1060 standard capillary cell. During measurements, the NPs were resuspended in PBS (2 mL) at pH 7.4 and sonicated for 5 min. The reported values are the average of five consecutive measurements.

3D Cell Culture

Human pancreatic carcinoma cells (MIA PaCa-2) were purchased from the American Type Culture Collection. The cells cultured in 2D were maintained in a Dulbecco’s modified Eagle medium from Invitrogen (Carlsbad, CA) supplemented with 10% fetal bovine serum (FBS), 4 mmol/L l-glutamine, 100 U/mL penicillin, and 100 mg/mL streptomycin (Invitrogen). 3D cell constructs were prepared as reported elsewhere, with slight modifications. (21) Briefly, cells cultured in 2D were washed with PBS and detached from the culture plate using trypsin–ethylenediaminetetraacetic acid (Invitrogen). Cells were settled by centrifugation at 200g for 5 min. Fresh culture medium was added. The cells were counted, and the concentration was adjusted to 1 × 106 cells/mL. After homogenizing, 10 μL of cell suspension drops were placed on the lid of a 35 mm cell culture dish. The lid was flipped into the chamber containing 2 mL of PBS. The cells were allowed to settle at the bottom of the drops and were transferred to a 35 mm suspension/nontreated culture dish after 24 h. The cells were finally placed inside a CO2 incubator with an orbital shaker (90 rpm).

Cell Incubation in NAs

In a 500 μL plastic vial, a 200 μL aliquot of NAs-647 or NAs-647–Tf2 stored in ethanol was added. The particles were collected by centrifugation, resuspended in a complete medium (200 μL), and sonicated for 5 min. NAs were then added to a 2 mL plastic vial containing 800 μL of the complete medium and the 3D models, which were transferred using 1 mL pipet tips. The vials were incubated for 2 h at 37 °C and 5% CO2. After that, the cells were washed with PBS twice. All the 3D models were transferred to a 35 mm nontreated culture dish with 3 mL of the complete medium. The cells evaluated on different time points were taken from the same culture dish.

Confocal Microscopy

In a 2 mL plastic vial, four to six cell constructs were collected using 1 mL pipet tips. The cells were settled and washed in PBS, whereas in 100 μL of PBS, Hoechst 33342 (Invitrogen; 80 μg/mL) and CellMask green plasma membrane stain (Invitrogen; 10 μg/mL) were added, and the cells were incubated at 37 °C and 5% CO2 for 15 min. Afterward, the cells were washed twice with PBS, transferred to a LabTek 8-well chambered cover glass, and added with a 1:1 solution of 70% glycerol and FBS. Imaging was performed on an Olympus FV1000 inverted confocal laser scanning microscope equipped with a thermostat chamber set at 37 °C and 5% CO2. The lasers for excitation were 405, 488, and 633 nm. Imaging was done 0, 24, 48, and 72 h after incubation. All images were analyzed using Fiji-ImageJ software version 1.51s.

Bradford Assay

In a 2 mL plastic vial, four to six cell constructs were collected using 1 mL pipet tips. The cells were settled and washed three times with cold PBS. For the final washing, the cells were centrifuged at 13 400 rpm, 4 °C for 10 min. The supernatant was removed, and the cells were added with 50 μL of lysis buffer. The samples were agitated for 1 h. The lysates were separated by centrifugation at 13 400 rpm, 4 °C for 10 min. The pellets were saved for gold quantification. The Bradford assay samples were prepared in 1:5 dilution in PBS. The calibration curve was prepared using bovine serum albumin standards. Samples, calibration solution, and blank (3 μL) were placed on 96-well plates, and 150 μL of Bradford assay solution (Thermo Fisher Scientific) was added. The plate was incubated for 10 min at room temperature, and the absorbance at 595 nm was recorded.

ICP-MS Analysis

Lysates and pellets were combined, dissolved in 1 mL ICP-MS-grade HNO3, and digested by microwave irradiation (200 °C/15 min) in borosilicate glass vessels. An aliquot (200 μL) of the digested sample solution was diluted to 2 mL with ICP-MS-grade water. The content of gold was determined by ICP-MS analysis against a standard calibration curve.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b01719.

  • Orthogonal view and bright-field microscopy image of 3D MIA PaCa-2; TEM ultrastructure of 3D MIA PaCa-2; size histograms and zeta potential values of NAs-647, NAs-647–Tf2 without GSH, and NAs-647–Tf2/GSH; and confocal microscopy images of 3D MIA PaCa-2 employed for double-color analysis (PDF)

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Author Information

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  • Corresponding Author
  • Authors
    • Ana Katrina Mapanao - Center for Nanotechnology Innovation, NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro, 12, 56126 Pisa, Italy;  NEST—Scuola Normale Superiore, Piazza San Silvestro, 12, 56126 Pisa, Italy
    • Melissa Santi - Center for Nanotechnology Innovation, NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro, 12, 56126 Pisa, Italy
    • Paolo Faraci - NEST—Scuola Normale Superiore, Piazza San Silvestro, 12, 56126 Pisa, Italy
    • Valentina Cappello - Center for Nanotechnology Innovation, NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro, 12, 56126 Pisa, Italy
    • Domenico Cassano - Center for Nanotechnology Innovation, NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro, 12, 56126 Pisa, Italy;  NEST—Scuola Normale Superiore, Piazza San Silvestro, 12, 56126 Pisa, Italy
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work is supported by the MFAG grant number 19852 from Associazione Italiana per la Ricerca sul Cancro (AIRC) provided to V.V.

