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Accelerating the Translation of Nanomaterials in Biomedicine

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† Center for Bioengineering, Department of Chemical Engineering, University of California, Santa Barbara, California 93106, United States
‡ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
§ National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, United States
∥ Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077
⊥ Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095, United States
# Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States
□ Departments of Materials Engineering and Bioengineering, University of Tokyo, Tokyo 113-8654, Japan
■ Department of Chemistry and International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States
○ Laboratory for Nanoengineering & Drug Delivery, Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States
● Department of Materials, Department of Bioengineering, Institute for Biomedical Engineering, Imperial College London, London SW7 2AZ, U.K.
△ Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States
▽ ▽School of Chemical and Biomedical Engineering and ▲School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798
▼ The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30322, United States
⬡ Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China
⬢ Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, North Carolina 27695, United States
†† Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
‡‡ Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27695, United States
*Address correspondence to [email protected], [email protected], [email protected]
Cite this: ACS Nano 2015, 9, 7, 6644–6654
Publication Date (Web):June 26, 2015
https://doi.org/10.1021/acsnano.5b03569

Copyright © 2015 American Chemical Society. This publication is available under these Terms of Use.

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Abstract

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Due to their size and tailorable physicochemical properties, nanomaterials are an emerging class of structures utilized in biomedical applications. There are now many prominent examples of nanomaterials being used to improve human health, in areas ranging from imaging and diagnostics to therapeutics and regenerative medicine. An overview of these examples reveals several common areas of synergy and future challenges. This Nano Focus discusses the current status and future potential of promising nanomaterials and their translation from the laboratory to the clinic, by highlighting a handful of successful examples.

This publication is licensed for personal use by The American Chemical Society.

Advances in medicine in the areas of genomics, proteomics, tissue engineering, and regenerative medicine are occurring at a rate that was previously unthinkable. The development of new materials resulting from these breakthroughs, such as those that can be used to replace blood vessels, to promote tissue growth, to monitor blood glucose levels, or to improve the bioavailability of drugs, has been equally rapid and diverse. (1, 2) One of the most exciting frontiers is the development of nanomaterials for biomedical applications. (3, 4) Nanomaterials have size-, shape-, and composition-dependent physical, chemical, optical, and electronic properties, among others, that can be designed and tuned, and they are showing great promise for the diagnosis, treatment, monitoring, and control of disease. (5-8) A recent survey found that more than 247 nanomaterial-based medical products have been approved by the Food and Drug Administration (FDA) and are currently in various stages of clinical study. (9) Their intended uses range from the treatment of clinically unresectable cancers to the preparation of antibacterial hand gels to the regeneration of heart tissue. At the same time, common themes emerge when discussing nanomaterials in medicine. Indeed, one of the biggest issues is how to translate nanomaterials from the laboratory to the clinic effectively.

In this Nano Focus, we highlight these discussions, which fall into three categories: nanotherapeutics, imaging and diagnostics, and tissue regeneration.

At the 2015 Materials Research Society (MRS) Spring Meeting in San Francisco (April 6–10), a special symposium focusing on translational research involving nanomaterials in the biomedical field was held. Researchers from all over the world gathered to exchange ideas and to discuss criteria for the selection, development, synthesis, and utilization of nanomaterials. In this Nano Focus, we highlight these discussions, which fall into three categories: nanotherapeutics, imaging and diagnostics, and tissue regeneration.

Enhancing Efficacy in Nanotherapeutics

Among the numerous nanomaterials explored in therapeutic applications, those often found in clinical trials are gold nanoparticles, polymeric nanoparticles, liposomes, and carbon-based nanomaterials. By sharing expertise across fields, researchers can accelerate the utilization of nanomaterials in addressing the challenges faced by traditional therapeutic agents.
Since the development of gold-nanoparticle-based spherical nucleic acids (SNAs) in 1996, (10) the Mirkin group at Northwestern University has exploited the properties of this class of nanostructures in many areas of biomedicine. Spherical nucleic acids typically consist of a nanoparticle core and a highly oriented and densely packed shell of oligonucleotides. (11) The properties of SNAs emerge from the orientation and arrangement of oligonucleotides on the surfaces of these particles. For example, SNAs are taken up into many different cell types (over 60 tested to date) at high levels and rates without the need for transfection agents, (12) have high affinities for nucleic acid targets (100 times greater than linear DNA of the same sequence), (13) and cross both the blood–brain barrier (14) and the epidermis (15) to reach difficult-to-target tissues in therapeutic applications. Success in the utilization of SNAs for intracellular mRNA detection has led to the commercialization of NanoFlare technology (16, 17) under the trade name SmartFlares (Merck Millipore in partnership with AuraSense, LLC, Skokie, Illinois), and SNAs have also been applied as agents in gene regulation as therapeutics for a host of cancers, including glioblastoma multiforme (an aggressive form of brain cancer), and skin disorders, among others. The Mirkin group has made progress in using SNAs as immunomodulatory agents. (18) Spherical nucleic acids functionalized with oligonucleotides displaying toll-like receptor (TLR)-agonist or TLR-antagonist activity were shown to be capable of either stimulating or modulating the activity of the immune system, respectively. Such structures do so with potencies up to several orders of magnitude higher than the conventional linear nucleic acids from which they are composed. This discovery paves the way for the development of SNAs as therapeutic cancer vaccines. Mirkin’s demonstration of the ability of SNAs to reduce tumor burden and to enhance survival in vivo, in mouse models of lymphoma, proved that immunomodulatory SNAs can be directed to activate the response of the immune system to destroy tumors in an antigen-specific manner (Figure 1).

Figure 1

Figure 1. In vivo activity of immunomodulatory SNAs as cancer vaccines.

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A fundamental challenge is the delivery of therapeutic molecules inside target cells in the body. Nanoparticles have shown immense promise as vehicles for intracellular delivery, with proof-of-principle experiments in humans being completed with small interfering RNA (siRNA). (19) However, there are many barriers to achieving safe and effective delivery systems (Figure 2), and potential delivery systems must have multiple functionalities to allow in vivo delivery, making the design criteria difficult to define for nanoparticles capable of accomplishing intracellular delivery. To accelerate the design and discovery process, the Anderson group at the Massachusetts Institute of Technology has pioneered combinatorial methods for nanoparticulate drug delivery. Combinatorial chemical methods have been developed to enable the rapid synthesis and characterization of a range of nanoformulations based on biodegradable polymers, lipid-like materials, and other materials. (20-22) These have generated new formulations with particular promise as delivery vehicles for RNA and other nucleic acids; (23) these formulations have the potential to be used as therapies for many diseases, including cancer. (24)
Furthermore, Shi at Brigham and Women’s Hospital/Harvard Medical School described the rational design and development of lipid–polymer hybrid nanoparticle platforms to address the bottlenecks faced in the delivery of RNA interference (RNAi) therapeutics, such as siRNA. (25-27) Specifically, the clinical applications of RNAi in cancer therapy are currently hindered by the challenge of achieving the effective systemic in vivo delivery of siRNA to tumors. Multiple physiological barriers, such as enzymatic degradation, rapid elimination by renal excretion or the mononuclear phagocyte system, and poor cellular uptake and endosomal escape, must be overcome. By utilizing hybrid nanoparticles, Shi achieved sustained gene silencing, and prolonged circulation of siRNA in the blood for high tumor extravasation and accumulation. The successful application of these RNAi nanoparticles to validate the therapeutic role of Prohibitin1 in non-small cell lung cancer treatment (27) indicates the significant potential of this platform for the validation of many other potential cancer targets and for the clinical development of novel cancer therapies.

Figure 2

Figure 2. Barriers to successful in vivo delivery of nucleic acids using nonviral vectors. Reprinted with permission from ref 19. Copyright 2014 Macmillan Publishers Ltd.

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Kataoka at the University of Tokyo has pioneered the synthesis and development of “polymeric micelle drugs”, which have proven useful for targeting a variety of drugs to tissues and organs and to tumors in particular. There has been significant recent progress in the clinical development of polymeric micelles loaded with a variety of cytotoxic reagents. Notably, five different micellar formulations have already been explored in clinical trials in Asia and the United States. (28) A version loaded with paclitaxel is in the final stage of a Phase III clinical trial in Japan for the treatment of recurrent breast cancer, and it is expected to proceed into the application for approval within a year. More recently, Kataoka and colleagues have been active in developing a second generation system of polymeric micelles installed with ligand moieties at their peripheries. Particularly, cRGD-conjugated polymeric micelles were able to cross the blood–brain tumor barrier via a transcytosis mechanism, achieving high efficacy in treating intractable orthotopic glioblastoma in animal experiments. (29) Antibody fragments can also be conjugated to polymeric micelles. In this way, higher drug payloads can be achieved without antibody precipitation or impaired binding compared to when drugs are directly conjugated to antibody molecules using more conventional approaches. (30)
In 1989, the Kabanov group at the University of North Carolina at Chapel Hill investigated the use of polymeric micelles for targeted drug delivery. (31) They discovered that Pluronic block copolymers can be used in the sensitization of multi-drug-resistant (MDR) cancer and cancer stem cells and elucidated the mechanisms responsible for these effects. (32) This research led to first-in-man polymeric micelle drug candidates for the treatment of cancer (SP1049C) that show high efficacy against advanced esophageal cancer in Phase II trials. (33) Recently, they discovered polymeric micelles based on amphiphilic poly(2-oxazoline) blocks with unprecedented high capacities for poorly soluble, uncharged drugs (e.g., taxanes) and drug combinations, enabling increasing therapeutic indices compared to current drug formulations. (34, 35)
Liposomes are another popular nanomaterial used in preclinical and clinical studies, but it is difficult to sustain release from these structures for more than a few days. The Venkatraman group at Nanyang Technological University has developed a subconjunctivally injected nanoliposome drug delivery system for the long-term (3–5 months) delivery of latanoprost that can be used in glaucoma treatment, which went from concept to clinic in less than 5 years (Figure 3). (36, 37) Glaucoma is a chronic progressive optic neuropathy that is characterized by optic nerve changes and visual field loss. Elevated intraocular pressure (IOP) is the main modifiable risk factor. The chronic instillation of daily eye drops to lower IOP is the primary treatment of choice, although this regimen requires patient adherence and correct performance. Hence, a sustained-delivery system would be a big boon to patients with glaucoma. Venkatraman’s group also explored the nanoparticle-mediated sustained delivery of siRNA for preventing fibrosis following surgery. (38) This method has applications in ocular and other types of surgeries/implantations. They have shown sustained efficacy of action with a siRNA-incorporated nanoparticle. As shown in the above two examples, the premise of their work rests on the ability of nanoparticles to sustain drug/protein/siRNA release.

Figure 3

Figure 3. Subconjunctival instillation of nanocarriers incorporating latanoprost lowers eye pressure in glaucoma patients for up to 3 months. Reproduced from ref 37. Copyright 2014 American Chemical Society.

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The Chow and Ho groups at the National University of Singapore and the University of California, Los Angeles (UCLA), respectively, study nanodiamonds, which are an emerging class of carbon-based nanomaterials, due to their advantageous surface characteristics. Nanodiamond facets mediate electrostatic properties that have resulted in potent and scalable anthracycline drug binding as well as marked enhancements in magnetic resonance imaging (MRI) efficiency. (39, 40) With regard to drug delivery, nanodiamond–doxorubicin compounds (NDX) were administered to treat drug-resistant breast and liver tumors in mouse models. This study demonstrated the nanodiamond-mediated improvement of drug tolerance; lethal dosages of doxorubicin delivered as NDX resulted in the smallest tumors observed (compared to saline controls and unmodified drug administration), and all of the treated mice survived the full duration of the study. (41) The active targeting of triple-negative breast tumors in vivo using nanodiamond–epirubicin complexes functionalized with the epidermal growth factor receptor (EGFR) antibody resulted in complete tumor regression. (42) More recently, nanodiamond–anthracycline agents have been used to treat hepatic cancer stem cells. (43)
Toward the further enhancement of the potency and safety of cancer therapies, a prevalent challenge in the field of nanomedicine is the ability to move beyond monotherapies toward combinatorial cancer treatments. Using phenotypic instead of genotypic profiling to drive combinatorial optimization, Ho and colleagues developed a powerful mechanism-independent engineering optimization platform, termed Feedback System Control.II (FSC.II), to identify globally optimized nanodiamond–anthracycline drug combinations rapidly. (44) FSC.II does not require the use of feedback, and instead, it utilizes a selected set of experimental validation assays to formulate phenotypic profiles from which drug combinations can rapidly be pin-pointed.
Mitragotri at the University of California, Santa Barbara, also translated nanomaterials to clinical applications (Figure 4). Specifically, he used gold-coated silica nanoparticles for the treatment of acne. These 150 nm, poly(ethylene glycol)-coated, silica–gold nanoparticles are designed to absorb near-infrared light and produce localized heating. The delivery of these nanoparticles into skin is a major hurdle due to the skin’s barrier properties. Mitragotri and colleagues showed that these nanoparticles can be delivered deep into the skin’s sebaceous glands using low-frequency ultrasound. (45) Ultrasound induces cavitation on the surface of the skin, which produces microjets and shock waves that open transport pathways into the glands. (46) Once delivered deep into the glands, the thermal activation of the nanoparticles using near-infrared light caused thermolysis and the inactivation of overactive sebaceous glands, the underlying pathology of acne. This nanoparticle-based technology provides several advantages over standard treatments for acne; for instance, systemic side effects are avoided with this treatment.

Figure 4

Figure 4. Schematic for the nanoparticle-based treatment of acne. Silica–gold nanoparticles are delivered into sebaceous glands using low-frequency ultrasound. Nanoparticles are then activated using near-infrared light to induce thermolysis. Reprinted with permission from ref 45. Copyright 2015 Elsevier.

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The Stevens group at the Imperial College of London and collaborators at the Houston Methodist Research Institute have recently reported engineering a platform of mesoporous silicon nanoneedles for the delivery of nanoparticle and other therapeutic payloads to cells and tissues (Figure 5A,B). (47, 48) This technology could prove transformative in the fields of drug delivery, regenerative medicine, and biosensing. The dynamics of the nanoneedle entry to the cell and study of the nanoneedle–cell interface have been elucidated and pave the way for highly controlled delivery of a range of nanoparticle payloads intracellularly. (47) Furthermore, the nanoneedle array can simultaneously deliver both DNA and siRNA with high efficiency (over 90%) and in vivo proved successful in upregulating blood vessel formation in muscle by delivery of the VEGF-165 gene (Figure 5C–E). (48) The Stevens group has also developed several other notable nanomaterials-based technologies, particularly enzyme-response nanoparticle systems that have a wide range of important impacts in the field of biosensing. (8, 49, 50)

Figure 5

Figure 5. Nanoneedle for the delivery of VEGF-165 to upregulate blood vessel formation in muscle. (A) Scanning electron microscope (SEM) micrographs showing the morphology of porous silicon nanoneedle arrays with pitches of 2 μm. Scale bars, 2 μm. (B) High-resolution SEM micrographs of nanoneedle tips showing the nanoneedles’ porous structure and the tunability of tip diameter from less than 100 nm to over 400 nm. Scale bars, 200 nm. (C) Intravital bright-field (top) and confocal (bottom) microscopy images of the vasculature of untreated (left) and hVEGF-165-treated muscles with either direct injection (center) or nanoinjection (right). The fluorescence signal originates from systemically injected FITC–dextran. Scale bars, bright-field 100 μm; confocal 50 μm. (D,E) Quantification of the fraction of fluorescent signal (dextran) (D) and the number of nodes in the vasculature per mm2 (E) within each field of view acquired for untreated control, intramuscular injection (IM) and nanoinjection. *p = 0.05, **p < 0.01, ***p < 0.001. Error bars represent the SD of the averages of five areas taken from three animals. Reprinted with permission of figure and caption text from ref 48. Copyright 2015 Macmillan Publishers Ltd.

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From the above discussion of a variety of nanomaterials as nanotherapeutic agents for enhancing treatment efficacy, we conclude that successful translation of nanomaterials relies on the identification of a clinical problem and innovative ideas to solve it through rational design. In addition, more and more versatile nanomaterials are being exploited in emerging research themes, areas such as cancer vaccines (51) and genome editing. (19)

Imaging and Diagnostics with High Sensitivity and Selectivity

Besides their use as therapeutic agents, nanomaterials are also being used for imaging and diagnostics purposes. The most well-known examples include silica nanoparticles, quantum dots, magnetic nanoparticles, and microbubbles. These nanostructures have been used to detect small molecules (like H2O2), cells including circulating tumor cells (CTCs), and tumor tissues.

Successful translation of nanomaterials relies on the identification of a clinical problem and innovative ideas to solve it through rational design

The Sun group at Brown University is interested in monitoring cellular H2O2, which is an important reactive oxygen species generated via oxygen metabolism; it is actively involved in cell signaling and cell growth. (52) Unfortunately, its uncontrolled overproduction can cause the detrimental oxidation of biomolecules and lead to aging, cancer, and other diseases. (53) Sun recently developed dumbbell (Au–Fe3O4 and PdPt–Fe3O4) and core/shell (Au/MnO) magnetic nanoparticles as sensitive probes for H2O2 detection. (54, 55) Dumbbell magnetic nanoparticles were prepared by the controlled nucleation and growth of Fe3O4 on presynthesized noble metal nanoparticles, while the core/shell Au/MnO nanoparticles were made by the controlled oxidation of AuMn alloy nanoparticles. Both dumbbell and core/shell nanoparticles are active for the electrochemical reduction of H2O2 with detection limits reaching as low as 5 nM. Highly sensitive electrochemical sensors have been used to monitor H2O2 concentration levels released from living cells; tumorigenic cells were found to have higher levels of H2O2 than nontumorigenic ones. These composite nanoparticle probes can be used in high-sensitivity cancer detection schemes and may also help to increase the efficacy of cancer therapies.
The Chen group at the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health uses nanomaterials as platforms to provide imaging contrast in positron emission tomography (PET). In medical imaging, PET can provide a direct, highly sensitive, and quantitative readout of organ/tissue targeting efficiency and pharmacokinetics. Compared with radiolabeled antibodies, proteins, peptides, and other biologically relevant molecules, radiolabeled nanoparticles represent a new frontier in molecular imaging probe design because they can combine different imaging modalities and targeting ligands in a single vector, synergistically improving the imaging quality. (56) However, the applications of radiolabeled nanoparticles are based on the premise that the radioisotopes are stably attached to the nanomaterials. Chen has developed general rules for selecting appropriate isotopes for given types of nanoparticles as well as adjusting the labeling reaction according to specific applications. The stability (colloidal and radiochemical) of the radiolabeled nanoparticles as well as their biological fate must be assessed; special attention should be paid to labeling strategies as they affect the stability of radiolabeled nanoparticles and might cause discrepancies in the interpretation of PET data (owing to the distribution of nanoparticles).
Wang’s group at the Chinese Academy of Sciences is interested in creating nano–bio interfaces with controllable adhesion properties. The cell-adhesive biointerfaces are based on the cooperative effects of multiscale structural matching and molecular recognition. (57) They explore the relationship between cell-specific adhesion and surface structure (with nanowires, (21) nanofibers, (58) nanofractals, (59) and soft nanotubes (60)). Also, they developed a series of biointerfaces with specific recognition and stimuli-responsive capture and release properties (i.e., temperature, (61) electric, (59) enzymatic, (21) and pH (62)). They have made progress in the isolation of viable rare CTCs from the blood via their designed cell-adhesive biointerfaces and developed adhesion-based CTC isolation approaches as cancer diagnostics with high efficiencies (>97%). (63) In particular, these biointerfaces with controlled cell adhesion are capable of capturing rare viable CTCs for early cancer detection and the monitoring of cancer therapy, single-cell gene analysis, (64) and other purposes.