References

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    Clearance Pathways and Tumor Targeting of Imaging Nanoparticles
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    ACS Nano (2015), 9 (7), 6655-6674CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    A review. A basic understanding of how imaging nanoparticles are removed from the normal organs/tissues but retained in the tumors is important for their future clin. applications in early cancer diagnosis and therapy. In this review, we discuss current understandings of clearance pathways and tumor targeting of small-mol.- and inorg.-nanoparticle-based imaging probes with an emphasis on mol. nanoprobes, a class of inorg. nanoprobes that can escape reticuloendothelial system (RES) uptake and be rapidly eliminated from the normal tissues/organs via kidneys but can still passively target the tumor with high efficiency through the enhanced permeability permeability and retention (EPR) effect. The impact of nanoparticle design (size, shape, and surface chem.) on their excretion, pharmacokinetics, and passive tumor targeting were quant. discussed. Synergetic integration of effective renal clearance and EPR effect offers a promising pathway to design low-toxicity and high-contrast-enhancement imaging nanoparticles that could meet with the clin. translational requirements of regulatory agencies.
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    The big picture on nanomedicine: the state of investigational and approved nanomedicine products
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    Developments in nanomedicine are expected to provide solns. to many of modern medicine's unsolved problems, so it is no surprise that the literature contains many articles discussing the subject. However, existing reviews tend to focus on specific sectors of nanomedicine or to take a very forward-looking stance and fail to provide a complete perspective on the current landscape. This article provides a more comprehensive and contemporary inventory of nanomedicine products. A keyword search of literature, clin. trial registries, and the Web yielded 247 nanomedicine products that are approved or in various stages of clin. study. Specific information on each was gathered, so the overall field could be described based on various dimensions, including FDA classification, approval status, nanoscale size, treated condition, nanostructure, and others. In addn. to documenting the many nanomedicine products already in use in humans, this study indentifies several interesting trends forecasting the future of nanomedicine.In this one of a kind review, the state of nanomedicine commercialization is discussed, concg. only on nanomedicine-based developments and products that are either in clin. trials or have already been approved for use.
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    Santi, M.; Maccari, G.; Mereghetti, P.; Voliani, V.; Rocchiccioli, S.; Ucciferri, N.; Luin, S.; Signore, G. Rational Design of a Transferrin-Binding Peptide Sequence Tailored to Targeted Nanoparticle Internalization. Bioconjugate Chem. 2017, 28, 471– 480,  DOI: 10.1021/acs.bioconjchem.6b00611
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    Bioconjugate Chemistry (2017), 28 (2), 471-480CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    The transferrin receptor (TfR) is a promising target in cancer therapy owing to its overexpression in most solid tumors and on the blood-brain barrier. Nanostructures chem. derivatized with transferrin are employed in TfR targeting but often lose their functionality upon injection in the bloodstream. As an alternative strategy, we rationally designed a peptide coating able to bind transferrin on suitable pockets not involved in binding to TfR or iron by using an iterative multiscale-modeling approach coupled with quant. structure-activity and relationship (QSAR) anal. and evolutionary algorithms. We tested that selected sequences have low aspecific protein adsorption and high binding energy toward transferrin, and one of them is efficiently internalized in cells with a transferrin-dependent pathway. Furthermore, it promotes transferrin-mediated endocytosis of gold nanoparticles by modifying their protein corona and promoting oriented adsorption of transferrin. This strategy leads to highly effective nanostructures, potentially useful in diagnostic and therapeutic applications, which exploit (and do not suffer) the protein solvation for achieving a better targeting.
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    A review. Remarkable progress has recently been made in the synthesis and characterization of engineered nanoparticles for imaging and treatment of cancers, resulting in several promising candidates in clin. trials. Despite these advances, clin. applications of nanoparticle-based therapeutic/imaging agents remain limited by biol., immunol., and translational barriers. In order to overcome the existing status quo in drug delivery, there is a need for open and frank discussion in the nanomedicine community on what is needed to make qual. leaps toward translation. In this Nano Focus, we present the main discussion topics and conclusions from a recent workshop: "Mechanisms and Barriers in Nanomedicine". The focus of this informal meeting was on biol., toxicol., immunol., and translational aspects of nanomedicine and approaches to move the field forward productively. We believe that these topics reflect the most important issues in cancer nanomedicine.
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    A review. In this review we provide an up to date snapshot of nanomedicines either currently approved by the US FDA, or in the FDA clin. trials process. We define nanomedicines as therapeutic or imaging agents which comprise a nanoparticle in order to control the biodistribution, enhance the efficacy, or otherwise reduce toxicity of a drug or biol. We identified 51 FDA-approved nanomedicines that met this definition and 77 products in clin. trials, with ∼40% of trials listed in clin. trials.gov started in 2014 or 2015. While FDA approved materials are heavily weighted to polymeric, liposomal, and nanocrystal formulations, there is a trend towards the development of more complex materials comprising micelles, protein-based NPs, and also the emergence of a variety of inorg. and metallic particles in clin. trials. We then provide an overview of the different material categories represented in our search, highlighting nanomedicines that have either been recently approved, or are already in clin. trials. We conclude with some comments on future perspectives for nanomedicines, which we expect to include more actively-targeted materials, multi-functional materials ("theranostics") and more complicated materials that blur the boundaries of traditional material categories. A key challenge for researchers, industry, and regulators is how to classify new materials and what addnl. testing (e.g. safety and toxicity) is required before products become available.
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    A review. The field of nanomedicines has expanded significantly in recent years in the breadth of compds. under development as well as in the types of technol. that are being applied to generate nanomedicines. The pathway to licensure of new nanomedicines is sufficiently well defined by existing regulations and guidance. The future of nanomedicines requires collaboration between industry and regulatory agencies to ensure that safe and effective nanomedicines emerge from this field.
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    Biodegradable Passion Fruit-Like Nano-Architectures as Carriers for Cisplatin Prodrug
    Cassano, Domenico; Santi, Melissa; Cappello, Valentina; Luin, Stefano; Signore, Giovanni; Voliani, Valerio
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    Accumulation of inorg. nanostructures in the excretory system organs increases their likelihood of toxicity and interference with common medical diagnoses. Thus, one of the major concerns regarding their clin. translation is related to their persistence in organisms. Here the authors demonstrate that nano-architectures composed by hollow silica nanocapsules embedding arrays of ultrasmall gold nanoparticles undergo biodegrdn. in cellular environment affording small, potentially clearable building blocks. Furthermore, the authors present their exploitation in glutathione-triggered release of covalently loaded cisplatin prodrug. This endogenously triggered release leads to high cytotoxicity to human pancreatic carcinoma cells, setting the way for promising applications to synergistic dual chemo/radio-therapy and radio-imaging.
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    Avigo, C.; Cassano, D.; Kusmic, C.; Voliani, V.; Menichetti, L. Enhanced Photoacoustic Signal of Passion Fruit-Like Nanoarchitectures in a Biological Environment. J. Phys. Chem. C 2017, 121, 6955– 6961,  DOI: 10.1021/acs.jpcc.6b11799
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    Avigo, Cinzia; Cassano, Domenico; Kusmic, Claudia; Voliani, Valerio; Menichetti, Luca
    Journal of Physical Chemistry C (2017), 121 (12), 6955-6961CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    PhotoAcoustic Imaging (PAI) is a promising noninvasive technique for mol. and cellular characterization of cancer. Cancer detection by PAI is an area of active research, and the recent advent of contrast agents based on near IR (NIR)-absorbing dyes or org./inorg. nanoparticles tremendously improved the specificity and the signal contrast. Here, the authors report the PhotoAcoustic (PA) signal enhancement produced by biodegradable passion fruit-like nano-architectures in phantoms and ex vivo. By this approach, the synergistic interaction between com. NIR-fluorophores and ultra-small metal nanoparticles is exploited to produce a PA signal enhancement in the biol. window. Moreover, the degrdn. of the nano-architectures is investigated in physiol. environment as ref. matrix.
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    Armanetti, P.; Pocoví-Martínez, S.; Flori, A.; Avigo, C.; Cassano, D.; Menichetti, L.; Voliani, V. Dual Photoacoustic/ultrasound Multi-Parametric Imaging from Passion Fruit-like Nano-Architectures. Nanomed. Nanotechnol. Biol. Med. 2018, 14, 1787– 1795,  DOI: 10.1016/j.nano.2018.05.007
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    Naked Nanoparticles in Silica Nanocapsules: A Versatile Family of Nanorattle Catalysts
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    ACS Applied Nano Materials (2018), 1 (4), 1836-1840CODEN: AANMF6; ISSN:2574-0970. (American Chemical Society)
    A generalized and robust protocol for the prodn. of a family of nanorattles comprising naked noble metals, metal oxide, and/or carbonaceous materials is reported. Their employment to methylene blue degrdn. was fully assessed as a model reaction, defining the most promising 1 for this reaction. The possibility of employing a single and scalable synthetic process for the prodn. of nanorattles with peculiar features for specific reactions dramatically enhances their future applications.
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    Cancer cells propagated in three-dimensional (3D) culture systems exhibit physiol. relevant cell-cell and cell-matrix interactions, gene expression and signaling pathway profiles, heterogeneity and structural complexity that reflect in vivo tumors. In recent years, development of various 3D models has improved the study of host-tumor interaction and use of high-throughput screening platforms for anti-cancer drug discovery and development. This review attempts to summarize the various 3D culture systems, with an emphasis on the most well characterized and widely applied model - multicellular tumor spheroids. This review also highlights the various techniques to generate tumor spheroids, methods to characterize them, and its applicability in cancer research.