Biomimetic and Bio-Inspired Scaffolds for Tissue Engineering

Nanomaterials for tissue engineering involve a broad spectrum of nanoscale formulations and structures developed to mimic tissue complexity and to modulate cellular function to yield therapeutic benefits.
The Xia group at the Georgia Institute of Technology and Emory University has been developing practical nanomaterials for medical applications. They use electrospun nanofibers in tissue engineering. (65) Electrospinning has been widely explored to process polymeric materials into nanofibers with tunable and controllable compositions, diameters, porosities, and surface properties. Owing to its small feature size, high porosity, and large surface area, a nonwoven mat of electrospun fibers can serve as a superb scaffold that mimics the extracellular matrix (ECM), which is critical to cell attachment and spreading. The nanofibers themselves can also be functionalized through the encapsulation or attachment of bioactive species, such as ECM proteins, enzymes, and growth factors. In addition, the nanofibers can be readily assembled into a wide variety of arrays or hierarchical structures by manipulating their alignment, stacking, or folding. All these attributes make electrospinning a powerful tool for generating nanostructured materials for a broad range of biomedical applications, including controlled release, drug delivery, and tissue engineering. Xia highlighted the use of aligned nanofibers to control the differentiation of embryonic stem cells into different types of neural lineages and to guide the outgrowth of neurites for peripheral nerve repair. (66) He also pointed out that nanofiber scaffolds could be designed for repairing injuries to the flexor tendon and the tendon-to-bone insertion site; (67) they could also be used as wound dressings for brain surgery. (68)
Karp from Brigham and Women’s Hospital suggests that different approaches are required for solving medical problems versus solving basic science problems. He asserts that one must develop design criteria relevant to solving the problem in animal models, while considering the multiple steps required to bring a technology from the laboratory to the clinic. One must think through scale-up, manufacturing, regulatory issues, and patent strategy and then impose these criteria to advance toward a potential solution. In particular, turning to nature for solutions can aid in the problem-solving process, recognizing that everything living has overcome challenges, and thus we are surrounded by solutions. Through elucidating mechanisms behind these solutions with state-of-the-art tools, he asserts that we can identify ideas to help overcome even the most challenging of problems. Karp has created tissue adhesives using inspiration from slugs and snails, (69) spiny-headed worms, (70) porcupine quills, (71) and spider webs. One of the adhesive technologies led to the formation of a company, Gecko Biomedical (Paris, France), and is on track to be tested for vascular graft applications in humans in late 2015. Of note is that, in these developments, failure should be embraced as part of the problem-solving process and is likely a prerequisite to success. In this work, it was important to build highly functional and multidisciplinary teams that know what resources are available in their environment and how to access them.
Teoh from Nanyang Technological University is interested in processing biomaterials in an environmentally friendly way. (72, 73) To this end, his group has unearthed a solvent-free approach known as cryomilling, where biomaterials are processed at near cryogenic temperatures. Polymer particle size reduction has been achieved due to the high-energy collision process, which occurs below the glass transition temperature. Particle sizes may be reduced to the nanoscale, where surface thermodynamics play critical roles in determining their behavior, particularly the interactions between two chemically distinct phases, as in the case of composite biomaterials. Notably, there is also a significant challenge in obtaining reproducible, well-distributed composites. They have demonstrated that a variety of composite biomaterials that incorporate second phases, such as inorganic elements, trace elements, and even drugs, may be processed efficiently via cryomilling. (73) This technique also addresses second phase distribution issues that plague many other processing techniques, such as solvent-casting, electrospinning, and melt extrusion.

Future Outlook

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Tremendously exciting advances in nanomaterials-based medical treatments, from cancer therapies, diabetes administration, and vaccine development to molecular diagnostics, tissue repair, and regeneration, are both underway and yet to come. The confluence of nanomaterials and emerging biomedical science provides vast commercial opportunities. While fundamental science has been fueled with numerous innovations over the past decade, as evidenced by the number of nanomaterial-associated formulations and devices in clinical development, the number of marketed products is still small, compared to traditional medications. Remaining challenges include effectively improving efficacy, while minimizing potential concerns, through the rational design and thorough evaluation of nanomaterials.

The confluence of nanomaterials and emerging biomedical science provides vast commercial opportunities.

In oncology nanomedicine, for example, the acceleration of the translation process relies profoundly on a thorough understanding of how nanocarriers interact with the physiological environment. In addition to general evaluations based on the enhanced permeability and retention effect, biodistribution, and clearance mechanisms, more precise details should be taken into account, such as how the particles pass through the tumor microenvironment and enter cells to reach active sites. (74, 75, 76) Moreover, in designing stimuli-responsive or programmable nanocarriers, (77, 78) a current theme in nanomedicine, closer investigations of the dynamic relationships between the phase transitions of materials and the relevant gradients in the biological environment, such as pH, redox, glucose, ATP, and enzyme activity, should enable more precise targeting and release. (79-82)
Second, a major stumbling block in the translation of nanomaterials for biomedical applications is safety concerns, especially for invasive administration. On one hand, clinical use requires the careful, prolonged evaluation of the local and systemic toxicity of nanomaterials as well as their potential immunogenicity. (83) On the other hand, there is an urgent need to invent and to tailor new materials with excellent biocompatibility. Ideas inspired by nature, mimicking the structures and composites of natural particles, including viruses, vesicles, and cells, have attracted increasing interest and brought promising outcomes.
Third, regarding the rational design of nanomaterials with specific physicochemical properties (84) for clinical applications, it is important to set uniformity in preclinical trials. Variability in particle size, surface properties, and stability as well as differences in cell lines, tumor properties, therapeutic doses, and pharmacokinetics/pharmacodynamics analysis have prevented the systematic comparison of relevant nanomaterials and have been an impediment to creating design rules for optimizing a specific formulation or device.
Last but not least, the design, development, and ultimately commercialization of clinically used nanomaterials require seamless collaboration and commitment between a broad range of research investigators, investors, and regulatory authorities. Key to these activities are platforms for fusing ideas to shepherd emerging technologies further along safe and effective pipelines.
Overall, given the progress that has been made so far, we are optimistic that nanomaterials-based clinical development will continue to be exciting, with growing numbers of innovations as well as those currently garnering FDA approval entering the clinic soon. We hope the ideas and concepts presented in this Nano Focus will be useful in the development of “ideal” nanomaterials features, the expansion of design criteria, and the enlightenment of research opportunities for evolving the next generations of biomedical materials. (85, 86, 87)

Author Information

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  • Corresponding Authors
    • Samir Mitragotri - Center for Bioengineering, Department of Chemical Engineering, University of California, Santa Barbara, California 93106, United States;  Email: [email protected] [email protected] [email protected]
    • Zhen Gu - Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, North Carolina 27695, United States;  Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States;  Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27695, United States;  Email: [email protected] [email protected] [email protected]
    • Chenjie Xu - Center for Bioengineering, Department of Chemical Engineering, University of California, Santa Barbara, California 93106, United States;  Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States;  National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, United States;  Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077;  Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095, United States;  Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States;  Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States;  Departments of Materials Engineering and Bioengineering, University of Tokyo, Tokyo 113-8654, Japan;  Department of Chemistry and International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States;  Laboratory for Nanoengineering & Drug Delivery, Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States;  Department of Materials, Department of Bioengineering, Institute for Biomedical Engineering, Imperial College London, London SW7 2AZ, U.K.;  Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States;  ▽School of Chemical and Biomedical Engineering and ▲School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798;  The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30322, United States;  Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China;  Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, North Carolina 27695, United States;  Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States;  Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27695, United States;  Email: [email protected] [email protected] [email protected]
  • Authors
    • Daniel G. Anderson - Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
    • Xiaoyuan Chen - National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, United States
    • Edward K. Chow - Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077
    • Dean Ho - Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095, United States
    • Alexander V. Kabanov - Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
    • Jeffrey M. Karp - Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States
    • Kazunori Kataoka - Departments of Materials Engineering and Bioengineering, University of Tokyo, Tokyo 113-8654, Japan
    • Chad A. Mirkin - Department of Chemistry and International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States
    • Sarah Hurst Petrosko - Department of Chemistry and International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States
    • Jinjun Shi - Laboratory for Nanoengineering & Drug Delivery, Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States
    • Molly M. Stevens - Department of Materials, Department of Bioengineering, Institute for Biomedical Engineering, Imperial College London, London SW7 2AZ, U.K.
    • Shouheng Sun - Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States
    • Sweehin Teoh - Center for Bioengineering, Department of Chemical Engineering, University of California, Santa Barbara, California 93106, United States;  Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States;  National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, United States;  Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077;  Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095, United States;  Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States;  Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States;  Departments of Materials Engineering and Bioengineering, University of Tokyo, Tokyo 113-8654, Japan;  Department of Chemistry and International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States;  Laboratory for Nanoengineering & Drug Delivery, Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States;  Department of Materials, Department of Bioengineering, Institute for Biomedical Engineering, Imperial College London, London SW7 2AZ, U.K.;  Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States;  ▽School of Chemical and Biomedical Engineering and ▲School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798;  The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30322, United States;  Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China;  Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, North Carolina 27695, United States;  Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States;  Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27695, United States
    • Subbu S. Venkatraman - Center for Bioengineering, Department of Chemical Engineering, University of California, Santa Barbara, California 93106, United States;  Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States;  National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, United States;  Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077;  Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095, United States;  Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States;  Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States;  Departments of Materials Engineering and Bioengineering, University of Tokyo, Tokyo 113-8654, Japan;  Department of Chemistry and International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, United States;  Laboratory for Nanoengineering & Drug Delivery, Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States;  Department of Materials, Department of Bioengineering, Institute for Biomedical Engineering, Imperial College London, London SW7 2AZ, U.K.;  Department of Chemistry, Brown University, Providence, Rhode Island 02912, United States;  ▽School of Chemical and Biomedical Engineering and ▲School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798;  The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30322, United States;  Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China;  Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, North Carolina 27695, United States;  Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States;  Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27695, United States
    • Younan Xia - The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30322, United States
    • Shutao Wang - Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China
  • Notes
    The authors declare the following competing financial interest(s): S.M. is a Scientific Advisor to Sebacia Inc. J.M.K. is part owner of and consultant to Gecko Biomedical.