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    Russell and Burch's The Principles of Humane Experimental Technique was first published in 1959. A Special Edition containing the original text was reissued in 1992, after its ideas had gained widespread interest in the scientific community. In the Principles, Russell and Burch proposed a new applied science that would improve the treatment of laboratory animals while advancing the quality of science in studies that use animals. They introduced and defined the terms replacement, reduction, and refinement, which subsequently have become known as 'alternatives' or 'alternative methods' for minimizing the potential for animal pain and distress in biomedical research. Here we describe and explain the original definitions of the 3Rs in the Principles, examine how current definitions differ among themselves and from Russell and Burch's definitions, and suggest relevant considerations for evaluating all definitions of the 3Rs.
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    Advanced Drug Delivery Reviews (2016), 99 (Part_A), 28-51CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
    Coating the surface of nanoparticles with polyethylene glycol (PEG), or "PEGylation", is a commonly used approach for improving the efficiency of drug and gene delivery to target cells and tissues. Building from the success of PEGylating proteins to improve systemic circulation time and decrease immunogenicity, the impact of PEG coatings on the fate of systemically administered nanoparticle formulations has, and continues to be, widely studied. PEG coatings on nanoparticles shield the surface from aggregation, opsonization, and phagocytosis, prolonging systemic circulation time. Here, we briefly describe the history of the development of PEGylated nanoparticle formulations for systemic administration, including how factors such as PEG mol. wt., PEG surface d., nanoparticle core properties, and repeated administration impact circulation time. A less frequently discussed topic, we then describe how PEG coatings on nanoparticles have also been utilized for overcoming various biol. barriers to efficient drug and gene delivery assocd. with other modes of administration, ranging from gastrointestinal to ocular. Finally, we describe both methods for PEGylating nanoparticles and methods for characterizing PEG surface d., a key factor in the effectiveness of the PEG surface coating for improving drug and gene delivery.
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  2. Melissa Santi, Ana Katrina Mapanao, Valentina Cappello, Valerio Voliani. Production of 3D Tumor Models of Head and Neck Squamous Cell Carcinomas for Nanotheranostics Assessment. ACS Biomaterials Science & Engineering 2020, 6 (9) , 4862-4869. https://doi.org/10.1021/acsbiomaterials.0c00617
  3. Domenico Cassano, Ana-Katrina Mapanao, Maria Summa, Ylea Vlamidis, Giulia Giannone, Melissa Santi, Elena Guzzolino, Letizia Pitto, Laura Poliseno, Rosalia Bertorelli, Valerio Voliani. Biosafety and Biokinetics of Noble Metals: The Impact of Their Chemical Nature. ACS Applied Bio Materials 2019, 2 (10) , 4464-4470. https://doi.org/10.1021/acsabm.9b00630
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  5. Melissa Santi, Valentina Frusca, Maria Laura Ermini, Ana Katrina Mapanao, Patrizia Sarogni, Alessandra Gonnelli, Noemi Giannini, Agata Zamborlin, Lorenzo Biancalana, Fabio Marchetti, Valerio Voliani. Hybrid nano-architectures loaded with metal complexes for the co-chemotherapy of head and neck carcinomas. Journal of Materials Chemistry B 2023, 11 (2) , 325-334. https://doi.org/10.1039/D2TB01930B
  6. Ana Katrina Mapanao, Patrizia Sarogni, Melissa Santi, Michele Menicagli, Alessandra Gonnelli, Agata Zamborlin, Maria Laura Ermini, Valerio Voliani. Pro-apoptotic and size-reducing effects of protein corona-modulating nano-architectures enclosing platinum prodrug in in vivo oral carcinoma. Biomaterials Science 2022, 10 (21) , 6135-6145. https://doi.org/10.1039/D2BM00994C
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  23. Marianna Galliani, Giovanni Signore. Poly(Lactide‐Co‐Glycolide) Nanoparticles Co‐Loaded with Chlorophyllin and Quantum Dots as Photodynamic Therapy Agents. ChemPlusChem 2019, 84 (11) , 1653-1658. https://doi.org/10.1002/cplu.201900342
  24. Domenico Cassano, Melissa Santi, Francesca D’Autilia, Ana Katrina Mapanao, Stefano Luin, Valerio Voliani. Photothermal effect by NIR-responsive excretable ultrasmall-in-nano architectures. Materials Horizons 2019, 6 (3) , 531-537. https://doi.org/10.1039/C9MH00096H
  25. Domenico Cassano, Maria Summa, Salvador Pocoví‐Martínez, Ana‐Katrina Mapanao, Tiziano Catelani, Rosalia Bertorelli, Valerio Voliani. Biodegradable Ultrasmall‐in‐Nano Gold Architectures: Mid‐Period In Vivo Distribution and Excretion Assessment. Particle & Particle Systems Characterization 2019, 36 (2) https://doi.org/10.1002/ppsc.201800464
  26. Mathilde Ménard, Florent Meyer, Ksenia Parkhomenko, Cédric Leuvrey, Grégory Francius, Sylvie Bégin-Colin, Damien Mertz. Mesoporous silica templated-albumin nanoparticles with high doxorubicin payload for drug delivery assessed with a 3-D tumor cell model. Biochimica et Biophysica Acta (BBA) - General Subjects 2019, 1863 (2) , 332-341. https://doi.org/10.1016/j.bbagen.2018.10.020
  27. Filippo Begarani, Domenico Cassano, Eleonora Margheritis, Roberto Marotta, Francesco Cardarelli, Valerio Voliani. Silica-Based Nanoparticles for Protein Encapsulation and Delivery. Nanomaterials 2018, 8 (11) , 886. https://doi.org/10.3390/nano8110886
  28. Ylea Vlamidis, Valerio Voliani. Bringing Again Noble Metal Nanoparticles to the Forefront of Cancer Therapy. Frontiers in Bioengineering and Biotechnology 2018, 6 https://doi.org/10.3389/fbioe.2018.00143
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  • Abstract

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    Figure 1

    Figure 1. (A) Bright-field microscopy image of the 3D MIA PaCa-2 cell culture prepared through the hanging method (scale bar: 100 μm). Zoomed-in bright-field (B) and confocal (C) microscopy images of the MIA PaCa-2 cultured in 3D (scale bars: 10 μm). Bright field (D) and confocal (E) microscopy images of MIA PaCa-2 cultured in 2D (scale bar: 10 μm). The nuclei (blue) and the cell membranes (green) were stained with Hoechst 33342 and CellMask green plasma membrane stain, respectively.

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    Figure 2

    Figure 2. (A) Scheme of the synthesis of NAs-647–Tf2. Gold USNPs were embedded in AlexaFluor-647-modified poly(l-lysine). The polymeric aggregates were employed as templates to form hollow silica nanocapsules (NAs) by a modified Stöber method. The surface of NAs was modified by silane–PEG–maleimide linkers. Finally, NAs were click-chemical functionalized by the peptide Tf2, and GSH was added to block the excess maleimide ends. (B) Background-subtracted UV–vis spectrum of standard NAs (the continuous black line) and NAs-647 (the red dashed line). Measurements were performed in PBS. (C) TEM images of NAs (left), NAs-647 (middle), and GSH-treated NAs-647–Tf2 (right). The Gray matrix is due to a not-completely-dry sample during the imaging. Scale bar: 50 nm.

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    Figure 3

    Figure 3. (A) Confocal images of 3D MIA PaCa-2 at four postincubation time points. Cells were incubated for 2 h on NAs-647 or NAs-647–Tf2. The signals for NAs are in red. The nuclei (blue) were stained with Hoechst 33342, and the cell membranes (green) were stained using a CellMask green plasma membrane stain. Inset: zoom-in on a single cell. Scale bars: 20 μm. (B) Quantitative analysis of gold detected by ICP-MS in the 3D MIA PaCa-2 spheroids incubated with NAs-647 (black) and NAs-647–Tf2 (red). The raw data were normalized for (i) the initial gold concentration during the incubation and (ii) the total protein content.