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    20
    Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling
    Sahay, Gaurav; Querbes, William; Alabi, Christopher; Eltoukhy, Ahmed; Sarkar, Sovan; Zurenko, Christopher; Karagiannis, Emmanouil; Love, Kevin; Chen, Delai; Zoncu, Roberto; Buganim, Yosef; Schroeder, Avi; Langer, Robert; Anderson, Daniel G.
    Nature Biotechnology (2013), 31 (7), 653-658CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
    Despite efforts to understand the interactions between nanoparticles and cells, the cellular processes that det. the efficiency of intracellular drug delivery remain unclear. Here we examine cellular uptake of short interfering RNA (siRNA) delivered in lipid nanoparticles (LNPs) using cellular trafficking probes in combination with automated high-throughput confocal microscopy. We also employed defined perturbations of cellular pathways paired with systems biol. approaches to uncover protein-protein and protein-small mol. interactions. We show that multiple cell signaling effectors are required for initial cellular entry of LNPs through macropinocytosis, including proton pumps, mTOR and cathepsins. siRNA delivery is substantially reduced as ≃70% of the internalized siRNA undergoes exocytosis through egress of LNPs from late endosomes/lysosomes. Niemann-Pick type C1 (NPC1) is shown to be an important regulator of the major recycling pathways of LNP-delivered siRNAs. NPC1-deficient cells show enhanced cellular retention of LNPs inside late endosomes and lysosomes, and increased gene silencing of the target gene. Our data suggest that siRNA delivery efficiency might be improved by designing delivery vehicles that can escape the recycling pathways.
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  21. 21
    Lovell, J. F.; Jin, C. S.; Huynh, E.; Jin, H.; Kim, C.; Rubinstein, J. L.; Chan, W. C.; Cao, W.; Wang, L. V.; Zheng, G. Porphysome Nanovesicles Generated by Porphyrin Bilayers for Use as Multimodal Biophotonic Contrast Agents Nat. Mater. 2011, 10, 324– 332
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    21
    Porphysome nanovesicles generated by porphyrin bilayers for use as multimodal biophotonic contrast agents
    Lovell, Jonathan F.; Jin, Cheng S.; Huynh, Elizabeth; Jin, Honglin; Kim, Chulhong; Rubinstein, John L.; Chan, Warren C. W.; Cao, Weiguo; Wang, Lihong V.; Zheng, Gang
    Nature Materials (2011), 10 (4), 324-332CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
    Optically active nanomaterials promise to advance a range of biophotonic techniques through nanoscale optical effects and integration of multiple imaging and therapeutic modalities. Here, we report the development of porphysomes; nanovesicles formed from self-assembled porphyrin bilayers that generated large, tunable extinction coeffs., structure-dependent fluorescence self-quenching and unique photothermal and photoacoustic properties. Porphysomes enabled the sensitive visualization of lymphatic systems using photoacoustic tomog. Near-IR fluorescence generation could be restored on dissocn., creating opportunities for low-background fluorescence imaging. As a result of their org. nature, porphysomes were enzymically biodegradable and induced minimal acute toxicity in mice with i.v. doses of 1000 mg kg-1. In a similar manner to liposomes, the large aq. core of porphysomes could be passively or actively loaded. Following systemic administration, porphysomes accumulated in tumors of xenograft-bearing mice and laser irradn. induced photothermal tumor ablation. The optical properties and biocompatibility of porphysomes demonstrate the multimodal potential of org. nanoparticles for biophotonic imaging and therapy.
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  22. 22
    Dahlman, J. E.; Barnes, C.; Khan, O. F.; Thiriot, A.; Jhunjunwala, S.; Shaw, T. E.; Xing, Y.; Sager, H. B.; Sahay, G.; Speciner, L. In Vivo Endothelial siRNA Delivery Using Polymeric Nanoparticles with Low Molecular Weight Nat. Nanotechnol. 2014, 9, 648– 655
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    22
    In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight
    Dahlman, James E.; Barnes, Carmen; Khan, Omar; Thiriot, Aude; Jhunjunwala, Siddharth; Shaw, Taylor E.; Xing, Yiping; Sager, Hendrik B.; Sahay, Gaurav; Speciner, Lauren; Bader, Andrew; Bogorad, Roman L.; Yin, Hao; Racie, Tim; Dong, Yizhou; Jiang, Shan; Seedorf, Danielle; Dave, Apeksha; Sandu, Kamaljeet S.; Webber, Matthew J.; Novobrantseva, Tatiana; Ruda, Vera M.; Lytton-Jean, Abigail K. R.; Levins, Christopher G.; Kalish, Brian; Mudge, Dayna K.; Perez, Mario; Abezgauz, Ludmila; Dutta, Partha; Smith, Lynelle; Charisse, Klaus; Kieran, Mark W.; Fitzgerald, Kevin; Nahrendorf, Matthias; Danino, Dganit; Tuder, Rubin M.; von Andrian, Ulrich H.; Akinc, Akin; Panigrahy, Dipak; Schroeder, Avi; Kotelianski, Victor; Langer, Robert; Anderson, Daniel G.
    Nature Nanotechnology (2014), 9 (8), 648-655CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
    Dysfunctional endothelium contributes to more diseases than any other tissue in the body. Small interfering RNAs (siRNAs) can help in the study and treatment of endothelial cells in vivo by durably silencing multiple genes simultaneously, but efficient siRNA delivery has so far remained challenging. Here, we show that polymeric nanoparticles made of low-mol.-wt. polyamines and lipids can deliver siRNA to endothelial cells with high efficiency, thereby facilitating the simultaneous silencing of multiple endothelial genes in vivo. Unlike lipid or lipid-like nanoparticles, this formulation does not significantly reduce gene expression in hepatocytes or immune cells even at the dosage necessary for endothelial gene silencing. These nanoparticles mediate the most durable non-liver silencing reported so far and facilitate the delivery of siRNAs that modify endothelial function in mouse models of vascular permeability, emphysema, primary tumor growth and metastasis.
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  23. 23
    Dong, Y.; Love, K. T.; Dorkin, J. R.; Sirirungruang, S.; Zhang, Y.; Chen, D.; Bogorad, R. L.; Yin, H.; Chen, Y.; Vegas, A. J. Lipopeptide Nanoparticles for Potent and Selective siRNA Delivery in Rodents and Nonhuman Primates Proc. Natl. Acad. Sci. U.S.A. 2014, 111, 3955– 3960
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    23
    Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates
    Dong, Yizhou; Love, Kevin T.; Dorkin, J. Robert; Sirirungruang, Sasilada; Zhang, Yunlong; Chen, Delai; Bogorad, Roman L.; Yin, Hao; Chen, Yi; Vegas, Arturo J.; Alabi, Christopher A.; Sahay, Gaurav; Olejnik, Karsten T.; Wang, Weiheng; Schroeder, Avi; Lytton-Jean, Abigail K. R.; Siegwart, Daniel J.; Akinc, Akin; Barnes, Carmen; Barros, Scott A.; Carioto, Mary; Fitzgerald, Kevin; Hettinger, Julia; Kumar, Varun; Novobrantseva, Tatiana I.; Qin, June; Querbes, William; Koteliansky, Victor; Langer, Robert; Anderson, Daniel G.
    Proceedings of the National Academy of Sciences of the United States of America (2014), 111 (11), 3955-3960CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    SiRNA therapeutics have promise for the treatment of a wide range of genetic disorders. Motivated by lipoproteins, we report lipopeptide nanoparticles as potent and selective siRNA carriers with a wide therapeutic index. Lead material cKK-E12 showed potent silencing effects in mice (ED50 ∼ 0.002 mg/kg), rats (ED50 < 0.01 mg/kg), and nonhuman primates (over 95% silencing at 0.3 mg/kg). Apolipoprotein E plays a significant role in the potency of cKK-E12 both in vitro and in vivo. CKK-E12 was highly selective toward liver parenchymal cell in vivo, with orders of magnitude lower doses needed to silence in hepatocytes compared with endothelial cells and immune cells in different organs. Toxicity studies showed that cKK-E12 was well tolerated in rats at a dose of 1 mg/kg (over 100-fold higher than the ED50). To our knowledge, this is the most efficacious and selective nonviral siRNA delivery system for gene silencing in hepatocytes reported to date.
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  24. 24
    Yin, H.; Xue, W.; Chen, S.; Bogorad, R. L.; Benedetti, E.; Grompe, M.; Koteliansky, V.; Sharp, P. A.; Jacks, T.; Anderson, D. G. Genome Editing with Cas9 in Adult Mice Corrects a Disease Mutation and Phenotype Nat. Biotechnol. 2014, 32, 551– 553
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    24
    Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype
    Yin, Hao; Xue, Wen; Chen, Sidi; Bogorad, Roman L.; Benedetti, Eric; Grompe, Markus; Koteliansky, Victor; Sharp, Phillip A.; Jacks, Tyler; Anderson, Daniel G.
    Nature Biotechnology (2014), 32 (6), 551-553CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
    The authors demonstrate CRISPR-Cas9-mediated correction of a Fah mutation in hepatocytes in a mouse model of the human disease hereditary tyrosinemia. Delivery of components of the CRISPR-Cas9 system by hydrodynamic injection resulted in initial expression of the wild-type Fah protein in ∼1/250 liver cells. Expansion of Fah-pos. hepatocytes rescued the body wt. loss phenotype. The authors' study indicates that CRISPR-Cas9-mediated genome editing is possible in adult animals and has potential for correction of human genetic diseases.
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  25. 25
    Shi, J.; Xiao, Z.; Votruba, A. R.; Vilos, C.; Farokhzad, O. C. Differentially Charged Hollow Core/Shell Lipid–Polymer–Lipid Hybrid Nanoparticles for Small Interfering RNA Delivery Angew. Chem., Int. Ed. 2011, 123, 7165– 7169
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  26. 26
    Shi, J.; Xu, Y.; Xu, X.; Zhu, X.; Pridgen, E.; Wu, J.; Votruba, A. R.; Swami, A.; Zetter, B. R.; Farokhzad, O. C. Hybrid Lipid–Polymer Nanoparticles for Sustained siRNA Delivery and Gene Silencing Nanomedicine 2014, 10, 897– 900
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    Zhu, X.; Xu, Y.; Solis, L. M.; Tao, W.; Wang, L.; Behrens, C.; Xu, X.; Zhao, L.; Liu, D.; Wu, J. Long-Circulating siRNA Nanoparticles for Validating Prohibitin1-Targeted Non-Small Cell Lung Cancer Treatment Proc. Natl. Acad. Sci. U.S.A. 2015,  DOI: 10.1073/pnas.1505629112
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  28. 28
    Cabral, H.; Kataoka, K. Progress of Drug-Loaded Polymeric Micelles into Clinical Studies J. Controlled Release 2014, 190, 465– 476
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    28
    Progress of drug-loaded polymeric micelles into clinical studies
    Cabral, Horacio; Kataoka, Kazunori
    Journal of Controlled Release (2014), 190 (), 465-476CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
    A review. Targeting tumors with long-circulating nano-scaled carriers is a promising strategy for systemic cancer treatment. Compared with free small therapeutic agents, nanocarriers can selectively accumulate in solid tumors through the enhanced permeability and retention (EPR) effect, which is characterized by leaky blood vessels and impaired lymphatic drainage in tumor tissues, and achieve superior therapeutic efficacy, while reducing side effects. In this way, drug-loaded polymeric micelles, i.e. self-assemblies of amphiphilic block copolymers consisting of a hydrophobic core as a drug reservoir and a poly(ethylene glycol) (PEG) hydrophilic shell, have demonstrated outstanding features as tumor-targeted nanocarriers with high translational potential, and several micelle formulations are currently under clin. evaluation. This review summarizes recent efforts in the development of these polymeric micelles and their performance in human studies, as well as our recent progress in polymeric micelles for the delivery of nucleic acids and imaging.
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  29. 29
    Miura, Y.; Takenaka, T.; Toh, K.; Wu, S.; Nishihara, H.; Kano, M. R.; Ino, Y.; Nomoto, T.; Matsumoto, Y.; Koyama, H. Cyclic RGD-Linked Polymeric Micelles for Targeted Delivery of Platinum Anticancer Drugs to Glioblastoma through the Blood–Brain Tumor Barrier ACS Nano 2013, 7, 8583– 8592
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    Ahn, J.; Miura, Y.; Yamada, N.; Chida, T.; Liu, X.; Kim, A.; Sato, R.; Tsumura, R.; Koga, Y.; Yasunaga, M. Antibody Fragment-Conjugated Polymeric Micelles Incorporating Platinum Drugs for Targeted Therapy of Pancreatic Cancer Biomaterials 2015, 39, 23– 30
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  31. 31
    Kabanov, A. V.; Chekhonin, V.; Alakhov, V. Y.; Batrakova, E.; Lebedev, A.; Melik-Nubarov, N.; Arzhakov, S.; Levashov, A.; Morozov, G.; Severin, E. The Neuroleptic Activity of Haloperidol Increases after Its Solubilization in Surfactant Micelles: Micelles as Microcontainers for Drug Targeting FEBS Lett. 1989, 258, 343– 345
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    Alakhova, D. Y.; Kabanov, A. V. Pluronics and MDR Reversal: An Update Mol. Pharmaceutics 2014, 11, 2566– 2578
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    32
    Pluronics and MDR Reversal: An Update
    Alakhova, Daria Y.; Kabanov, Alexander V.
    Molecular Pharmaceutics (2014), 11 (8), 2566-2578CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    A review. Multidrug resistance (MDR) remains one of the biggest obstacles for effective cancer therapy. Currently there are only few methods that are available clin. that are used to bypass MDR with very limited success. In this review we describe how MDR can be overcome by a simple yet effective approach of using amphiphilic block copolymers. Triblock copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), arranged in a triblock structure PEO-PPO-PEO, Pluronics or "poloxamers", raised a considerable interest in the drug delivery field. Previous studies demonstrated that Pluronics sensitize MDR cancer cells resulting in increased cytotoxic activity of Dox, paclitaxel, and other drugs by 2-3 orders of magnitude. Pluronics can also prevent the development of MDR in vitro and in vivo. Addnl., promising results of clin. studies of Dox/Pluronic formulation reinforced the need to ascertain a thorough understanding of Pluronic effects in tumors. These effects are extremely comprehensive and appear on the level of plasma membranes, mitochondria, and regulation of gene expression selectively in MDR cancer cells. Moreover, it has been demonstrated recently that Pluronics can effectively deplete tumorigenic intrinsically drug-resistant cancer stem cells (CSC). Interestingly, sensitization of MDR and inhibition of drug efflux transporters is not specific or selective to Pluronics. Other amphiphilic polymers have shown similar activities in various exptl. models. This review summarizes recent advances of understanding the Pluronic effects in sensitization and prevention of MDR.
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  33. 33
    Valle, J. W.; Armstrong, A.; Newman, C.; Alakhov, V.; Pietrzynski, G.; Brewer, J.; Campbell, S.; Corrie, P.; Rowinsky, E. K.; Ranson, M. A Phase 2 Study of SP1049C, Doxorubicin in P-Glycoprotein-Targeting Pluronics, in Patients with Advanced Adenocarcinoma of the Esophagus and Gastroesophageal Junction Invest. New Drugs 2011, 29, 1029– 1037
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  34. 34
    Han, Y.; He, Z.; Schulz, A.; Bronich, T. K.; Jordan, R.; Luxenhofer, R.; Kabanov, A. V. Synergistic Combinations of Multiple Chemotherapeutic Agents in High Capacity Poly(2-oxazoline) Micelles Mol. Pharmaceutics 2012, 9, 2302– 2313
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    Synergistic Combinations of Multiple Chemotherapeutic Agents in High Capacity Poly(2-oxazoline) Micelles
    Han, Yingchao; He, Zhijian; Schulz, Anita; Bronich, Tatiana K.; Jordan, Rainer; Luxenhofer, Robert; Kabanov, Alexander V.
    Molecular Pharmaceutics (2012), 9 (8), 2302-2313CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    Many effective drugs for cancer treatment are poorly water-sol. In combination chemotherapy, needed excipients in additive formulations are often toxic and restrict their applications in clin. intervention. Here, we report on amphiphilic poly(2-oxazoline)s (POx) micelles as a promising high capacity delivery platform for multidrug cancer chemotherapy. A variety of binary and ternary drugs combinations of paclitaxel (PTX), docetaxel (DTX), 17-allylamino-17-demethoxygeldanamycin (17-AAG), etoposide (ETO) and bortezomib (BTZ) were solubilized in defined polymeric micelles achieving unprecedented high total loading capacities of up to 50 wt. % drug per final formulation. Multidrug loaded POx micelles showed enhanced stability in comparison to single-drug loaded micelles. Drug ratio dependent synergistic cytotoxicity of micellar ETO/17-AAG was obsd. in MCF-7 cancer cells and of micellar BTZ/17-AAG in MCF-7, PC3, MDA-MB-231 and HepG2 cells.
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  35. 35
    He, Z.; Schulz, A.; Wan, X.; Seitz, J.; Bludau, H.; Alakhova, D. Y.; Darr, D. B.; Perou, C. M.; Jordan, R.; Ojima, I. Poly(2-oxazoline) Based Micelles with High Capacity for 3rd Generation Taxoids: Preparation, In Vitro and In Vivo Evaluation J. Controlled Release 2015, 208, 67– 75
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  36. 36
    Natarajan, J. V.; Ang, M.; Darwitan, A.; Chattopadhyay, S.; Wong, T. T.; Venkatraman, S. S. Nanomedicine for Glaucoma: Liposomes Provide Sustained Release of Latanoprost in the Eye Int. J. Nanomed. 2012, 7, 123– 131
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    36
    Nanomedicine for glaucoma: liposomes provide sustained release of latanoprost in the eye
    Natarajan, Jayaganesh V.; Ang, Marcus; Darwitan, Anastasia; Chattopadhyay, Sujay; Wong, Tina T.; Venkatraman, Subbu S.
    International Journal of Nanomedicine (2012), 7 (), 123-131CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)
    The development and therapeutic evaluation of a liposomal nanocarrier for sustained release of latanoprost, in the rabbit eye are described. Latanoprost-loaded egg-phosphatidylcholine (EggPC) liposomes were prepd. using the film hydration technique. The delivery vehicles were nano-sized (Z avg = 109 ± 18 nm), had a narrow poly dispersity index (PDI = 0.19 ± 0.04) and a very high loading efficiency (94% ± 5%). Based on in vitro data, this formulation for lowering intraocular pressure (IOP) in rabbit eyes was evaluated. Following a single subconjunctival injection of the latanoprost loaded formulation, the eyes were clin. monitored and the IOP recorded. Latanoprost-loaded EggPC liposomes demonstrated a high drug/lipid mole ratio of 0.181, remained stable for at least 6 mo on storage (4°C) and at least 1 mo at 25°C. A slow and sustained release of 60% of latanoprost was achieved by 14 days in the in vitro release study. The same formulation demonstrated a greater sustained IOP lowering effect compared with daily administration of topical latanoprost beyond 90 days (4.8 ± 1.5 vs 2.5 ± 0.9 mmHg; P < 0.001). No signs of inflammation were evident in the eyes from slit-lamp examn. anal. The loading required for a long-term sustained delivery of latanoprost for up to 90 days in the rabbit eyes was achieved with EggPC liposomes. A single injection of latanoprost-loaded EggPC liposomes can lower the IOP for up to 90 days, with a greater IOP lowering effect than daily topical administration of latanoprost.
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  37. 37
    Natarajan, J. V.; Darwitan, A.; Barathi, V. A.; Ang, M.; Htoon, H. M.; Boey, F.; Tam, K. C.; Wong, T. T.; Venkatraman, S. S. Sustained Drug Release in Nanomedicine: A Long-Acting Nanocarrier-Based Formulation for Glaucoma ACS Nano 2014, 8, 419– 429
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  38. 38
    Tan, Y. F.; Mundargi, R. C.; Chen, M. H. A.; Lessig, J.; Neu, B.; Venkatraman, S. S.; Wong, T. T. Layer-by-Layer Nanoparticles as an Efficient siRNA Delivery Vehicle for SPARC Silencing Small 2014, 10, 1790– 1798
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    There is no corresponding record for this reference.
  39. 39
    Huang, H.; Pierstorff, E.; Osawa, E.; Ho, D. Active Nanodiamond Hydrogels for Chemotherapeutic Delivery Nano Lett. 2007, 7, 3305– 3314
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    39
    Active nanodiamond hydrogels for chemotherapeutic delivery
    Huang, Houjin; Pierstorff, Erik; Osawa, Eiji; Ho, Dean
    Nano Letters (2007), 7 (11), 3305-3314CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
    Nanodiamond materials can serve as highly versatile platforms for the controlled functionalization and delivery of a wide spectrum of therapeutic elements. In this work, doxorubicin hydrochloride (DOX), an apoptosis-inducing drug widely used in chemotherapy, was successfully applied toward the functionalization of nanodiamond materials (NDs, 2-8 nm) and introduced toward murine macrophages as well as human colorectal carcinoma cells with preserved efficacy. The adsorption of DOX onto the NDs and its reversible release were achieved by regulating Cl- ion concn., and the NDs were found to be able to efficiently ferry the drug inside living cells. Comprehensive bioassays were performed to assess and confirm the innate biocompatibility of the NDs, via real-time quant. polymerase chain reaction (RT-PCR), and electrophoretic DNA fragmentation as well as MTT anal. confirmed the functional apoptosis-inducing mechanisms driven by the DOX-functionalized NDs. We extended the applicability of the DOX-ND composites toward a translational context, where MTT assays were performed on the HT-29 colon cancer cell line to assess DOX-ND induced cell death and ND-mediated chemotherapeutic sequestering for potential slow/sustained released capabilities. These and other medically relevant capabilities enabled by the NDs forge its strong potential as a therapeutically significant nanomaterial.
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  40. 40
    Manus, L. M.; Mastarone, D. J.; Waters, E. A.; Zhang, X.-Q.; Schultz-Sikma, E. A.; MacRenaris, K. W.; Ho, D.; Meade, T. J. Gd(III)-Nanodiamond Conjugates for MRI Contrast Enhancement Nano Lett. 2010, 10, 484– 489
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    Chow, E. K.; Zhang, X.-Q.; Chen, M.; Lam, R.; Robinson, E.; Huang, H.; Schaffer, D.; Osawa, E.; Goga, A.; Ho, D. Nanodiamond Therapeutic Delivery Agents Mediate Enhanced Chemoresistant Tumor Treatment Sci. Transl. Med. 2011, 3, 73ra21
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    41
    Nanodiamond therapeutic delivery agents mediate enhanced chemoresistant tumor treatment
    Chow, Edward K.; Zhang, Xue-Qing; Chen, Mark; Lam, Robert; Robinson, Erik; Huang, Houjin; Schaffer, Daniel; Osawa, Eiji; Goga, Andrei; Ho, Dean
    Science Translational Medicine (2011), 3 (73), 73ra21/1-73ra21/10CODEN: STMCBQ; ISSN:1946-6242. (American Association for the Advancement of Science)
    Enhancing chemotherapeutic efficiency through improved drug delivery would facilitate treatment of chemoresistant cancers, such as recurrent mammary tumors and liver cancer. One way to improve drug delivery is through the use of nanodiamond (ND) therapies, which are both scalable and biocompatible. Here, we examd. the efficacy of an ND-conjugated chemotherapeutic in mouse models of liver and mammary cancer. A complex (NDX) of ND and doxorubicin (Dox) overcame drug efflux and significantly increased apoptosis and tumor growth inhibition beyond conventional Dox treatment in both murine liver tumor and mammary carcinoma models. Unmodified Dox treatment represents the clin. std. for most cancer treatment regimens, and NDX had significantly decreased toxicity in vivo compared to std. Dox treatment. Thus, ND-conjugated chemotherapy represents a promising, biocompatible strategy for overcoming chemoresistance and enhancing chemotherapy efficacy and safety.
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  42. 42
    Moore, L.; Chow, E. K.-H.; Osawa, E.; Bishop, J. M.; Ho, D. Diamond-Lipid Hybrids Enhance Chemotherapeutic Tolerance and Mediate Tumor Regression Adv. Mater. 2013, 25, 3532– 3541
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    42
    Diamond-Lipid Hybrids Enhance Chemotherapeutic Tolerance and Mediate Tumor Regression
    Moore, Laura; Chow, Edward Kai-Hua; Osawa, Eiji; Bishop, J. Michael; Ho, Dean
    Advanced Materials (Weinheim, Germany) (2013), 25 (26), 3532-3541CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Self-assembled nanodiamond-lipid hybrid particlees (NDLPs) harness the potent interaction between the nanodiamond (ND)-surface and small mols., while providing a mechanism for cell-targeted imaging and therapy of triple neg. breast cancers. Epidermal growth factor receptor-targeted NDLPs are highly biocompatible particles that provide cell-specific imaging, promote tumor retention of ND-complexes, prevent epirubicin toxicity and mediate regression of triple neg. breast cancers.
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  43. 43
    Wang, X.; Low, X. C.; Hou, W.; Abdullah, L. N.; Toh, T. B.; Mohd Abdul Rashid, M.; Ho, D.; Chow, E. K.-H. Epirubicin-Adsorbed Nanodiamonds Kill Chemoresistant Hepatic Cancer Stem Cells ACS Nano 2014, 8, 12151– 12166
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    43
    Epirubicin-Adsorbed Nanodiamonds Kill Chemoresistant Hepatic Cancer Stem Cells
    Wang, Xin; Low, Xinyi Casuarine; Hou, Weixin; Abdullah, Lissa Nurrul; Toh, Tan Boon; Mohd. Abdul Rashid, Masturah; Ho, Dean; Chow, Edward Kai-Hua
    ACS Nano (2014), 8 (12), 12151-12166CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Chemoresistance is a primary cause of treatment failure in cancer and a common property of tumor-initiating cancer stem cells. Overcoming mechanisms of chemoresistance, particularly in cancer stem cells, can markedly enhance cancer therapy and prevent recurrence and metastasis. This study demonstrates that the delivery of Epirubicin by nanodiamonds is a highly effective nanomedicine-based approach to overcoming chemoresistance in hepatic cancer stem cells. The potent phys. adsorption of Epirubicin to nanodiamonds creates a rapidly synthesized and stable nanodiamond-drug complex that promotes endocytic uptake and enhanced tumor cell retention. These attributes mediate the effective killing of both cancer stem cells and noncancer stem cells in vitro and in vivo. Enhanced treatment of both tumor cell populations results in an improved impairment of secondary tumor formation in vivo compared with treatment by unmodified chemotherapeutics. On the basis of these results, nanodiamond-mediated drug delivery may serve as a powerful method for overcoming chemoresistance in cancer stem cells and markedly improving overall treatment against hepatic cancers.
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  44. 44
    Wang, H.; Lee, D.-K.; Chen, K.-Y.; Chen, J.-Y.; Zhang, K.; Silva, A.; Ho, C.-M.; Ho, D. Mechanism-Independent Optimization of Combinatorial Nanodiamond and Unmodified Drug Delivery Using a Phenotypically Driven Platform Technology ACS Nano 2015, 9, 3332– 3344
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    Paithankar, D.; Hwang, B. H.; Munavalli, G.; Kauvar, A.; Lloyd, J.; Blomgren, R.; Faupel, L.; Meyer, T.; Mitragotri, S. Ultrasonic Delivery of Silica–Gold Nanoshells for Photothermolysis of Sebaceous Glands in Humans: Nanotechnology from the Bench to Clinic J. Controlled Release 2015, 206, 30– 36
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    Tezel, A.; Mitragotri, S. Interactions of Inertial Cavitation Bubbles with Stratum Corneum Lipid Bilayers during Low-Frequency Sonophoresis Biophys. J. 2003, 85, 3502– 3512
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    Chiappini, C.; Martinez, J. O.; De Rosa, E.; Almeida, C. S.; Tasciotti, E.; Stevens, M. M. Biodegradable Nanoneedles for Localized Delivery of Nanoparticles in Vivo: Exploring the Biointerface ACS Nano 2015, 9, 5500– 5509
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    47
    Biodegradable Nanoneedles for Localized Delivery of Nanoparticles in Vivo: Exploring the Biointerface
    Chiappini, Ciro; Martinez, Jonathan O.; De Rosa, Enrica; Almeida, Carina S.; Tasciotti, Ennio; Stevens, Molly M.
    ACS Nano (2015), 9 (5), 5500-5509CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Nanoneedles display potential in mediating the delivery of drugs and biologicals, as well as intracellular sensing and single-cell stimulation, through direct access to the cell cytoplasm. Nanoneedles enable cytosolic delivery, negotiating the cell membrane and the endolysosomal system, thus overcoming these major obstacles to the efficacy of nanotherapeutics. The low toxicity and minimal invasiveness of nanoneedles have a potential for the sustained nonimmunogenic delivery of payloads in vivo, provided that the development of biocompatible nanoneedles with a simple deployment strategy is achieved. Here we present a mesoporous silicon nanoneedle array that achieves a tight interface with the cell, rapidly negotiating local biol. barriers to grant temporary access to the cytosol with minimal impact on cell viability. The tightness of this interfacing enables both delivery of cell-impermeant quantum dots in vivo and live intracellular sensing of pH. Dissecting the biointerface over time elucidated the dynamics of cell assocn. and nanoneedle biodegrdn., showing rapid interfacing leading to cytosolic payload delivery within less than 30 min in vitro. The rapid and simple application of nanoneedles in vivo to the surface of tissues with different architectures invariably resulted in the localized delivery of quantum dots to the superficial cells and their prolonged retention. This investigation provides an understanding of the dynamics of nanoneedles' biointerface and delivery, outlining a strategy for highly local intracellular delivery of nanoparticles and cell-impermeant payloads within live tissues.
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  48. 48
    Chiappini, C.; De Rosa, E.; Martinez, J.; Liu, X.; Steele, J.; Stevens, M.; Tasciotti, E. Biodegradable Silicon Nanoneedles Delivering Nucleic Acids Intracellularly Induce Localized In Vivo Neovascularization Nat. Mater. 2015, 14, 532– 539
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    48
    Biodegradable silicon nanoneedles delivering nucleic acids intracellularly induce localized in vivo neovascularization
    Chiappini, C.; De Rosa, E.; Martinez, J. O.; Liu, X.; Steele, J.; Stevens, M. M.; Tasciotti, E.
    Nature Materials (2015), 14 (5), 532-539CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
    The controlled delivery of nucleic acids to selected tissues remains an inefficient process mired by low transfection efficacy, poor scalability because of varying efficiency with cell type and location, and questionable safety as a result of toxicity issues arising from the typical materials and procedures employed. High efficiency and minimal toxicity in vitro has been shown for intracellular delivery of nuclei acids by using nanoneedles, yet extending these characteristics to in vivo delivery has been difficult, as current interfacing strategies rely on complex equipment or active cell internalization through prolonged interfacing. Here, we show that a tunable array of biodegradable nanoneedles fabricated by metal-assisted chem. etching of silicon can access the cytosol to co-deliver DNA and siRNA with an efficiency greater than 90%, and that in vivo the nanoneedles transfect the VEGF-165 gene, inducing sustained neovascularization and a localized sixfold increase in blood perfusion in a target region of the muscle.
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    De La Rica, R.; Stevens, M. M. Plasmonic ELISA for the Ultrasensitive Detection of Disease Biomarkers with the Naked Eye Nat. Nanotechnol. 2012, 7, 821– 824
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    Plasmonic ELISA for the ultrasensitive detection of disease biomarkers with the naked eye
    de la Rica, Roberto; Stevens, Molly M.
    Nature Nanotechnology (2012), 7 (12), 821-824CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
    In resource-constrained countries, affordable methodologies for the detection of disease biomarkers at ultralow concns. can potentially improve the std. of living. However, current strategies for ultrasensitive detection often require sophisticated instruments that may not be available in labs. with fewer resources. Here, the authors circumvent this problem by introducing a signal generation mechanism for biosensing that enables the detection of a few mols. of analyte with the naked eye. The enzyme label of an ELISA controls the growth of gold nanoparticles and generates colored solns. with distinct tonality when the analyte is present. Prostate specific antigen (PSA) and HIV-1 capsid antigen p24 were detected in whole serum at the ultralow concn. of 1 × 10-18 g ml-1. P24 was also detected with the naked eye in the sera of HIV-infected patients showing viral loads undetectable by a gold std. nucleic acid-based test.
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  50. 50
    Chapman, R.; Lin, Y.; Burnapp, M.; Bentham, A.; Hillier, D.; Zabron, A.; Khan, S.; Tyreman, M.; Stevens, M. M. Multivalent Nanoparticle Networks Enable Point-of-Care Detection of Human Phospholipase-A2 in Serum ACS Nano 2015, 9, 2565– 2573
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    50
    Multivalent Nanoparticle Networks Enable Point-of-Care Detection of Human Phospholipase-A2 in Serum
    Chapman, Robert; Lin, Yiyang; Burnapp, Mark; Bentham, Andrew; Hillier, David; Zabron, Abigail; Khan, Shahid; Tyreman, Matthew; Stevens, Molly M.
    ACS Nano (2015), 9 (3), 2565-2573CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    A rapid and highly sensitive point-of-care (PoC) lateral flow assay for phospholipase A2 (PLA2) is demonstrated in serum through the enzyme-triggered release of a new class of biotinylated multiarmed polymers from a liposome substrate. Signal from the enzyme activity is generated by the adhesion of polystreptavidin-coated gold nanoparticle networks to the lateral flow device, which leads to the appearance of a red test line due to the localized surface plasmon resonance effect of the gold. The use of a liposome as the enzyme substrate and multivalent linkers to link the nanoparticles leads to amplification of the signal, as the cleavage of a small amt. of lipids is able to release a large amt. of polymer linker and adhesion of an even larger amt. of gold nanoparticles. By optimizing the mol. wt. and multivalency of these biotinylated polymer linkers, the sensitivity of the device can be tuned to enable naked-eye detection of 1 nM human PLA2 in serum within 10 min. This high sensitivity enabled the correct diagnosis of pancreatitis in diseased clin. samples against a set of healthy controls using PLA2 activity in a point-of-care device for the first time.
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    Dewitte, H.; Verbeke, R.; Breckpot, K.; De Smedt, S. C.; Lentacker, I. Nanoparticle Design To Induce Tumor Immunity and Challenge the Suppressive Tumor Microenvironment Nano Today 2014, 9, 743– 758
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    Nanoparticle design to induce tumor immunity and challenge the suppressive tumor microenvironment
    Dewitte, Heleen; Verbeke, Rein; Breckpot, Karine; De Smedt, Stefaan C.; Lentacker, Ine
    Nano Today (2014), 9 (6), 743-758CODEN: NTAOCG; ISSN:1748-0132. (Elsevier Ltd.)
    A review. Over the years research in the field of cancer immunotherapy has flourished, bringing about crucial breakthroughs, but at the same time revealing new and important pathways of immune suppression that put a break on the success of cancer immunotherapy. This review focuses on how nano- and micromaterials can be used to induce antitumor immune responses and what their role in overcoming immune suppression could be. It is now beyond question that this requires elegantly designed particles that can reach their target cells, deliver antigenic cargo and most importantly immune stimulants in order to provoke and sustain antitumor immunity.
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    Gough, D. R.; Cotter, T. G. Hydrogen Peroxide: A Jekyll and Hyde Signalling Molecule Cell Death Dis. 2011, 2, e213
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    Hydrogen peroxide: a Jekyll and Hyde signalling molecule
    Gough, D. R.; Cotter, T. G.
    Cell Death & Disease (2011), 2 (Oct.), e213/1-e213/8CODEN: CDDEA4; ISSN:2041-4889. (Nature Publishing Group)
    A review. Reactive oxygen species (ROS) are a group of mols. produced in the cell through metab. of oxygen. Endogenous ROS such as hydrogen peroxide (H2O2) have long been recognized as destructive mols. The well-established roles they have in the phagosome and genomic instability has led to the characterization of these mols. as non-specific agents of destruction. Interestingly, there is a growing body of literature suggesting a less sinister role for this Jekyll and Hyde mol. It is now evident that at lower physiol. levels, H2O2 can act as a classical intracellular signalling mol. regulating kinase-driven pathways. The newly discovered biol. functions attributed to ROS include proliferation, migration, anoikis, survival and autophagy. Furthermore, recent advances in detection and quantification of ROS-family members have revealed that the diverse functions of ROS can be detd. by the subcellular source, location and duration of these mols. within the cell. In light of this confounding paradox, we will examine the factors and circumstances that det. whether H2O2 acts in a pro-survival or deleterious manner.
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    Lobo, V.; Patil, A.; Phatak, A.; Chandra, N. Free Radicals, Antioxidants and Functional Foods: Impact on Human Health Pharmacogn. Rev. 2010, 4, 118– 126
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    Free radicals, antioxidants and functional foods: Impact on human health
    Lobo V; Patil A; Phatak A; Chandra N
    Pharmacognosy reviews (2010), 4 (8), 118-26 ISSN:.
    In recent years, there has been a great deal of attention toward the field of free radical chemistry. Free radicals reactive oxygen species and reactive nitrogen species are generated by our body by various endogenous systems, exposure to different physiochemical conditions or pathological states. A balance between free radicals and antioxidants is necessary for proper physiological function. If free radicals overwhelm the body's ability to regulate them, a condition known as oxidative stress ensues. Free radicals thus adversely alter lipids, proteins, and DNA and trigger a number of human diseases. Hence application of external source of antioxidants can assist in coping this oxidative stress. Synthetic antioxidants such as butylated hydroxytoluene and butylated hydroxyanisole have recently been reported to be dangerous for human health. Thus, the search for effective, nontoxic natural compounds with antioxidative activity has been intensified in recent years. The present review provides a brief overview on oxidative stress mediated cellular damages and role of dietary antioxidants as functional foods in the management of human diseases.
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  54. 54
    Sun, X.; Guo, S.; Liu, Y.; Sun, S. Dumbbell-like PtPd–Fe3O4 Nanoparticles for Enhanced Electrochemical Detection of H2O2 Nano Lett. 2012, 12, 4859– 4863
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    Zhu, H.; Sigdel, A.; Zhang, S.; Su, D.; Xi, Z.; Li, Q.; Sun, S. Core/Shell Au/MnO Nanoparticles Prepared through Controlled Oxidation of AuMn as an Electrocatalyst for Sensitive H2O2 Detection Angew. Chem., Int. Ed. 2014, 53, 12508– 12512
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    Core/Shell Au/MnO Nanoparticles Prepared Through Controlled Oxidation of AuMn as an Electrocatalyst for Sensitive H2O2 Detection
    Zhu, Huiyuan; Sigdel, Aruna; Zhang, Sen; Su, Dong; Xi, Zheng; Li, Qing; Sun, Shouheng
    Angewandte Chemie, International Edition (2014), 53 (46), 12508-12512CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Monodisperse 5 nm AuMn nanoparticles were synthesized by hydride redn. of manganese acetylacetonate in the presence of Au nanoparticles. The alloy was formed through fast Mn diffusion into the Au structure. The AuMn nanoparticles were converted to Au-MnO composite particles through air annealing at 170 °C. These Au-MnO particles, esp. the core/shell Au/MnO nanoparticles, were active for the electrochem. redn. of H2O2, with a detection limit reaching 8 nΜ. This highly sensitive electrochem. sensor based on the Au/MnO nanoparticles was used to monitor H2O2 concns. released from living cells, from which tumorigenic cells were discovered to release higher levels of H2O2 than the non-tumorigenic cells.
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    Sun, X.; Cai, W.; Chen, X. Positron Emission Tomography Imaging Using Radiolabeled Inorganic Nanomaterials Acc. Chem. Res. 2015, 48, 286– 294
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    Positron Emission Tomography Imaging Using Radiolabeled Inorganic Nanomaterials
    Sun, Xiaolian; Cai, Weibo; Chen, Xiaoyuan
    Accounts of Chemical Research (2015), 48 (2), 286-294CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review. Positron emission tomog. (PET) is a radionuclide imaging technol. that plays an important role in preclin. and clin. research. With administration of a small amt. of radiotracer, PET imaging can provide a noninvasive, highly sensitive, and quant. readout of its organ/tissue targeting efficiency and pharmacokinetics. Various radiotracers have been designed to target specific mol. events. Compared with antibodies, proteins, peptides, and other biol. relevant mols., nanoparticles represent a new frontier in mol. imaging probe design, enabling the attachment of different imaging modalities, targeting ligands, and therapeutic payloads in a single vector. We introduce the radiolabeled nanoparticle platforms that we and others have developed. Due to the fundamental differences in the various nanoparticles and radioisotopes, most radiolabeling methods are designed case-by-case. We focus on some general rules about selecting appropriate isotopes for given types of nanoparticles, as well as adjusting the labeling strategies according to specific applications. We classified these radiolabeling methods into four categories: (1) complexation reaction of radiometal ions with chelators via coordination chem.; (2) direct bombardment of nanoparticles via hadronic projectiles; (3) synthesis of nanoparticles using a mixt. of radioactive and nonradioactive precursors; (4) chelator-free postsynthetic radiolabeling. Method 1 is generally applicable to different nanomaterials as long as the surface chem. is well-designed. However, the addn. of chelators brings concerns of possible changes to the physicochem. properties of nanomaterials and detachment of the radiometal. Methods 2 and 3 have improved radiochem. stability. The applications are, however, limited by the possible damage to the nanocomponent caused by the proton beams (method 2) and harsh synthetic conditions (method 3). Method 4 is still in its infancy. Although being fast and specific, only a few combinations of isotopes and nanoparticles have been explored. Since the applications of radiolabeled nanoparticles are based on the premise that the radioisotopes are stably attached to the nanomaterials, stability (colloidal and radiochem.) assessment of radiolabeled nanoparticles is also highlighted. Despite the fact that thousands of nanomaterials have been developed for clin. research, only very few have moved to humans. One major reason is the lack of understanding of the biol. behavior of nanomaterials. We discuss specific examples of using PET imaging to monitor the in vivo fate of radiolabeled nanoparticles, emphasizing the importance of labeling strategies and caution in interpreting PET data. Design considerations for radiolabeled nanoplatforms for multimodal mol. imaging are also illustrated, with a focus on strategies to combine the strengths of different imaging modalities and to prolong the circulation time.
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    Liu, X.; Wang, S. Three-Dimensional Nano-Biointerface as a New Platform for Guiding Cell Fate Chem. Soc. Rev. 2014, 43, 2385– 2401
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    Three-dimensional nano-biointerface as a new platform for guiding cell fate
    Liu, Xueli; Wang, Shutao
    Chemical Society Reviews (2014), 43 (8), 2385-2401CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. Three-dimensional nano-biointerface has been emerging as an important topic for chem., nanotechnol., and life sciences in recent years. Understanding the exchanges of materials, signals, and energy at biol. interfaces has inspired and helped the serial design of three-dimensional nano-biointerfaces. The intimate interactions between cells and nanostructures bring many novel properties, making three-dimensional nano-biointerfaces a powerful platform to guide cell fate in a controllable and accurate way. These advantages and capabilities endow three-dimensional nano-biointerfaces with an indispensable role in developing advanced biol. science and technol. This tutorial review is mainly focused on the recent progress of three-dimensional nano-biointerfaces and highlights the new explorations and unique phenomena of three-dimensional nano-biointerfaces for cell-related fundamental studies and biomedical applications. Some basic bio-inspired principles for the design and creation of three-dimensional nano-biointerfaces are also delivered in this review. Current and further challenges of three-dimensional nano-biointerfaces are finally addressed and proposed.
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  58. 58
    Ma, L.; Yang, G.; Wang, N.; Zhang, P. C.; Guo, F. Y.; Meng, J. X.; Zhang, F. L.; Hu, Z. J.; Wang, S. T.; Zhao, Y. Trap Effect of Three-Dimensional Fibers Network for High Efficient Cancer-Cell Capture Adv. Healthcare Mater. 2015, 4, 838– 843
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    58
    Trap Effect of Three-Dimensional Fibers Network for High Efficient Cancer-Cell Capture
    Ma, Lan; Yang, Gao; Wang, Nue; Zhang, Pengchao; Guo, Fengyun; Meng, Jingxin; Zhang, Feilong; Hu, Zuojun; Wang, Shutao; Zhao, Yong
    Advanced Healthcare Materials (2015), 4 (6), 838-843CODEN: AHMDBJ; ISSN:2192-2640. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Aim of this study was to design a 3D stereo biointerface composed of micro/nano-scale hierarchical fibrous network, which processes outstanding capability of capturing rare no. of cancer cells. 3D fibrous interface via electrospinning technol. was fabricated by choosing polystyrene raw material to construct the fibrous interface because the stiffness. Cancer cell capture mechanism of the 3D fibrous interface used immunofluorescent staining to characterize the cytoskeletal organization of MCF7 cells was explored.
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  59. 59
    Zhang, P.; Chen, L.; Xu, T.; Liu, H.; Liu, X.; Meng, J.; Yang, G.; Jiang, L.; Wang, S. Programmable Fractal Nanostructured Interfaces for Specific Recognition and Electrochemical Release of Cancer Cells Adv. Mater. 2013, 25, 3566– 3570
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    59
    Programmable Fractal Nanostructured Interfaces for Specific Recognition and Electrochemical Release of Cancer Cells
    Zhang, Pengchao; Chen, Li; Xu, Tailin; Liu, Hongliang; Liu, Xueli; Meng, Jingxin; Yang, Gao; Jiang, Lei; Wang, Shutao
    Advanced Materials (Weinheim, Germany) (2013), 25 (26), 3566-3570CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Inspired by the fractal nanostructures on the surface of cancer cells, the authors have successfully prepd. programmable fractal gold nanostructure (FAuNS) interfaces that can induce topog. recognition and dramatically enhance the capture efficiency of cancer cells. The anti-EpCAM-coated FAuNS interfaces can not only recognize EpCAM-pos. cancer cells with high specificity, but also reduce nonspecific adhesion of EpCAM-neg. cancer cells. Using the anti-EpCAM-coated FAuNS interfaces, cancer cells can be reliably captured from artificial blood samples. Furthermore, the FAuNS interfaces can achieve efficient release of the captured cells without damage through an electrochem. process. This study has achieved great progress in the functional design of bio-interfaces for cell-based cancer diagnosis: from fortuitous discovery to elaborate programming, from single capture to controlled capture/release, and from low viability to high viability of released cells.
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  60. 60
    Liu, X.; Chen, L.; Liu, H.; Yang, G.; Zhang, P.; Han, D.; Wang, S.; Jiang, L. Bio-Inspired Soft Polystyrene Nanotube Substrate for Rapid and Highly Efficient Breast Cancer Cell Capture NPG Asia Mater. 2013, 5, e63
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    Liu, H.; Liu, X.; Meng, J.; Zhang, P.; Yang, G.; Su, B.; Sun, K.; Chen, L.; Han, D.; Wang, S.; Jiang, L. Hydrophobic Interaction-Mediated Capture and Release of Cancer Cells on Thermoresponsive Nanostructured Surfaces Adv. Mater. 2013, 25, 922– 927
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    61
    Hydrophobic Interaction-Mediated Capture and Release of Cancer Cells on Thermoresponsive Nanostructured Surfaces
    Liu, Hongliang; Liu, Xueli; Meng, Jingxin; Zhang, Pengchao; Yang, Gao; Su, Bin; Sun, Kang; Chen, Li; Han, Dong; Wang, Shutao; Jiang, Lei
    Advanced Materials (Weinheim, Germany) (2013), 25 (6), 922-927CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
    By utilizing the synergistic effect of hydrophobic interactions and topog. interactions, the authors successfully constructed a unique thermoresponsive nanostructured surface (poly(N-isopropylacrylamide) (PNIPAAm)-coated silicon nanopillar array) to reversibly capture and release targeted cancer cells without damage. Introduction of hydrophobic interactions between the hydrophobic anchor (i.e., biotin-BSA) and the thermoresponsive surface (i.e., PSiNP) can promote immobilization of targeted mols., thereby enhancing the specificity of the designed platform to targeted cancer cells. Furthermore, topog. interactions between nanostructured substrates and targeted cancer cells are important to improve the cell-capture/release performance. Moreover, the capability of this designed platform to keep cells undamaged during the processes of capture/release would facilitate the subsequent cell culture and single cell anal. The present work provides a new clue in the design of bio-interfacial materials and offers a general strategy to fabricate next-generation artificial smart surfaces, which would be useful for reversible capture/release of targeted cells, bacteria and viruses.
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  62. 62
    Liu, H. L.; Li, Y. Y.; Sun, K.; Fan, J. B.; Zhang, P. C.; Meng, J. X.; Wang, S. T.; Jiang, L. Dual-Responsive Surfaces Modified with Phenylboronic Acid-Containing Polymer Brush To Reversibly Capture and Release Cancer Cells J. Am. Chem. Soc. 2013, 135, 7603– 7609
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    62
    Dual-Responsive Surfaces Modified with Phenylboronic Acid-Containing Polymer Brush To Reversibly Capture and Release Cancer Cells
    Liu, Hongliang; Li, Yingying; Sun, Kang; Fan, Junbing; Zhang, Pengchao; Meng, Jingxin; Wang, Shutao; Jiang, Lei
    Journal of the American Chemical Society (2013), 135 (20), 7603-7609CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Artificial stimuli-responsive surfaces that can mimic the dynamic function of living systems have attracted much attention. However, there exist few artificial systems capable of responding to dual- or multistimulation as the natural system does. Herein, we synthesize a pH and glucose dual-responsive surface by grafting poly(acrylamidophenylboronic acid) (polyAAPBA) brush from aligned silicon nanowire (SiNW) array. The as-prepd. surface can reversibly capture and release targeted cancer cells by precisely controlling pH and glucose concn., exhibiting dual-responsive AND logic. In the presence of 70 mM glucose, the surface is pH responsive, which can vary from a cell-adhesive state to a cell-repulsive state by changing the pH from 6.8 to 7.8. While keeping the pH at 7.8, the surface becomes glucose responsive-capturing cells in the absence of glucose and releasing cells by adding 70 mM glucose. Through simultaneously changing the pH and glucose concn. from pH 6.8/0 mM glucose to pH 7.8/70 mM glucose, the surface is dual responsive with the capability to switch between cell capture and release for at least 5 cycles. The cell capture and release process on this dual-responsive surface is noninvasive with cell viability higher than 95%. Moreover, topog. interaction between the aligned SiNW array and cell protrusions greatly amplifies the responsiveness and accelerates the response rate of the dual-responsive surface between cell capture and release. The responsive mechanism of the dual-responsive surface is systematically studied using a quartz crystal microbalance, which shows that the competitive binding between polyAAPBA/sialic acid and polyAAPBA/glucose contributes to the dual response. Such dual-responsive surface can significantly impact biomedical and biol. applications including cell-based diagnostics, in vivo drug delivery, etc.
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    Wang, S.; Liu, K.; Liu, J.; Yu, Z. T. F.; Xu, X.; Zhao, L.; Lee, T.; Lee, E. K.; Reiss, J.; Lee, Y.-K. Highly Efficient Capture of Circulating Tumor Cells by Using Nanostructured Silicon Substrates with Integrated Chaotic Micromixers Angew. Chem., Int. Ed. 2011, 50, 3084– 3088
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    ACS Nano (2014), 8 (2), 1878-1885CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
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    Achieving significant adhesion to soft tissues while minimizing tissue damage poses a considerable clinical challenge. Chemical-based adhesives require tissue-specific reactive chemistry, typically inducing a significant inflammatory response. Staples are fraught with limitations including high-localized tissue stress and increased risk of infection, and nerve and blood vessel damage. Here inspired by the endoparasite Pomphorhynchus laevis, which swells its proboscis to attach to its host's intestinal wall, we have developed a biphasic microneedle array that mechanically interlocks with tissue through swellable microneedle tips, achieving ~3.5-fold increase in adhesion strength compared with staples in skin graft fixation, and removal force of ~4.5 N cm(-2) from intestinal mucosal tissue. Comprising a poly(styrene)-block-poly(acrylic acid) swellable tip and non-swellable polystyrene core, conical microneedles penetrate tissue with minimal insertion force and depth, yet high adhesion strength in their swollen state. Uniquely, this design provides universal soft tissue adhesion with minimal damage, less traumatic removal, reduced risk of infection and delivery of bioactive therapeutics.
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    A review. Spurred by recent progress in materials chem. and drug delivery, stimuli-responsive devices that deliver a drug in spatial-, temporal- and dosage-controlled fashions have become possible. Implementation of such devices requires the use of biocompatible materials that are susceptible to a specific phys. incitement or that, in response to a specific stimulus, undergo a protonation, a hydrolytic cleavage or a (supra)mol. conformational change. In this Review, we discuss recent advances in the design of nanoscale stimuli-responsive systems that are able to control drug biodistribution in response to specific stimuli, either exogenous (variations in temp., magnetic field, ultrasound intensity, light or elec. pulses) or endogenous (changes in pH, enzyme concn. or redox gradients).
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    A review. Protein therapeutics have emerged as a significant role in treatment of a broad spectrum of diseases, including cancer, metabolic disorders and autoimmune diseases. The efficacy of protein therapeutics, however, is limited by their instability, immunogenicity and short half-life. In order to overcome these barriers, tremendous efforts have recently been made in developing controlled protein delivery systems. Stimuli-triggered release is an appealing and promising approach for protein delivery and has made protein delivery with both spatiotemporal- and dosage-controlled manners possible. This review surveys recent advances in controlled protein delivery of proteins or peptides using stimuli-responsive nanomaterials. Strategies utilizing both physiol. and external stimuli are introduced and discussed.
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    Gu, Z.; Aimetti, A. A.; Wang, Q.; Dang, T. T.; Zhang, Y.; Veiseh, O.; Cheng, H.; Langer, R. S.; Anderson, D. G. Injectable Nano-network for Glucose-Mediated Insulin Delivery ACS Nano 2013, 7, 4194– 4201
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    ACS Nano (2013), 7 (5), 4194-4201CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Diabetes mellitus, a disorder of glucose regulation, is a global burden affecting 366 million people across the world. An artificial "closed-loop" system able to mimic pancreas activity and release insulin in response to glucose level changes has the potential to improve patient compliance and health. Herein we develop a glucose-mediated release strategy for the self-regulated delivery of insulin using an injectable and acid-degradable polymeric network. Formed by electrostatic interaction between oppositely charged dextran nanoparticles loaded with insulin and glucose-specific enzymes, the nanocomposite-based porous architecture can be dissocd. and subsequently release insulin in a hyperglycemic state through the catalytic conversion of glucose into gluconic acid. In vitro insulin release can be modulated in a pulsatile profile in response to glucose concns. In vivo studies validated that these formulations provided improved glucose control in type 1 diabetic mice s.c. administered with a degradable nano-network. A single injection of the developed nano-network facilitated stabilization of the blood glucose levels in the normoglycemic state (<200 mg/dL) for up to 10 days.
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    Stimuli-triggered drug delivery systems have been increasingly used to promote physiological specificity and on-demand therapeutic efficacy of anticancer drugs. Here we utilize adenosine-5'-triphosphate (ATP) as a trigger for the controlled release of anticancer drugs. We demonstrate that polymeric nanocarriers functionalized with an ATP-binding aptamer-incorporated DNA motif can selectively release the intercalating doxorubicin via a conformational switch when in an ATP-rich environment. The half-maximal inhibitory concentration of ATP-responsive nanovehicles is 0.24 μM in MDA-MB-231 cells, a 3.6-fold increase in the cytotoxicity compared with that of non-ATP-responsive nanovehicles. Equipped with an outer shell crosslinked by hyaluronic acid, a specific tumour-targeting ligand, the ATP-responsive nanocarriers present an improvement in the chemotherapeutic inhibition of tumour growth using xenograft MDA-MB-231 tumour-bearing mice. This ATP-triggered drug release system provides a more sophisticated drug delivery system, which can differentiate ATP levels to facilitate the selective release of drugs.
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    ACS Nano (2013), 7 (8), 6758-6766CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    A glucose-responsive closed-loop insulin delivery system represents the ideal treatment of type 1 diabetes mellitus. In this study, we develop uniform injectable microgels for controlled glucose-responsive release of insulin. Monodisperse microgels (256 ± 18 μm), consisting of a pH-responsive chitosan matrix, enzyme nanocapsules, and recombinant human insulin, were fabricated through a one-step electrospray procedure. Glucose-specific enzymes were covalently encapsulated into the nanocapsules to improve enzymic stability by protecting from denaturation and immunogenicity as well as to minimize loss due to diffusion from the matrix. The microgel system swelled when subjected to hyperglycemic conditions, as a result of the enzymic conversion of glucose into gluconic acid and protonation of the chitosan network. Acting as a self-regulating valve system, microgels were adjusted to release insulin at basal release rates under normoglycemic conditions and at higher rates under hyperglycemic conditions. Finally, we demonstrated that these microgels with enzyme nanocapsules facilitate insulin release and result in a redn. of blood glucose levels in a mouse model of type 1 diabetes.
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    The formulation and delivery of biopharmaceutical drugs, such as monoclonal antibodies and recombinant proteins, poses substantial challenges owing to their large size and susceptibility to degrdn. In this Review we highlight recent advances in formulation and delivery strategies - such as the use of microsphere-based controlled-release technologies, protein modification methods that make use of polyethylene glycol and other polymers, and genetic manipulation of biopharmaceutical drugs - and discuss their advantages and limitations. We also highlight current and emerging delivery routes that provide an alternative to injection, including transdermal, oral and pulmonary delivery routes. In addn., the potential of targeted and intracellular protein delivery is discussed.
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    A review. Early science fiction envisioned the future of drug delivery as targeted micrometer-scale submarines and cyborg body parts. Here we describe the progression of the field toward technologies that are now beginning to capture aspects of this early vision. Specifically, we focus on the two most prominent types of systems in drug delivery: the intravascular micro/nano drug carriers for delivery to the site of pathol. and drug-loaded implantable devices that facilitate release with the predefined kinetics or in response to a specific cue. We discuss the unmet clin. needs that inspire these designs, the physiol. factors that pose difficult challenges for their realization, and viable technologies that promise robust solns. We also offer a perspective on where drug delivery may be in the next 50 years based on expected advances in material engineering and in the context of future diagnostics.
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    A review is given on the development and applications of micro- and nanoscale technologies for biomedicine. Engineered surface topog. of tissue engineering scaffolds, nanoparticles for siRNA and drug delivery, imaging, and biosensing, microfabricated structures to control tissue culture conditions, and biomaterials generate the biochem. and biomech. microenvironment for directing the differentiation of adult stem cells are included.
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  • Abstract