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  • References

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      Rational Design of a Transferrin-Binding Peptide Sequence Tailored to Targeted Nanoparticle Internalization
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      Mechanisms and Barriers in Cancer Nanomedicine: Addressing Challenges, Looking for Solutions
      Anchordoquy, Thomas J.; Barenholz, Yechezkel; Boraschi, Diana; Chorny, Michael; Decuzzi, Paolo; Dobrovolskaia, Marina A.; Farhangrazi, Z. Shadi; Farrell, Dorothy; Gabizon, Alberto; Ghandehari, Hamidreza; Godin, Biana; La-Beck, Ninh M.; Ljubimova, Julia; Moghimi, S. Moein; Pagliaro, Len; Park, Ji-Ho; Peer, Dan; Ruoslahti, Erkki; Serkova, Natalie J.; Simberg, Dmitri
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      A review. Remarkable progress has recently been made in the synthesis and characterization of engineered nanoparticles for imaging and treatment of cancers, resulting in several promising candidates in clin. trials. Despite these advances, clin. applications of nanoparticle-based therapeutic/imaging agents remain limited by biol., immunol., and translational barriers. In order to overcome the existing status quo in drug delivery, there is a need for open and frank discussion in the nanomedicine community on what is needed to make qual. leaps toward translation. In this Nano Focus, we present the main discussion topics and conclusions from a recent workshop: "Mechanisms and Barriers in Nanomedicine". The focus of this informal meeting was on biol., toxicol., immunol., and translational aspects of nanomedicine and approaches to move the field forward productively. We believe that these topics reflect the most important issues in cancer nanomedicine.
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      A review. In this review we provide an up to date snapshot of nanomedicines either currently approved by the US FDA, or in the FDA clin. trials process. We define nanomedicines as therapeutic or imaging agents which comprise a nanoparticle in order to control the biodistribution, enhance the efficacy, or otherwise reduce toxicity of a drug or biol. We identified 51 FDA-approved nanomedicines that met this definition and 77 products in clin. trials, with ∼40% of trials listed in clin. trials.gov started in 2014 or 2015. While FDA approved materials are heavily weighted to polymeric, liposomal, and nanocrystal formulations, there is a trend towards the development of more complex materials comprising micelles, protein-based NPs, and also the emergence of a variety of inorg. and metallic particles in clin. trials. We then provide an overview of the different material categories represented in our search, highlighting nanomedicines that have either been recently approved, or are already in clin. trials. We conclude with some comments on future perspectives for nanomedicines, which we expect to include more actively-targeted materials, multi-functional materials ("theranostics") and more complicated materials that blur the boundaries of traditional material categories. A key challenge for researchers, industry, and regulators is how to classify new materials and what addnl. testing (e.g. safety and toxicity) is required before products become available.
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      11
      The nanomedicines alliance: an industry perspective on nanomedicines
      Malinoski, Frank J.
      Nanomedicine (New York, NY, United States) (2014), 10 (8), 1819-1820CODEN: NANOBF; ISSN:1549-9634. (Elsevier)
      A review. The field of nanomedicines has expanded significantly in recent years in the breadth of compds. under development as well as in the types of technol. that are being applied to generate nanomedicines. The pathway to licensure of new nanomedicines is sufficiently well defined by existing regulations and guidance. The future of nanomedicines requires collaboration between industry and regulatory agencies to ensure that safe and effective nanomedicines emerge from this field.
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      Cassano, D.; Pocoví-Martínez, S.; Voliani, V. Ultrasmall-in-Nano Approach: Enabling the Translation of Metal Nanomaterials to Clinics. Bioconjugate Chem. 2017, 29, 4,  DOI: 10.1021/acs.bioconjchem.7b00664
      There is no corresponding record for this reference.
    13. 13
      Cassano, D.; Martir, D. R.; Signore, G.; Piazza, V.; Voliani, V. Biodegradable Hollow Silica Nanospheres Containing Gold Nanoparticle Arrays. Chem. Commun. 2015, 51, 9939– 9941,  DOI: 10.1039/c5cc02771c
      There is no corresponding record for this reference.
    14. 14
      Cassano, D.; Santi, M.; Cappello, V.; Luin, S.; Signore, G.; Voliani, V. Biodegradable Passion Fruit-Like Nano-Architectures as Carriers for Cisplatin Prodrug. Part. Part. Syst. Charact. 2016, 33, 818– 824,  DOI: 10.1002/ppsc.201600175
      14
      Biodegradable Passion Fruit-Like Nano-Architectures as Carriers for Cisplatin Prodrug
      Cassano, Domenico; Santi, Melissa; Cappello, Valentina; Luin, Stefano; Signore, Giovanni; Voliani, Valerio
      Particle & Particle Systems Characterization (2016), 33 (11), 818-824CODEN: PPCHEZ; ISSN:1521-4117. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Accumulation of inorg. nanostructures in the excretory system organs increases their likelihood of toxicity and interference with common medical diagnoses. Thus, one of the major concerns regarding their clin. translation is related to their persistence in organisms. Here the authors demonstrate that nano-architectures composed by hollow silica nanocapsules embedding arrays of ultrasmall gold nanoparticles undergo biodegrdn. in cellular environment affording small, potentially clearable building blocks. Furthermore, the authors present their exploitation in glutathione-triggered release of covalently loaded cisplatin prodrug. This endogenously triggered release leads to high cytotoxicity to human pancreatic carcinoma cells, setting the way for promising applications to synergistic dual chemo/radio-therapy and radio-imaging.