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    Figure 1

    Figure 1. In vivo activity of immunomodulatory SNAs as cancer vaccines.

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    Figure 2

    Figure 2. Barriers to successful in vivo delivery of nucleic acids using nonviral vectors. Reprinted with permission from ref 19. Copyright 2014 Macmillan Publishers Ltd.

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    Figure 3

    Figure 3. Subconjunctival instillation of nanocarriers incorporating latanoprost lowers eye pressure in glaucoma patients for up to 3 months. Reproduced from ref 37. Copyright 2014 American Chemical Society.

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    Figure 4

    Figure 4. Schematic for the nanoparticle-based treatment of acne. Silica–gold nanoparticles are delivered into sebaceous glands using low-frequency ultrasound. Nanoparticles are then activated using near-infrared light to induce thermolysis. Reprinted with permission from ref 45. Copyright 2015 Elsevier.

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    Figure 5

    Figure 5. Nanoneedle for the delivery of VEGF-165 to upregulate blood vessel formation in muscle. (A) Scanning electron microscope (SEM) micrographs showing the morphology of porous silicon nanoneedle arrays with pitches of 2 μm. Scale bars, 2 μm. (B) High-resolution SEM micrographs of nanoneedle tips showing the nanoneedles’ porous structure and the tunability of tip diameter from less than 100 nm to over 400 nm. Scale bars, 200 nm. (C) Intravital bright-field (top) and confocal (bottom) microscopy images of the vasculature of untreated (left) and hVEGF-165-treated muscles with either direct injection (center) or nanoinjection (right). The fluorescence signal originates from systemically injected FITC–dextran. Scale bars, bright-field 100 μm; confocal 50 μm. (D,E) Quantification of the fraction of fluorescent signal (dextran) (D) and the number of nodes in the vasculature per mm2 (E) within each field of view acquired for untreated control, intramuscular injection (IM) and nanoinjection. *p = 0.05, **p < 0.01, ***p < 0.001. Error bars represent the SD of the averages of five areas taken from three animals. Reprinted with permission of figure and caption text from ref 48. Copyright 2015 Macmillan Publishers Ltd.

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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XktVKlsQ%253D%253D&md5=0ccb9d7fab59aee9e0984c4e7d905d37
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      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXot1Cmsb8%253D&md5=e5991ab32775f3a8087d38645f967d68
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      Zheng, Dan; Giljohann, David A.; Chen, David L.; Massich, Matthew D.; Wang, Xiao-Qi; Iordanov, Hristo; Mirkin, Chad A.; Paller, Amy S.
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      Topical application of nucleic acids offers many potential therapeutic advantages for suppressing genes in the skin, and potentially for systemic gene delivery. However, the epidermal barrier typically precludes entry of gene-suppressing therapy unless the barrier is disrupted. We now show that spherical nucleic acid nanoparticle conjugates (SNA-NCs), gold cores surrounded by a dense shell of highly oriented, covalently immobilized siRNA, freely penetrate almost 100% of keratinocytes in vitro, mouse skin, and human epidermis within hours after application. Significantly, these structures can be delivered in a com. moisturizer or phosphate-buffered saline, and do not require barrier disruption or transfection agents, such as liposomes, peptides, or viruses. SNA-NCs targeting epidermal growth factor receptor (EGFR), an important gene for epidermal homeostasis, are >100-fold more potent and suppress longer than siRNA delivered with com. lipid agents in cultured keratinocytes. Topical delivery of 1.5 μM EGFR siRNA (50 nM SNA-NCs) for 3 wk to hairless mouse skin almost completely abolishes EGFR expression, suppresses downstream ERK phosphorylation, and reduces epidermal thickness by almost 40%. Similarly, EGFR mRNA in human skin equiv. is reduced by 52% after 60 h of treatment with 25 nM EGFR SNA-NCs. Treated skin shows no clin. or histol. evidence of toxicity. No cytokine activation in mouse blood or tissue samples is obsd., and after 3 wk of topical skin treatment, the SNA structures are virtually undetectable in internal organs. SNA conjugates may be promising agents for personalized, topically delivered gene therapy of cutaneous tumors, skin inflammation, and dominant neg. genetic skin disorders.
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      Halo, Tiffany L.; McMahon, Kaylin M.; Angeloni, Nicholas L.; Xu, Yilin; Wang, Wei; Chinen, Alyssa B.; Malin, Dmitry; Strekalova, Elena; Cryns, Vincent L.; Cheng, Chonghui; Mirkin, Chad A.; Thaxton, C. Shad
      Proceedings of the National Academy of Sciences of the United States of America (2014), 111 (48), 17104-17109CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Metastasis portends a poor prognosis for cancer patients. Primary tumor cells disseminate through the bloodstream before the appearance of detectable metastatic lesions. The anal. of cancer cells in blood-so-called circulating tumor cells (CTCs)-may provide unprecedented opportunities for metastatic risk assessment and investigation. NanoFlares are nanoconstructs that enable live-cell detection of intracellular mRNA. NanoFlares, when coupled with flow cytometry, can be used to fluorescently detect genetic markers of CTCs in the context of whole blood. They allow one to detect as few as 100 live cancer cells per mL of blood and subsequently culture those cells. This technique can also be used to detect CTCs in a murine model of metastatic breast cancer. As such, NanoFlares provide, to our knowledge, the first genetic-based approach for detecting, isolating, and characterizing live cancer cells from blood and may provide new opportunities for cancer diagnosis, prognosis, and personalized therapy.
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    18. 18
      Radovic-Moreno, A. F.; Chernyak, N.; Mader, C. C.; Nallagatla, S.; Kang, R. S.; Hao, L.; Walker, D. A.; Halo, T. L.; Merkel, T. J.; Rische, C. H. Immunomodulatory Spherical Nucleic Acids Proc. Natl. Acad. Sci. U.S.A. 2015, 112, 3892– 3897
      18
      Immunomodulatory spherical nucleic acids
      Radovic-Moreno, Aleksandar F.; Chernyak, Natalia; Mader, Christopher C.; Nallagatla, Subbarao; Kang, Richard S.; Hao, Liangliang; Walker, David A.; Halo, Tiffany L.; Merkel, Timothy J.; Rische, Clayton H.; Anantatmula, Sagar; Burkhart, Merideth; Mirkin, Chad A.; Gryaznov, Sergei M.
      Proceedings of the National Academy of Sciences of the United States of America (2015), 112 (13), 3892-3897CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Immunomodulatory nucleic acids have extraordinary promise for treating disease, yet clin. progress has been limited by a lack of tools to safely increase activity in patients. Immunomodulatory nucleic acids act by agonizing or antagonizing endosomal toll-like receptors (TLR3, TLR7/8, and TLR9), proteins involved in innate immune signaling. Immunomodulatory spherical nucleic acids (SNAs) that stimulate (immunostimulatory, IS-SNA) or regulate (immunoregulatory, IR-SNA) immunity by engaging TLRs have been designed, synthesized, and characterized. Compared with free oligonucleotides, IS-SNAs exhibit up to 80-fold increases in potency, 700-fold higher antibody titers, 400-fold higher cellular responses to a model antigen, and improved treatment of mice with lymphomas. IR-SNAs exhibit up to eightfold increases in potency and 30% greater redn. in fibrosis score in mice with nonalcoholic steatohepatitis (NASH). Given the clin. potential of SNAs due to their potency, defined chem. nature, and good tolerability, SNAs are attractive new modalities for developing immunotherapies.
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    19. 19
      Yin, H.; Kanasty, R. L.; Eltoukhy, A. A.; Vegas, A. J.; Dorkin, J. R.; Anderson, D. G. Non-viral Vectors for Gene-Based Therapy Nat. Rev. Genet. 2014, 15, 541– 555
      19
      Non-viral vectors for gene-based therapy
      Yin, Hao; Kanasty, Rosemary L.; Eltoukhy, Ahmed A.; Vegas, Arturo J.; Dorkin, J. Robert; Anderson, Daniel G.
      Nature Reviews Genetics (2014), 15 (8), 541-555CODEN: NRGAAM; ISSN:1471-0056. (Nature Publishing Group)
      Gene-based therapy is the intentional modulation of gene expression in specific cells to treat pathol. conditions. This modulation is accomplished by introducing exogenous nucleic acids such as DNA, mRNA, small interfering RNA (siRNA), microRNA (miRNA) or antisense oligonucleotides. Given the large size and the neg. charge of these macromols., their delivery is typically mediated by carriers or vectors. In this Review, we introduce the biol. barriers to gene delivery in vivo and discuss recent advances in material sciences, nanotechnol. and nucleic acid chem. that have yielded promising non-viral delivery systems, some of which are currently undergoing testing in clin. trials. The diversity of these systems highlights the recent progress of gene-based therapy using non-viral approaches.
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    20. 20
      Sahay, G.; Querbes, W.; Alabi, C.; Eltoukhy, A.; Sarkar, S.; Zurenko, C.; Karagiannis, E.; Love, K.; Chen, D.; Zoncu, R. Efficiency of siRNA Delivery by Lipid Nanoparticles Is Limited by Endocytic Recycling Nat. Biotechnol. 2013, 31, 653– 658
      20
      Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling
      Sahay, Gaurav; Querbes, William; Alabi, Christopher; Eltoukhy, Ahmed; Sarkar, Sovan; Zurenko, Christopher; Karagiannis, Emmanouil; Love, Kevin; Chen, Delai; Zoncu, Roberto; Buganim, Yosef; Schroeder, Avi; Langer, Robert; Anderson, Daniel G.
      Nature Biotechnology (2013), 31 (7), 653-658CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
      Despite efforts to understand the interactions between nanoparticles and cells, the cellular processes that det. the efficiency of intracellular drug delivery remain unclear. Here we examine cellular uptake of short interfering RNA (siRNA) delivered in lipid nanoparticles (LNPs) using cellular trafficking probes in combination with automated high-throughput confocal microscopy. We also employed defined perturbations of cellular pathways paired with systems biol. approaches to uncover protein-protein and protein-small mol. interactions. We show that multiple cell signaling effectors are required for initial cellular entry of LNPs through macropinocytosis, including proton pumps, mTOR and cathepsins. siRNA delivery is substantially reduced as ≃70% of the internalized siRNA undergoes exocytosis through egress of LNPs from late endosomes/lysosomes. Niemann-Pick type C1 (NPC1) is shown to be an important regulator of the major recycling pathways of LNP-delivered siRNAs. NPC1-deficient cells show enhanced cellular retention of LNPs inside late endosomes and lysosomes, and increased gene silencing of the target gene. Our data suggest that siRNA delivery efficiency might be improved by designing delivery vehicles that can escape the recycling pathways.
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    21. 21
      Lovell, J. F.; Jin, C. S.; Huynh, E.; Jin, H.; Kim, C.; Rubinstein, J. L.; Chan, W. C.; Cao, W.; Wang, L. V.; Zheng, G. Porphysome Nanovesicles Generated by Porphyrin Bilayers for Use as Multimodal Biophotonic Contrast Agents Nat. Mater. 2011, 10, 324– 332
      21
      Porphysome nanovesicles generated by porphyrin bilayers for use as multimodal biophotonic contrast agents
      Lovell, Jonathan F.; Jin, Cheng S.; Huynh, Elizabeth; Jin, Honglin; Kim, Chulhong; Rubinstein, John L.; Chan, Warren C. W.; Cao, Weiguo; Wang, Lihong V.; Zheng, Gang
      Nature Materials (2011), 10 (4), 324-332CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
      Optically active nanomaterials promise to advance a range of biophotonic techniques through nanoscale optical effects and integration of multiple imaging and therapeutic modalities. Here, we report the development of porphysomes; nanovesicles formed from self-assembled porphyrin bilayers that generated large, tunable extinction coeffs., structure-dependent fluorescence self-quenching and unique photothermal and photoacoustic properties. Porphysomes enabled the sensitive visualization of lymphatic systems using photoacoustic tomog. Near-IR fluorescence generation could be restored on dissocn., creating opportunities for low-background fluorescence imaging. As a result of their org. nature, porphysomes were enzymically biodegradable and induced minimal acute toxicity in mice with i.v. doses of 1000 mg kg-1. In a similar manner to liposomes, the large aq. core of porphysomes could be passively or actively loaded. Following systemic administration, porphysomes accumulated in tumors of xenograft-bearing mice and laser irradn. induced photothermal tumor ablation. The optical properties and biocompatibility of porphysomes demonstrate the multimodal potential of org. nanoparticles for biophotonic imaging and therapy.
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    22. 22
      Dahlman, J. E.; Barnes, C.; Khan, O. F.; Thiriot, A.; Jhunjunwala, S.; Shaw, T. E.; Xing, Y.; Sager, H. B.; Sahay, G.; Speciner, L. In Vivo Endothelial siRNA Delivery Using Polymeric Nanoparticles with Low Molecular Weight Nat. Nanotechnol. 2014, 9, 648– 655
      22
      In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight
      Dahlman, James E.; Barnes, Carmen; Khan, Omar; Thiriot, Aude; Jhunjunwala, Siddharth; Shaw, Taylor E.; Xing, Yiping; Sager, Hendrik B.; Sahay, Gaurav; Speciner, Lauren; Bader, Andrew; Bogorad, Roman L.; Yin, Hao; Racie, Tim; Dong, Yizhou; Jiang, Shan; Seedorf, Danielle; Dave, Apeksha; Sandu, Kamaljeet S.; Webber, Matthew J.; Novobrantseva, Tatiana; Ruda, Vera M.; Lytton-Jean, Abigail K. R.; Levins, Christopher G.; Kalish, Brian; Mudge, Dayna K.; Perez, Mario; Abezgauz, Ludmila; Dutta, Partha; Smith, Lynelle; Charisse, Klaus; Kieran, Mark W.; Fitzgerald, Kevin; Nahrendorf, Matthias; Danino, Dganit; Tuder, Rubin M.; von Andrian, Ulrich H.; Akinc, Akin; Panigrahy, Dipak; Schroeder, Avi; Kotelianski, Victor; Langer, Robert; Anderson, Daniel G.
      Nature Nanotechnology (2014), 9 (8), 648-655CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
      Dysfunctional endothelium contributes to more diseases than any other tissue in the body. Small interfering RNAs (siRNAs) can help in the study and treatment of endothelial cells in vivo by durably silencing multiple genes simultaneously, but efficient siRNA delivery has so far remained challenging. Here, we show that polymeric nanoparticles made of low-mol.-wt. polyamines and lipids can deliver siRNA to endothelial cells with high efficiency, thereby facilitating the simultaneous silencing of multiple endothelial genes in vivo. Unlike lipid or lipid-like nanoparticles, this formulation does not significantly reduce gene expression in hepatocytes or immune cells even at the dosage necessary for endothelial gene silencing. These nanoparticles mediate the most durable non-liver silencing reported so far and facilitate the delivery of siRNAs that modify endothelial function in mouse models of vascular permeability, emphysema, primary tumor growth and metastasis.
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    23. 23
      Dong, Y.; Love, K. T.; Dorkin, J. R.; Sirirungruang, S.; Zhang, Y.; Chen, D.; Bogorad, R. L.; Yin, H.; Chen, Y.; Vegas, A. J. Lipopeptide Nanoparticles for Potent and Selective siRNA Delivery in Rodents and Nonhuman Primates Proc. Natl. Acad. Sci. U.S.A. 2014, 111, 3955– 3960
      23
      Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates
      Dong, Yizhou; Love, Kevin T.; Dorkin, J. Robert; Sirirungruang, Sasilada; Zhang, Yunlong; Chen, Delai; Bogorad, Roman L.; Yin, Hao; Chen, Yi; Vegas, Arturo J.; Alabi, Christopher A.; Sahay, Gaurav; Olejnik, Karsten T.; Wang, Weiheng; Schroeder, Avi; Lytton-Jean, Abigail K. R.; Siegwart, Daniel J.; Akinc, Akin; Barnes, Carmen; Barros, Scott A.; Carioto, Mary; Fitzgerald, Kevin; Hettinger, Julia; Kumar, Varun; Novobrantseva, Tatiana I.; Qin, June; Querbes, William; Koteliansky, Victor; Langer, Robert; Anderson, Daniel G.
      Proceedings of the National Academy of Sciences of the United States of America (2014), 111 (11), 3955-3960CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      SiRNA therapeutics have promise for the treatment of a wide range of genetic disorders. Motivated by lipoproteins, we report lipopeptide nanoparticles as potent and selective siRNA carriers with a wide therapeutic index. Lead material cKK-E12 showed potent silencing effects in mice (ED50 ∼ 0.002 mg/kg), rats (ED50 < 0.01 mg/kg), and nonhuman primates (over 95% silencing at 0.3 mg/kg). Apolipoprotein E plays a significant role in the potency of cKK-E12 both in vitro and in vivo. CKK-E12 was highly selective toward liver parenchymal cell in vivo, with orders of magnitude lower doses needed to silence in hepatocytes compared with endothelial cells and immune cells in different organs. Toxicity studies showed that cKK-E12 was well tolerated in rats at a dose of 1 mg/kg (over 100-fold higher than the ED50). To our knowledge, this is the most efficacious and selective nonviral siRNA delivery system for gene silencing in hepatocytes reported to date.
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    24. 24
      Yin, H.; Xue, W.; Chen, S.; Bogorad, R. L.; Benedetti, E.; Grompe, M.; Koteliansky, V.; Sharp, P. A.; Jacks, T.; Anderson, D. G. Genome Editing with Cas9 in Adult Mice Corrects a Disease Mutation and Phenotype Nat. Biotechnol. 2014, 32, 551– 553
      24
      Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype
      Yin, Hao; Xue, Wen; Chen, Sidi; Bogorad, Roman L.; Benedetti, Eric; Grompe, Markus; Koteliansky, Victor; Sharp, Phillip A.; Jacks, Tyler; Anderson, Daniel G.
      Nature Biotechnology (2014), 32 (6), 551-553CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
      The authors demonstrate CRISPR-Cas9-mediated correction of a Fah mutation in hepatocytes in a mouse model of the human disease hereditary tyrosinemia. Delivery of components of the CRISPR-Cas9 system by hydrodynamic injection resulted in initial expression of the wild-type Fah protein in ∼1/250 liver cells. Expansion of Fah-pos. hepatocytes rescued the body wt. loss phenotype. The authors' study indicates that CRISPR-Cas9-mediated genome editing is possible in adult animals and has potential for correction of human genetic diseases.
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    25. 25
      Shi, J.; Xiao, Z.; Votruba, A. R.; Vilos, C.; Farokhzad, O. C. Differentially Charged Hollow Core/Shell Lipid–Polymer–Lipid Hybrid Nanoparticles for Small Interfering RNA Delivery Angew. Chem., Int. Ed. 2011, 123, 7165– 7169
      There is no corresponding record for this reference.
    26. 26
      Shi, J.; Xu, Y.; Xu, X.; Zhu, X.; Pridgen, E.; Wu, J.; Votruba, A. R.; Swami, A.; Zetter, B. R.; Farokhzad, O. C. Hybrid Lipid–Polymer Nanoparticles for Sustained siRNA Delivery and Gene Silencing Nanomedicine 2014, 10, 897– 900
      There is no corresponding record for this reference.
    27. 27
      Zhu, X.; Xu, Y.; Solis, L. M.; Tao, W.; Wang, L.; Behrens, C.; Xu, X.; Zhao, L.; Liu, D.; Wu, J. Long-Circulating siRNA Nanoparticles for Validating Prohibitin1-Targeted Non-Small Cell Lung Cancer Treatment Proc. Natl. Acad. Sci. U.S.A. 2015,  DOI: 10.1073/pnas.1505629112
      There is no corresponding record for this reference.
    28. 28
      Cabral, H.; Kataoka, K. Progress of Drug-Loaded Polymeric Micelles into Clinical Studies J. Controlled Release 2014, 190, 465– 476
      28
      Progress of drug-loaded polymeric micelles into clinical studies
      Cabral, Horacio; Kataoka, Kazunori
      Journal of Controlled Release (2014), 190 (), 465-476CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
      A review. Targeting tumors with long-circulating nano-scaled carriers is a promising strategy for systemic cancer treatment. Compared with free small therapeutic agents, nanocarriers can selectively accumulate in solid tumors through the enhanced permeability and retention (EPR) effect, which is characterized by leaky blood vessels and impaired lymphatic drainage in tumor tissues, and achieve superior therapeutic efficacy, while reducing side effects. In this way, drug-loaded polymeric micelles, i.e. self-assemblies of amphiphilic block copolymers consisting of a hydrophobic core as a drug reservoir and a poly(ethylene glycol) (PEG) hydrophilic shell, have demonstrated outstanding features as tumor-targeted nanocarriers with high translational potential, and several micelle formulations are currently under clin. evaluation. This review summarizes recent efforts in the development of these polymeric micelles and their performance in human studies, as well as our recent progress in polymeric micelles for the delivery of nucleic acids and imaging.
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    29. 29
      Miura, Y.; Takenaka, T.; Toh, K.; Wu, S.; Nishihara, H.; Kano, M. R.; Ino, Y.; Nomoto, T.; Matsumoto, Y.; Koyama, H. Cyclic RGD-Linked Polymeric Micelles for Targeted Delivery of Platinum Anticancer Drugs to Glioblastoma through the Blood–Brain Tumor Barrier ACS Nano 2013, 7, 8583– 8592
      There is no corresponding record for this reference.
    30. 30
      Ahn, J.; Miura, Y.; Yamada, N.; Chida, T.; Liu, X.; Kim, A.; Sato, R.; Tsumura, R.; Koga, Y.; Yasunaga, M. Antibody Fragment-Conjugated Polymeric Micelles Incorporating Platinum Drugs for Targeted Therapy of Pancreatic Cancer Biomaterials 2015, 39, 23– 30
      There is no corresponding record for this reference.
    31. 31
      Kabanov, A. V.; Chekhonin, V.; Alakhov, V. Y.; Batrakova, E.; Lebedev, A.; Melik-Nubarov, N.; Arzhakov, S.; Levashov, A.; Morozov, G.; Severin, E. The Neuroleptic Activity of Haloperidol Increases after Its Solubilization in Surfactant Micelles: Micelles as Microcontainers for Drug Targeting FEBS Lett. 1989, 258, 343– 345
      There is no corresponding record for this reference.
    32. 32
      Alakhova, D. Y.; Kabanov, A. V. Pluronics and MDR Reversal: An Update Mol. Pharmaceutics 2014, 11, 2566– 2578
      32
      Pluronics and MDR Reversal: An Update
      Alakhova, Daria Y.; Kabanov, Alexander V.
      Molecular Pharmaceutics (2014), 11 (8), 2566-2578CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      A review. Multidrug resistance (MDR) remains one of the biggest obstacles for effective cancer therapy. Currently there are only few methods that are available clin. that are used to bypass MDR with very limited success. In this review we describe how MDR can be overcome by a simple yet effective approach of using amphiphilic block copolymers. Triblock copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), arranged in a triblock structure PEO-PPO-PEO, Pluronics or "poloxamers", raised a considerable interest in the drug delivery field. Previous studies demonstrated that Pluronics sensitize MDR cancer cells resulting in increased cytotoxic activity of Dox, paclitaxel, and other drugs by 2-3 orders of magnitude. Pluronics can also prevent the development of MDR in vitro and in vivo. Addnl., promising results of clin. studies of Dox/Pluronic formulation reinforced the need to ascertain a thorough understanding of Pluronic effects in tumors. These effects are extremely comprehensive and appear on the level of plasma membranes, mitochondria, and regulation of gene expression selectively in MDR cancer cells. Moreover, it has been demonstrated recently that Pluronics can effectively deplete tumorigenic intrinsically drug-resistant cancer stem cells (CSC). Interestingly, sensitization of MDR and inhibition of drug efflux transporters is not specific or selective to Pluronics. Other amphiphilic polymers have shown similar activities in various exptl. models. This review summarizes recent advances of understanding the Pluronic effects in sensitization and prevention of MDR.