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    15. 15
      Avigo, C.; Cassano, D.; Kusmic, C.; Voliani, V.; Menichetti, L. Enhanced Photoacoustic Signal of Passion Fruit-Like Nanoarchitectures in a Biological Environment. J. Phys. Chem. C 2017, 121, 6955– 6961,  DOI: 10.1021/acs.jpcc.6b11799
      15
      Enhanced Photoacoustic Signal of Passion Fruit-Like Nanoarchitectures in a Biological Environment
      Avigo, Cinzia; Cassano, Domenico; Kusmic, Claudia; Voliani, Valerio; Menichetti, Luca
      Journal of Physical Chemistry C (2017), 121 (12), 6955-6961CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      PhotoAcoustic Imaging (PAI) is a promising noninvasive technique for mol. and cellular characterization of cancer. Cancer detection by PAI is an area of active research, and the recent advent of contrast agents based on near IR (NIR)-absorbing dyes or org./inorg. nanoparticles tremendously improved the specificity and the signal contrast. Here, the authors report the PhotoAcoustic (PA) signal enhancement produced by biodegradable passion fruit-like nano-architectures in phantoms and ex vivo. By this approach, the synergistic interaction between com. NIR-fluorophores and ultra-small metal nanoparticles is exploited to produce a PA signal enhancement in the biol. window. Moreover, the degrdn. of the nano-architectures is investigated in physiol. environment as ref. matrix.
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    16. 16
      d’Amora, M.; Cassano, D.; Pocoví-Martínez, S.; Giordani, S.; Voliani, V. Biodistribution and Biocompatibility of Passion Fruit-like Nano-Architectures in Zebrafish. Nanotoxicology 2018, 1– 9,  DOI: 10.1080/17435390.2018.1498551
      There is no corresponding record for this reference.
    17. 17
      Armanetti, P.; Pocoví-Martínez, S.; Flori, A.; Avigo, C.; Cassano, D.; Menichetti, L.; Voliani, V. Dual Photoacoustic/ultrasound Multi-Parametric Imaging from Passion Fruit-like Nano-Architectures. Nanomed. Nanotechnol. Biol. Med. 2018, 14, 1787– 1795,  DOI: 10.1016/j.nano.2018.05.007
      There is no corresponding record for this reference.
    18. 18
      Pocoví-Martínez, S.; Cassano, D.; Voliani, V. Naked Nanoparticles in Silica Nanocapsules: A Versatile Family of Nanorattle Catalysts. ACS Appl. Nano Mater. 2018, 1, 1836– 1840,  DOI: 10.1021/acsanm.8b00247
      18
      Naked Nanoparticles in Silica Nanocapsules: A Versatile Family of Nanorattle Catalysts
      Pocovi-Martinez, Salvador; Cassano, Domenico; Voliani, Valerio
      ACS Applied Nano Materials (2018), 1 (4), 1836-1840CODEN: AANMF6; ISSN:2574-0970. (American Chemical Society)
      A generalized and robust protocol for the prodn. of a family of nanorattles comprising naked noble metals, metal oxide, and/or carbonaceous materials is reported. Their employment to methylene blue degrdn. was fully assessed as a model reaction, defining the most promising 1 for this reaction. The possibility of employing a single and scalable synthetic process for the prodn. of nanorattles with peculiar features for specific reactions dramatically enhances their future applications.
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    19. 19
      Nath, S.; Devi, G. R. Three-Dimensional Culture Systems in Cancer Research: Focus on Tumor Spheroid Model. Pharmacol. Ther. 2016, 163, 94– 108,  DOI: 10.1016/j.pharmthera.2016.03.013
      19
      Three-dimensional culture systems in cancer research: Focus on tumor spheroid model
      Nath, Sritama; Devi, Gayathri R.
      Pharmacology & Therapeutics (2016), 163 (), 94-108CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)
      Cancer cells propagated in three-dimensional (3D) culture systems exhibit physiol. relevant cell-cell and cell-matrix interactions, gene expression and signaling pathway profiles, heterogeneity and structural complexity that reflect in vivo tumors. In recent years, development of various 3D models has improved the study of host-tumor interaction and use of high-throughput screening platforms for anti-cancer drug discovery and development. This review attempts to summarize the various 3D culture systems, with an emphasis on the most well characterized and widely applied model - multicellular tumor spheroids. This review also highlights the various techniques to generate tumor spheroids, methods to characterize them, and its applicability in cancer research.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmtVSgsLk%253D&md5=5ea2141b4cd53d1959ebf2065e866ea2
    20. 20
      Tannenbaum, J.; Bennett, B. T. Russell and Burch’s 3Rs Then and Now: The Need for Clarity in Definition and Purpose. J. Am. Assoc. Lab. Anim. Sci. 2015, 54, 120– 132
      20
      Russell and Burch's 3Rs then and now: the need for clarity in definition and purpose
      Tannenbaum Jerrold; Bennett B Taylor
      Journal of the American Association for Laboratory Animal Science : JAALAS (2015), 54 (2), 120-32 ISSN:.