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    33. 33
      Valle, J. W.; Armstrong, A.; Newman, C.; Alakhov, V.; Pietrzynski, G.; Brewer, J.; Campbell, S.; Corrie, P.; Rowinsky, E. K.; Ranson, M. A Phase 2 Study of SP1049C, Doxorubicin in P-Glycoprotein-Targeting Pluronics, in Patients with Advanced Adenocarcinoma of the Esophagus and Gastroesophageal Junction Invest. New Drugs 2011, 29, 1029– 1037
      There is no corresponding record for this reference.
    34. 34
      Han, Y.; He, Z.; Schulz, A.; Bronich, T. K.; Jordan, R.; Luxenhofer, R.; Kabanov, A. V. Synergistic Combinations of Multiple Chemotherapeutic Agents in High Capacity Poly(2-oxazoline) Micelles Mol. Pharmaceutics 2012, 9, 2302– 2313
      34
      Synergistic Combinations of Multiple Chemotherapeutic Agents in High Capacity Poly(2-oxazoline) Micelles
      Han, Yingchao; He, Zhijian; Schulz, Anita; Bronich, Tatiana K.; Jordan, Rainer; Luxenhofer, Robert; Kabanov, Alexander V.
      Molecular Pharmaceutics (2012), 9 (8), 2302-2313CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      Many effective drugs for cancer treatment are poorly water-sol. In combination chemotherapy, needed excipients in additive formulations are often toxic and restrict their applications in clin. intervention. Here, we report on amphiphilic poly(2-oxazoline)s (POx) micelles as a promising high capacity delivery platform for multidrug cancer chemotherapy. A variety of binary and ternary drugs combinations of paclitaxel (PTX), docetaxel (DTX), 17-allylamino-17-demethoxygeldanamycin (17-AAG), etoposide (ETO) and bortezomib (BTZ) were solubilized in defined polymeric micelles achieving unprecedented high total loading capacities of up to 50 wt. % drug per final formulation. Multidrug loaded POx micelles showed enhanced stability in comparison to single-drug loaded micelles. Drug ratio dependent synergistic cytotoxicity of micellar ETO/17-AAG was obsd. in MCF-7 cancer cells and of micellar BTZ/17-AAG in MCF-7, PC3, MDA-MB-231 and HepG2 cells.
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    35. 35
      He, Z.; Schulz, A.; Wan, X.; Seitz, J.; Bludau, H.; Alakhova, D. Y.; Darr, D. B.; Perou, C. M.; Jordan, R.; Ojima, I. Poly(2-oxazoline) Based Micelles with High Capacity for 3rd Generation Taxoids: Preparation, In Vitro and In Vivo Evaluation J. Controlled Release 2015, 208, 67– 75
      There is no corresponding record for this reference.
    36. 36
      Natarajan, J. V.; Ang, M.; Darwitan, A.; Chattopadhyay, S.; Wong, T. T.; Venkatraman, S. S. Nanomedicine for Glaucoma: Liposomes Provide Sustained Release of Latanoprost in the Eye Int. J. Nanomed. 2012, 7, 123– 131
      36
      Nanomedicine for glaucoma: liposomes provide sustained release of latanoprost in the eye
      Natarajan, Jayaganesh V.; Ang, Marcus; Darwitan, Anastasia; Chattopadhyay, Sujay; Wong, Tina T.; Venkatraman, Subbu S.
      International Journal of Nanomedicine (2012), 7 (), 123-131CODEN: IJNNHQ; ISSN:1178-2013. (Dove Medical Press Ltd.)
      The development and therapeutic evaluation of a liposomal nanocarrier for sustained release of latanoprost, in the rabbit eye are described. Latanoprost-loaded egg-phosphatidylcholine (EggPC) liposomes were prepd. using the film hydration technique. The delivery vehicles were nano-sized (Z avg = 109 ± 18 nm), had a narrow poly dispersity index (PDI = 0.19 ± 0.04) and a very high loading efficiency (94% ± 5%). Based on in vitro data, this formulation for lowering intraocular pressure (IOP) in rabbit eyes was evaluated. Following a single subconjunctival injection of the latanoprost loaded formulation, the eyes were clin. monitored and the IOP recorded. Latanoprost-loaded EggPC liposomes demonstrated a high drug/lipid mole ratio of 0.181, remained stable for at least 6 mo on storage (4°C) and at least 1 mo at 25°C. A slow and sustained release of 60% of latanoprost was achieved by 14 days in the in vitro release study. The same formulation demonstrated a greater sustained IOP lowering effect compared with daily administration of topical latanoprost beyond 90 days (4.8 ± 1.5 vs 2.5 ± 0.9 mmHg; P < 0.001). No signs of inflammation were evident in the eyes from slit-lamp examn. anal. The loading required for a long-term sustained delivery of latanoprost for up to 90 days in the rabbit eyes was achieved with EggPC liposomes. A single injection of latanoprost-loaded EggPC liposomes can lower the IOP for up to 90 days, with a greater IOP lowering effect than daily topical administration of latanoprost.
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    37. 37
      Natarajan, J. V.; Darwitan, A.; Barathi, V. A.; Ang, M.; Htoon, H. M.; Boey, F.; Tam, K. C.; Wong, T. T.; Venkatraman, S. S. Sustained Drug Release in Nanomedicine: A Long-Acting Nanocarrier-Based Formulation for Glaucoma ACS Nano 2014, 8, 419– 429
      There is no corresponding record for this reference.
    38. 38
      Tan, Y. F.; Mundargi, R. C.; Chen, M. H. A.; Lessig, J.; Neu, B.; Venkatraman, S. S.; Wong, T. T. Layer-by-Layer Nanoparticles as an Efficient siRNA Delivery Vehicle for SPARC Silencing Small 2014, 10, 1790– 1798
      There is no corresponding record for this reference.
    39. 39
      Huang, H.; Pierstorff, E.; Osawa, E.; Ho, D. Active Nanodiamond Hydrogels for Chemotherapeutic Delivery Nano Lett. 2007, 7, 3305– 3314
      39
      Active nanodiamond hydrogels for chemotherapeutic delivery
      Huang, Houjin; Pierstorff, Erik; Osawa, Eiji; Ho, Dean
      Nano Letters (2007), 7 (11), 3305-3314CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
      Nanodiamond materials can serve as highly versatile platforms for the controlled functionalization and delivery of a wide spectrum of therapeutic elements. In this work, doxorubicin hydrochloride (DOX), an apoptosis-inducing drug widely used in chemotherapy, was successfully applied toward the functionalization of nanodiamond materials (NDs, 2-8 nm) and introduced toward murine macrophages as well as human colorectal carcinoma cells with preserved efficacy. The adsorption of DOX onto the NDs and its reversible release were achieved by regulating Cl- ion concn., and the NDs were found to be able to efficiently ferry the drug inside living cells. Comprehensive bioassays were performed to assess and confirm the innate biocompatibility of the NDs, via real-time quant. polymerase chain reaction (RT-PCR), and electrophoretic DNA fragmentation as well as MTT anal. confirmed the functional apoptosis-inducing mechanisms driven by the DOX-functionalized NDs. We extended the applicability of the DOX-ND composites toward a translational context, where MTT assays were performed on the HT-29 colon cancer cell line to assess DOX-ND induced cell death and ND-mediated chemotherapeutic sequestering for potential slow/sustained released capabilities. These and other medically relevant capabilities enabled by the NDs forge its strong potential as a therapeutically significant nanomaterial.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtFWqtbnN&md5=9d9cfcf2fc872204a9edc47cdb35d587
    40. 40
      Manus, L. M.; Mastarone, D. J.; Waters, E. A.; Zhang, X.-Q.; Schultz-Sikma, E. A.; MacRenaris, K. W.; Ho, D.; Meade, T. J. Gd(III)-Nanodiamond Conjugates for MRI Contrast Enhancement Nano Lett. 2010, 10, 484– 489
      There is no corresponding record for this reference.
    41. 41
      Chow, E. K.; Zhang, X.-Q.; Chen, M.; Lam, R.; Robinson, E.; Huang, H.; Schaffer, D.; Osawa, E.; Goga, A.; Ho, D. Nanodiamond Therapeutic Delivery Agents Mediate Enhanced Chemoresistant Tumor Treatment Sci. Transl. Med. 2011, 3, 73ra21
      41
      Nanodiamond therapeutic delivery agents mediate enhanced chemoresistant tumor treatment
      Chow, Edward K.; Zhang, Xue-Qing; Chen, Mark; Lam, Robert; Robinson, Erik; Huang, Houjin; Schaffer, Daniel; Osawa, Eiji; Goga, Andrei; Ho, Dean
      Science Translational Medicine (2011), 3 (73), 73ra21/1-73ra21/10CODEN: STMCBQ; ISSN:1946-6242. (American Association for the Advancement of Science)
      Enhancing chemotherapeutic efficiency through improved drug delivery would facilitate treatment of chemoresistant cancers, such as recurrent mammary tumors and liver cancer. One way to improve drug delivery is through the use of nanodiamond (ND) therapies, which are both scalable and biocompatible. Here, we examd. the efficacy of an ND-conjugated chemotherapeutic in mouse models of liver and mammary cancer. A complex (NDX) of ND and doxorubicin (Dox) overcame drug efflux and significantly increased apoptosis and tumor growth inhibition beyond conventional Dox treatment in both murine liver tumor and mammary carcinoma models. Unmodified Dox treatment represents the clin. std. for most cancer treatment regimens, and NDX had significantly decreased toxicity in vivo compared to std. Dox treatment. Thus, ND-conjugated chemotherapy represents a promising, biocompatible strategy for overcoming chemoresistance and enhancing chemotherapy efficacy and safety.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXksVGltbc%253D&md5=c7bd1fa493743fd9bd00c703060ea99f
    42. 42
      Moore, L.; Chow, E. K.-H.; Osawa, E.; Bishop, J. M.; Ho, D. Diamond-Lipid Hybrids Enhance Chemotherapeutic Tolerance and Mediate Tumor Regression Adv. Mater. 2013, 25, 3532– 3541
      42
      Diamond-Lipid Hybrids Enhance Chemotherapeutic Tolerance and Mediate Tumor Regression
      Moore, Laura; Chow, Edward Kai-Hua; Osawa, Eiji; Bishop, J. Michael; Ho, Dean
      Advanced Materials (Weinheim, Germany) (2013), 25 (26), 3532-3541CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Self-assembled nanodiamond-lipid hybrid particlees (NDLPs) harness the potent interaction between the nanodiamond (ND)-surface and small mols., while providing a mechanism for cell-targeted imaging and therapy of triple neg. breast cancers. Epidermal growth factor receptor-targeted NDLPs are highly biocompatible particles that provide cell-specific imaging, promote tumor retention of ND-complexes, prevent epirubicin toxicity and mediate regression of triple neg. breast cancers.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlvVWhtb8%253D&md5=af567fd5c90d5f64151e169fa5c7cf1b
    43. 43
      Wang, X.; Low, X. C.; Hou, W.; Abdullah, L. N.; Toh, T. B.; Mohd Abdul Rashid, M.; Ho, D.; Chow, E. K.-H. Epirubicin-Adsorbed Nanodiamonds Kill Chemoresistant Hepatic Cancer Stem Cells ACS Nano 2014, 8, 12151– 12166
      43
      Epirubicin-Adsorbed Nanodiamonds Kill Chemoresistant Hepatic Cancer Stem Cells
      Wang, Xin; Low, Xinyi Casuarine; Hou, Weixin; Abdullah, Lissa Nurrul; Toh, Tan Boon; Mohd. Abdul Rashid, Masturah; Ho, Dean; Chow, Edward Kai-Hua
      ACS Nano (2014), 8 (12), 12151-12166CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Chemoresistance is a primary cause of treatment failure in cancer and a common property of tumor-initiating cancer stem cells. Overcoming mechanisms of chemoresistance, particularly in cancer stem cells, can markedly enhance cancer therapy and prevent recurrence and metastasis. This study demonstrates that the delivery of Epirubicin by nanodiamonds is a highly effective nanomedicine-based approach to overcoming chemoresistance in hepatic cancer stem cells. The potent phys. adsorption of Epirubicin to nanodiamonds creates a rapidly synthesized and stable nanodiamond-drug complex that promotes endocytic uptake and enhanced tumor cell retention. These attributes mediate the effective killing of both cancer stem cells and noncancer stem cells in vitro and in vivo. Enhanced treatment of both tumor cell populations results in an improved impairment of secondary tumor formation in vivo compared with treatment by unmodified chemotherapeutics. On the basis of these results, nanodiamond-mediated drug delivery may serve as a powerful method for overcoming chemoresistance in cancer stem cells and markedly improving overall treatment against hepatic cancers.
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    44. 44
      Wang, H.; Lee, D.-K.; Chen, K.-Y.; Chen, J.-Y.; Zhang, K.; Silva, A.; Ho, C.-M.; Ho, D. Mechanism-Independent Optimization of Combinatorial Nanodiamond and Unmodified Drug Delivery Using a Phenotypically Driven Platform Technology ACS Nano 2015, 9, 3332– 3344
      There is no corresponding record for this reference.
    45. 45
      Paithankar, D.; Hwang, B. H.; Munavalli, G.; Kauvar, A.; Lloyd, J.; Blomgren, R.; Faupel, L.; Meyer, T.; Mitragotri, S. Ultrasonic Delivery of Silica–Gold Nanoshells for Photothermolysis of Sebaceous Glands in Humans: Nanotechnology from the Bench to Clinic J. Controlled Release 2015, 206, 30– 36
      There is no corresponding record for this reference.
    46. 46
      Tezel, A.; Mitragotri, S. Interactions of Inertial Cavitation Bubbles with Stratum Corneum Lipid Bilayers during Low-Frequency Sonophoresis Biophys. J. 2003, 85, 3502– 3512
      There is no corresponding record for this reference.
    47. 47
      Chiappini, C.; Martinez, J. O.; De Rosa, E.; Almeida, C. S.; Tasciotti, E.; Stevens, M. M. Biodegradable Nanoneedles for Localized Delivery of Nanoparticles in Vivo: Exploring the Biointerface ACS Nano 2015, 9, 5500– 5509
      47
      Biodegradable Nanoneedles for Localized Delivery of Nanoparticles in Vivo: Exploring the Biointerface
      Chiappini, Ciro; Martinez, Jonathan O.; De Rosa, Enrica; Almeida, Carina S.; Tasciotti, Ennio; Stevens, Molly M.
      ACS Nano (2015), 9 (5), 5500-5509CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Nanoneedles display potential in mediating the delivery of drugs and biologicals, as well as intracellular sensing and single-cell stimulation, through direct access to the cell cytoplasm. Nanoneedles enable cytosolic delivery, negotiating the cell membrane and the endolysosomal system, thus overcoming these major obstacles to the efficacy of nanotherapeutics. The low toxicity and minimal invasiveness of nanoneedles have a potential for the sustained nonimmunogenic delivery of payloads in vivo, provided that the development of biocompatible nanoneedles with a simple deployment strategy is achieved. Here we present a mesoporous silicon nanoneedle array that achieves a tight interface with the cell, rapidly negotiating local biol. barriers to grant temporary access to the cytosol with minimal impact on cell viability. The tightness of this interfacing enables both delivery of cell-impermeant quantum dots in vivo and live intracellular sensing of pH. Dissecting the biointerface over time elucidated the dynamics of cell assocn. and nanoneedle biodegrdn., showing rapid interfacing leading to cytosolic payload delivery within less than 30 min in vitro. The rapid and simple application of nanoneedles in vivo to the surface of tissues with different architectures invariably resulted in the localized delivery of quantum dots to the superficial cells and their prolonged retention. This investigation provides an understanding of the dynamics of nanoneedles' biointerface and delivery, outlining a strategy for highly local intracellular delivery of nanoparticles and cell-impermeant payloads within live tissues.
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    48. 48
      Chiappini, C.; De Rosa, E.; Martinez, J.; Liu, X.; Steele, J.; Stevens, M.; Tasciotti, E. Biodegradable Silicon Nanoneedles Delivering Nucleic Acids Intracellularly Induce Localized In Vivo Neovascularization Nat. Mater. 2015, 14, 532– 539
      48
      Biodegradable silicon nanoneedles delivering nucleic acids intracellularly induce localized in vivo neovascularization
      Chiappini, C.; De Rosa, E.; Martinez, J. O.; Liu, X.; Steele, J.; Stevens, M. M.; Tasciotti, E.
      Nature Materials (2015), 14 (5), 532-539CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
      The controlled delivery of nucleic acids to selected tissues remains an inefficient process mired by low transfection efficacy, poor scalability because of varying efficiency with cell type and location, and questionable safety as a result of toxicity issues arising from the typical materials and procedures employed. High efficiency and minimal toxicity in vitro has been shown for intracellular delivery of nuclei acids by using nanoneedles, yet extending these characteristics to in vivo delivery has been difficult, as current interfacing strategies rely on complex equipment or active cell internalization through prolonged interfacing. Here, we show that a tunable array of biodegradable nanoneedles fabricated by metal-assisted chem. etching of silicon can access the cytosol to co-deliver DNA and siRNA with an efficiency greater than 90%, and that in vivo the nanoneedles transfect the VEGF-165 gene, inducing sustained neovascularization and a localized sixfold increase in blood perfusion in a target region of the muscle.
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    49. 49
      De La Rica, R.; Stevens, M. M. Plasmonic ELISA for the Ultrasensitive Detection of Disease Biomarkers with the Naked Eye Nat. Nanotechnol. 2012, 7, 821– 824
      49
      Plasmonic ELISA for the ultrasensitive detection of disease biomarkers with the naked eye
      de la Rica, Roberto; Stevens, Molly M.
      Nature Nanotechnology (2012), 7 (12), 821-824CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
      In resource-constrained countries, affordable methodologies for the detection of disease biomarkers at ultralow concns. can potentially improve the std. of living. However, current strategies for ultrasensitive detection often require sophisticated instruments that may not be available in labs. with fewer resources. Here, the authors circumvent this problem by introducing a signal generation mechanism for biosensing that enables the detection of a few mols. of analyte with the naked eye. The enzyme label of an ELISA controls the growth of gold nanoparticles and generates colored solns. with distinct tonality when the analyte is present. Prostate specific antigen (PSA) and HIV-1 capsid antigen p24 were detected in whole serum at the ultralow concn. of 1 × 10-18 g ml-1. P24 was also detected with the naked eye in the sera of HIV-infected patients showing viral loads undetectable by a gold std. nucleic acid-based test.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFOmtL7M&md5=254ba8523fde48ce231333251cf5d179
    50. 50
      Chapman, R.; Lin, Y.; Burnapp, M.; Bentham, A.; Hillier, D.; Zabron, A.; Khan, S.; Tyreman, M.; Stevens, M. M. Multivalent Nanoparticle Networks Enable Point-of-Care Detection of Human Phospholipase-A2 in Serum ACS Nano 2015, 9, 2565– 2573
      50
      Multivalent Nanoparticle Networks Enable Point-of-Care Detection of Human Phospholipase-A2 in Serum
      Chapman, Robert; Lin, Yiyang; Burnapp, Mark; Bentham, Andrew; Hillier, David; Zabron, Abigail; Khan, Shahid; Tyreman, Matthew; Stevens, Molly M.
      ACS Nano (2015), 9 (3), 2565-2573CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      A rapid and highly sensitive point-of-care (PoC) lateral flow assay for phospholipase A2 (PLA2) is demonstrated in serum through the enzyme-triggered release of a new class of biotinylated multiarmed polymers from a liposome substrate. Signal from the enzyme activity is generated by the adhesion of polystreptavidin-coated gold nanoparticle networks to the lateral flow device, which leads to the appearance of a red test line due to the localized surface plasmon resonance effect of the gold. The use of a liposome as the enzyme substrate and multivalent linkers to link the nanoparticles leads to amplification of the signal, as the cleavage of a small amt. of lipids is able to release a large amt. of polymer linker and adhesion of an even larger amt. of gold nanoparticles. By optimizing the mol. wt. and multivalency of these biotinylated polymer linkers, the sensitivity of the device can be tuned to enable naked-eye detection of 1 nM human PLA2 in serum within 10 min. This high sensitivity enabled the correct diagnosis of pancreatitis in diseased clin. samples against a set of healthy controls using PLA2 activity in a point-of-care device for the first time.
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    51. 51
      Dewitte, H.; Verbeke, R.; Breckpot, K.; De Smedt, S. C.; Lentacker, I. Nanoparticle Design To Induce Tumor Immunity and Challenge the Suppressive Tumor Microenvironment Nano Today 2014, 9, 743– 758
      51
      Nanoparticle design to induce tumor immunity and challenge the suppressive tumor microenvironment
      Dewitte, Heleen; Verbeke, Rein; Breckpot, Karine; De Smedt, Stefaan C.; Lentacker, Ine
      Nano Today (2014), 9 (6), 743-758CODEN: NTAOCG; ISSN:1748-0132. (Elsevier Ltd.)
      A review. Over the years research in the field of cancer immunotherapy has flourished, bringing about crucial breakthroughs, but at the same time revealing new and important pathways of immune suppression that put a break on the success of cancer immunotherapy. This review focuses on how nano- and micromaterials can be used to induce antitumor immune responses and what their role in overcoming immune suppression could be. It is now beyond question that this requires elegantly designed particles that can reach their target cells, deliver antigenic cargo and most importantly immune stimulants in order to provoke and sustain antitumor immunity.