      Russell and Burch's The Principles of Humane Experimental Technique was first published in 1959. A Special Edition containing the original text was reissued in 1992, after its ideas had gained widespread interest in the scientific community. In the Principles, Russell and Burch proposed a new applied science that would improve the treatment of laboratory animals while advancing the quality of science in studies that use animals. They introduced and defined the terms replacement, reduction, and refinement, which subsequently have become known as 'alternatives' or 'alternative methods' for minimizing the potential for animal pain and distress in biomedical research. Here we describe and explain the original definitions of the 3Rs in the Principles, examine how current definitions differ among themselves and from Russell and Burch's definitions, and suggest relevant considerations for evaluating all definitions of the 3Rs.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2Mjgslyktg%253D%253D&md5=0497d85f77fe2a1aef622ba0bcde4a32
    21. 21
      Foty, R. A Simple Hanging Drop Cell Culture Protocol for Generation of 3D Spheroids. J. Visualized Exp. 2011, 20, 4– 7,  DOI: 10.3791/2720
      There is no corresponding record for this reference.
    22. 22
      Suk, J. S.; Xu, Q.; Kim, N.; Hanes, J.; Ensign, L. M. PEGylation as a Strategy for Improving Nanoparticle-Based Drug and Gene Delivery. Adv. Drug Deliv. Rev. 2016, 99, 28,  DOI: 10.1016/j.addr.2015.09.012
      22
      PEGylation as a strategy for improving nanoparticle-based drug and gene delivery
      Suk, Jung Soo; Xu, Qingguo; Kim, Namho; Hanes, Justin; Ensign, Laura M.
      Advanced Drug Delivery Reviews (2016), 99 (Part_A), 28-51CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
      Coating the surface of nanoparticles with polyethylene glycol (PEG), or "PEGylation", is a commonly used approach for improving the efficiency of drug and gene delivery to target cells and tissues. Building from the success of PEGylating proteins to improve systemic circulation time and decrease immunogenicity, the impact of PEG coatings on the fate of systemically administered nanoparticle formulations has, and continues to be, widely studied. PEG coatings on nanoparticles shield the surface from aggregation, opsonization, and phagocytosis, prolonging systemic circulation time. Here, we briefly describe the history of the development of PEGylated nanoparticle formulations for systemic administration, including how factors such as PEG mol. wt., PEG surface d., nanoparticle core properties, and repeated administration impact circulation time. A less frequently discussed topic, we then describe how PEG coatings on nanoparticles have also been utilized for overcoming various biol. barriers to efficient drug and gene delivery assocd. with other modes of administration, ranging from gastrointestinal to ocular. Finally, we describe both methods for PEGylating nanoparticles and methods for characterizing PEG surface d., a key factor in the effectiveness of the PEG surface coating for improving drug and gene delivery.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1CqurrP&md5=fecfbdedd72ee97571c913a9ac3cd93f
    23. 23
      Sahoo, S. K.; Labhasetwar, V. Enhanced Antiproliferative Activity of Transferrin-Conjugated Paclitaxel-Loaded Nanoparticles Is Mediated via Sustained Intracellular Drug Retention. Mol. Pharm. 2005, 2, 373– 383,  DOI: 10.1021/mp050032z
      23
      Enhanced antiproliferative activity of transferrin-conjugated paclitaxel-loaded nanoparticles is mediated via sustained intracellular drug retention
      Sahoo, Sanjeeb K.; Labhasetwar, Vinod
      Molecular Pharmaceutics (2005), 2 (5), 373-383CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      We studied the mol. mechanism of greater efficacy of paclitaxel-loaded nanoparticles (Tx-NPs) following conjugation to transferrin (Tf) ligand in breast cancer cell line. NPs were formulated using biodegradable polymer, poly(lactic-co-glycolide) (PLGA), with encapsulated Tx and conjugated to Tf ligand via an epoxy linker. Tf-conjugated NPs demonstrated greater and sustained antiproliferative activity of the drug in dose- and time-dependent studies compared to that with drug in soln. or unconjugated NPs in MCF-7 and MCF-7/Adr cells. The mechanism of greater antiproliferative activity of the drug with conjugated NPs was detd. to be due to their greater cellular uptake and reduced exocytosis compared to that of unconjugated NPs, thus leading to higher and sustained intracellular drug levels. The increase in antiproliferative activity of the drug with incubation time in MCF-7/Adr cells with Tf-conjugated NPs suggests that the drug resistance can be overcome by sustaining intracellular drug retention. The intracellular disposition characteristics of Tf-conjugated NPs following their cellular uptake via Tf receptors could have been different from that of unconjugated NPs via nonspecific endocytic pathway, thus influencing the NP uptake, their intracellular retention, and hence the therapeutic efficacy of the encapsulated drug.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXltl2gtLo%253D&md5=9cdefd79882346061f6886a9b068d052
    24. 24
      Bergamini, L.; Voliani, V.; Cappello, V.; Nifosì, R.; Corni, S. Non-Linear Optical Response by Functionalized Gold Nanospheres: Identifying Design Principles to Maximize the Molecular Photo-Release. Nanoscale 2015, 7, 13345– 13357,  DOI: 10.1039/c5nr03037d
      There is no corresponding record for this reference.

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    • Orthogonal view and bright-field microscopy image of 3D MIA PaCa-2; TEM ultrastructure of 3D MIA PaCa-2; size histograms and zeta potential values of NAs-647, NAs-647–Tf2 without GSH, and NAs-647–Tf2/GSH; and confocal microscopy images of 3D MIA PaCa-2 employed for double-color analysis (PDF)


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