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    52. 52
      Gough, D. R.; Cotter, T. G. Hydrogen Peroxide: A Jekyll and Hyde Signalling Molecule Cell Death Dis. 2011, 2, e213
      52
      Hydrogen peroxide: a Jekyll and Hyde signalling molecule
      Gough, D. R.; Cotter, T. G.
      Cell Death & Disease (2011), 2 (Oct.), e213/1-e213/8CODEN: CDDEA4; ISSN:2041-4889. (Nature Publishing Group)
      A review. Reactive oxygen species (ROS) are a group of mols. produced in the cell through metab. of oxygen. Endogenous ROS such as hydrogen peroxide (H2O2) have long been recognized as destructive mols. The well-established roles they have in the phagosome and genomic instability has led to the characterization of these mols. as non-specific agents of destruction. Interestingly, there is a growing body of literature suggesting a less sinister role for this Jekyll and Hyde mol. It is now evident that at lower physiol. levels, H2O2 can act as a classical intracellular signalling mol. regulating kinase-driven pathways. The newly discovered biol. functions attributed to ROS include proliferation, migration, anoikis, survival and autophagy. Furthermore, recent advances in detection and quantification of ROS-family members have revealed that the diverse functions of ROS can be detd. by the subcellular source, location and duration of these mols. within the cell. In light of this confounding paradox, we will examine the factors and circumstances that det. whether H2O2 acts in a pro-survival or deleterious manner.
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    53. 53
      Lobo, V.; Patil, A.; Phatak, A.; Chandra, N. Free Radicals, Antioxidants and Functional Foods: Impact on Human Health Pharmacogn. Rev. 2010, 4, 118– 126
      53
      Free radicals, antioxidants and functional foods: Impact on human health
      Lobo V; Patil A; Phatak A; Chandra N
      Pharmacognosy reviews (2010), 4 (8), 118-26 ISSN:.
      In recent years, there has been a great deal of attention toward the field of free radical chemistry. Free radicals reactive oxygen species and reactive nitrogen species are generated by our body by various endogenous systems, exposure to different physiochemical conditions or pathological states. A balance between free radicals and antioxidants is necessary for proper physiological function. If free radicals overwhelm the body's ability to regulate them, a condition known as oxidative stress ensues. Free radicals thus adversely alter lipids, proteins, and DNA and trigger a number of human diseases. Hence application of external source of antioxidants can assist in coping this oxidative stress. Synthetic antioxidants such as butylated hydroxytoluene and butylated hydroxyanisole have recently been reported to be dangerous for human health. Thus, the search for effective, nontoxic natural compounds with antioxidative activity has been intensified in recent years. The present review provides a brief overview on oxidative stress mediated cellular damages and role of dietary antioxidants as functional foods in the management of human diseases.
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    54. 54
      Sun, X.; Guo, S.; Liu, Y.; Sun, S. Dumbbell-like PtPd–Fe3O4 Nanoparticles for Enhanced Electrochemical Detection of H2O2 Nano Lett. 2012, 12, 4859– 4863
      There is no corresponding record for this reference.
    55. 55
      Zhu, H.; Sigdel, A.; Zhang, S.; Su, D.; Xi, Z.; Li, Q.; Sun, S. Core/Shell Au/MnO Nanoparticles Prepared through Controlled Oxidation of AuMn as an Electrocatalyst for Sensitive H2O2 Detection Angew. Chem., Int. Ed. 2014, 53, 12508– 12512
      55
      Core/Shell Au/MnO Nanoparticles Prepared Through Controlled Oxidation of AuMn as an Electrocatalyst for Sensitive H2O2 Detection
      Zhu, Huiyuan; Sigdel, Aruna; Zhang, Sen; Su, Dong; Xi, Zheng; Li, Qing; Sun, Shouheng
      Angewandte Chemie, International Edition (2014), 53 (46), 12508-12512CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Monodisperse 5 nm AuMn nanoparticles were synthesized by hydride redn. of manganese acetylacetonate in the presence of Au nanoparticles. The alloy was formed through fast Mn diffusion into the Au structure. The AuMn nanoparticles were converted to Au-MnO composite particles through air annealing at 170 °C. These Au-MnO particles, esp. the core/shell Au/MnO nanoparticles, were active for the electrochem. redn. of H2O2, with a detection limit reaching 8 nΜ. This highly sensitive electrochem. sensor based on the Au/MnO nanoparticles was used to monitor H2O2 concns. released from living cells, from which tumorigenic cells were discovered to release higher levels of H2O2 than the non-tumorigenic cells.
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    56. 56
      Sun, X.; Cai, W.; Chen, X. Positron Emission Tomography Imaging Using Radiolabeled Inorganic Nanomaterials Acc. Chem. Res. 2015, 48, 286– 294
      56
      Positron Emission Tomography Imaging Using Radiolabeled Inorganic Nanomaterials
      Sun, Xiaolian; Cai, Weibo; Chen, Xiaoyuan
      Accounts of Chemical Research (2015), 48 (2), 286-294CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. Positron emission tomog. (PET) is a radionuclide imaging technol. that plays an important role in preclin. and clin. research. With administration of a small amt. of radiotracer, PET imaging can provide a noninvasive, highly sensitive, and quant. readout of its organ/tissue targeting efficiency and pharmacokinetics. Various radiotracers have been designed to target specific mol. events. Compared with antibodies, proteins, peptides, and other biol. relevant mols., nanoparticles represent a new frontier in mol. imaging probe design, enabling the attachment of different imaging modalities, targeting ligands, and therapeutic payloads in a single vector. We introduce the radiolabeled nanoparticle platforms that we and others have developed. Due to the fundamental differences in the various nanoparticles and radioisotopes, most radiolabeling methods are designed case-by-case. We focus on some general rules about selecting appropriate isotopes for given types of nanoparticles, as well as adjusting the labeling strategies according to specific applications. We classified these radiolabeling methods into four categories: (1) complexation reaction of radiometal ions with chelators via coordination chem.; (2) direct bombardment of nanoparticles via hadronic projectiles; (3) synthesis of nanoparticles using a mixt. of radioactive and nonradioactive precursors; (4) chelator-free postsynthetic radiolabeling. Method 1 is generally applicable to different nanomaterials as long as the surface chem. is well-designed. However, the addn. of chelators brings concerns of possible changes to the physicochem. properties of nanomaterials and detachment of the radiometal. Methods 2 and 3 have improved radiochem. stability. The applications are, however, limited by the possible damage to the nanocomponent caused by the proton beams (method 2) and harsh synthetic conditions (method 3). Method 4 is still in its infancy. Although being fast and specific, only a few combinations of isotopes and nanoparticles have been explored. Since the applications of radiolabeled nanoparticles are based on the premise that the radioisotopes are stably attached to the nanomaterials, stability (colloidal and radiochem.) assessment of radiolabeled nanoparticles is also highlighted. Despite the fact that thousands of nanomaterials have been developed for clin. research, only very few have moved to humans. One major reason is the lack of understanding of the biol. behavior of nanomaterials. We discuss specific examples of using PET imaging to monitor the in vivo fate of radiolabeled nanoparticles, emphasizing the importance of labeling strategies and caution in interpreting PET data. Design considerations for radiolabeled nanoplatforms for multimodal mol. imaging are also illustrated, with a focus on strategies to combine the strengths of different imaging modalities and to prolong the circulation time.
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    57. 57
      Liu, X.; Wang, S. Three-Dimensional Nano-Biointerface as a New Platform for Guiding Cell Fate Chem. Soc. Rev. 2014, 43, 2385– 2401
      57
      Three-dimensional nano-biointerface as a new platform for guiding cell fate
      Liu, Xueli; Wang, Shutao
      Chemical Society Reviews (2014), 43 (8), 2385-2401CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Three-dimensional nano-biointerface has been emerging as an important topic for chem., nanotechnol., and life sciences in recent years. Understanding the exchanges of materials, signals, and energy at biol. interfaces has inspired and helped the serial design of three-dimensional nano-biointerfaces. The intimate interactions between cells and nanostructures bring many novel properties, making three-dimensional nano-biointerfaces a powerful platform to guide cell fate in a controllable and accurate way. These advantages and capabilities endow three-dimensional nano-biointerfaces with an indispensable role in developing advanced biol. science and technol. This tutorial review is mainly focused on the recent progress of three-dimensional nano-biointerfaces and highlights the new explorations and unique phenomena of three-dimensional nano-biointerfaces for cell-related fundamental studies and biomedical applications. Some basic bio-inspired principles for the design and creation of three-dimensional nano-biointerfaces are also delivered in this review. Current and further challenges of three-dimensional nano-biointerfaces are finally addressed and proposed.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXks12hsrk%253D&md5=3cd6577d42bbed4b083db7ef620fae8a
    58. 58
      Ma, L.; Yang, G.; Wang, N.; Zhang, P. C.; Guo, F. Y.; Meng, J. X.; Zhang, F. L.; Hu, Z. J.; Wang, S. T.; Zhao, Y. Trap Effect of Three-Dimensional Fibers Network for High Efficient Cancer-Cell Capture Adv. Healthcare Mater. 2015, 4, 838– 843
      58
      Trap Effect of Three-Dimensional Fibers Network for High Efficient Cancer-Cell Capture
      Ma, Lan; Yang, Gao; Wang, Nue; Zhang, Pengchao; Guo, Fengyun; Meng, Jingxin; Zhang, Feilong; Hu, Zuojun; Wang, Shutao; Zhao, Yong
      Advanced Healthcare Materials (2015), 4 (6), 838-843CODEN: AHMDBJ; ISSN:2192-2640. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Aim of this study was to design a 3D stereo biointerface composed of micro/nano-scale hierarchical fibrous network, which processes outstanding capability of capturing rare no. of cancer cells. 3D fibrous interface via electrospinning technol. was fabricated by choosing polystyrene raw material to construct the fibrous interface because the stiffness. Cancer cell capture mechanism of the 3D fibrous interface used immunofluorescent staining to characterize the cytoskeletal organization of MCF7 cells was explored.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmslynu7s%253D&md5=45c52336b181c35d96bfd7aaf2c148c0
    59. 59
      Zhang, P.; Chen, L.; Xu, T.; Liu, H.; Liu, X.; Meng, J.; Yang, G.; Jiang, L.; Wang, S. Programmable Fractal Nanostructured Interfaces for Specific Recognition and Electrochemical Release of Cancer Cells Adv. Mater. 2013, 25, 3566– 3570
      59
      Programmable Fractal Nanostructured Interfaces for Specific Recognition and Electrochemical Release of Cancer Cells
      Zhang, Pengchao; Chen, Li; Xu, Tailin; Liu, Hongliang; Liu, Xueli; Meng, Jingxin; Yang, Gao; Jiang, Lei; Wang, Shutao
      Advanced Materials (Weinheim, Germany) (2013), 25 (26), 3566-3570CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Inspired by the fractal nanostructures on the surface of cancer cells, the authors have successfully prepd. programmable fractal gold nanostructure (FAuNS) interfaces that can induce topog. recognition and dramatically enhance the capture efficiency of cancer cells. The anti-EpCAM-coated FAuNS interfaces can not only recognize EpCAM-pos. cancer cells with high specificity, but also reduce nonspecific adhesion of EpCAM-neg. cancer cells. Using the anti-EpCAM-coated FAuNS interfaces, cancer cells can be reliably captured from artificial blood samples. Furthermore, the FAuNS interfaces can achieve efficient release of the captured cells without damage through an electrochem. process. This study has achieved great progress in the functional design of bio-interfaces for cell-based cancer diagnosis: from fortuitous discovery to elaborate programming, from single capture to controlled capture/release, and from low viability to high viability of released cells.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXosVersr8%253D&md5=dfc18c81635c9b4af685cdfca6d3d134
    60. 60
      Liu, X.; Chen, L.; Liu, H.; Yang, G.; Zhang, P.; Han, D.; Wang, S.; Jiang, L. Bio-Inspired Soft Polystyrene Nanotube Substrate for Rapid and Highly Efficient Breast Cancer Cell Capture NPG Asia Mater. 2013, 5, e63
      There is no corresponding record for this reference.
    61. 61
      Liu, H.; Liu, X.; Meng, J.; Zhang, P.; Yang, G.; Su, B.; Sun, K.; Chen, L.; Han, D.; Wang, S.; Jiang, L. Hydrophobic Interaction-Mediated Capture and Release of Cancer Cells on Thermoresponsive Nanostructured Surfaces Adv. Mater. 2013, 25, 922– 927
      61
      Hydrophobic Interaction-Mediated Capture and Release of Cancer Cells on Thermoresponsive Nanostructured Surfaces
      Liu, Hongliang; Liu, Xueli; Meng, Jingxin; Zhang, Pengchao; Yang, Gao; Su, Bin; Sun, Kang; Chen, Li; Han, Dong; Wang, Shutao; Jiang, Lei
      Advanced Materials (Weinheim, Germany) (2013), 25 (6), 922-927CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)
      By utilizing the synergistic effect of hydrophobic interactions and topog. interactions, the authors successfully constructed a unique thermoresponsive nanostructured surface (poly(N-isopropylacrylamide) (PNIPAAm)-coated silicon nanopillar array) to reversibly capture and release targeted cancer cells without damage. Introduction of hydrophobic interactions between the hydrophobic anchor (i.e., biotin-BSA) and the thermoresponsive surface (i.e., PSiNP) can promote immobilization of targeted mols., thereby enhancing the specificity of the designed platform to targeted cancer cells. Furthermore, topog. interactions between nanostructured substrates and targeted cancer cells are important to improve the cell-capture/release performance. Moreover, the capability of this designed platform to keep cells undamaged during the processes of capture/release would facilitate the subsequent cell culture and single cell anal. The present work provides a new clue in the design of bio-interfacial materials and offers a general strategy to fabricate next-generation artificial smart surfaces, which would be useful for reversible capture/release of targeted cells, bacteria and viruses.
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    62. 62
      Liu, H. L.; Li, Y. Y.; Sun, K.; Fan, J. B.; Zhang, P. C.; Meng, J. X.; Wang, S. T.; Jiang, L. Dual-Responsive Surfaces Modified with Phenylboronic Acid-Containing Polymer Brush To Reversibly Capture and Release Cancer Cells J. Am. Chem. Soc. 2013, 135, 7603– 7609
      62
      Dual-Responsive Surfaces Modified with Phenylboronic Acid-Containing Polymer Brush To Reversibly Capture and Release Cancer Cells
      Liu, Hongliang; Li, Yingying; Sun, Kang; Fan, Junbing; Zhang, Pengchao; Meng, Jingxin; Wang, Shutao; Jiang, Lei
      Journal of the American Chemical Society (2013), 135 (20), 7603-7609CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Artificial stimuli-responsive surfaces that can mimic the dynamic function of living systems have attracted much attention. However, there exist few artificial systems capable of responding to dual- or multistimulation as the natural system does. Herein, we synthesize a pH and glucose dual-responsive surface by grafting poly(acrylamidophenylboronic acid) (polyAAPBA) brush from aligned silicon nanowire (SiNW) array. The as-prepd. surface can reversibly capture and release targeted cancer cells by precisely controlling pH and glucose concn., exhibiting dual-responsive AND logic. In the presence of 70 mM glucose, the surface is pH responsive, which can vary from a cell-adhesive state to a cell-repulsive state by changing the pH from 6.8 to 7.8. While keeping the pH at 7.8, the surface becomes glucose responsive-capturing cells in the absence of glucose and releasing cells by adding 70 mM glucose. Through simultaneously changing the pH and glucose concn. from pH 6.8/0 mM glucose to pH 7.8/70 mM glucose, the surface is dual responsive with the capability to switch between cell capture and release for at least 5 cycles. The cell capture and release process on this dual-responsive surface is noninvasive with cell viability higher than 95%. Moreover, topog. interaction between the aligned SiNW array and cell protrusions greatly amplifies the responsiveness and accelerates the response rate of the dual-responsive surface between cell capture and release. The responsive mechanism of the dual-responsive surface is systematically studied using a quartz crystal microbalance, which shows that the competitive binding between polyAAPBA/sialic acid and polyAAPBA/glucose contributes to the dual response. Such dual-responsive surface can significantly impact biomedical and biol. applications including cell-based diagnostics, in vivo drug delivery, etc.
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    63. 63
      Wang, S.; Liu, K.; Liu, J.; Yu, Z. T. F.; Xu, X.; Zhao, L.; Lee, T.; Lee, E. K.; Reiss, J.; Lee, Y.-K. Highly Efficient Capture of Circulating Tumor Cells by Using Nanostructured Silicon Substrates with Integrated Chaotic Micromixers Angew. Chem., Int. Ed. 2011, 50, 3084– 3088
      63
      Highly Efficient Capture of Circulating Tumor Cells by Using Nanostructured Silicon Substrates with Integrated Chaotic Micromixers
      Wang, Shutao; Liu, Kan; Liu, Jian; Yu, Zeta T.-F.; Xu, Xiaowen; Zhao, Libo; Lee, Tom; Lee, Eun Kyung; Reiss, Jean; Lee, Yi-Kuen; Chung, Leland W. K.; Huang, Jiaoti; Rettig, Matthew; Seligson, David; Duraiswamy, Kumaran N.; Shen, Clifton K.-F.; Tseng, Hsian-Rong
      Angewandte Chemie, International Edition (2011), 50 (13), 3084-3088, S3084/1-S3084/15CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The authors introduce a new circulating tumor cells (CTC)-capture platform that integrates two functional components: (1) a patterned silicon nanopillar (SiNP) substrate with anti-EpCAM coating for recognizing/capturing EpCAM-expressing cells, and (2) an overlaid polydimethylsiloxane (PDMS) chip with a serpentine chaotic mixing channel that encourages increased cell-substrate contact frequency. When a blood sample contg. CTCs flows through the device, the embedded chevron-shaped micropatterns on the channel roof induce vertical flow in the microchannel. Consequently, the contact frequency between CTCs and the SiNP substrate increases, resulting in enhanced CTC capture. The performance of this integrated device was first characterized with a cell suspension of an EpCAM-pos. breast cancer cell line (MCF-7) in cell culture medium or phosphate-buffered saline (PBS) at flow rates of 0.5-7 mL/h. An optimal flow rate (1.0 mL/h) was detd. according to the resulting cell-capture efficiency. Finally, the optimal conditions were employed to capture and count CTCs from blood samples collected from prostate cancer patients with different degrees of tumor spread and with different sensitivity to treatments.
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    64. 64
      Duan, R.; Zuo, X.; Wang, S.; Quan, X.; Chen, D.; Chen, Z.; Jiang, L.; Fan, C.; Xia, F. Lab in a Tube: Ultrasensitive Detection of MicroRNAs at the Single-Cell Level and in Breast Cancer Patients Using Quadratic Isothermal Amplification J. Am. Chem. Soc. 2013, 135, 4604– 4607
      There is no corresponding record for this reference.
    65. 65
      Liu, W.; Thomopoulos, S.; Xia, Y. Electrospun Nanofibers for Regenerative Medicine Adv. Healthcare Mater. 2012, 1, 10– 25
      65
      Electrospun nanofibers for regenerative medicine
      Liu, Wenying; Thomopoulos, Stavros; Xia, Younan
      Advanced Healthcare Materials (2012), 1 (1), 10-25CODEN: AHMDBJ; ISSN:2192-2640. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. This Progress Report reviews recent progress in applying electrospun nanofibers to the emerging field of regenerative medicine. It begins with a brief introduction to electrospinning and nanofibers, with a focus on issues related to the selection of materials, incorporation of bioactive mols., degrdn. characteristics, control of mech. properties, and facilitation of cell infiltration. Next, a no. of approaches to fabricate scaffolds from electrospun nanofibers are discussed, including techniques for controlling the alignment of nanofibers and for producing scaffolds with complex architectures. The article also highlights applications of the nanofiber-based scaffolds in 4 areas of regenerative medicine that involve nerves, dural tissues, tendons, and the tendon-to-bone insertion site. The Progress Report concludes with perspectives on challenges and future directions for design, fabrication, and utilization of scaffolds based on electrospun nanofibers.
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    66. 66
      Xie, J.; Liu, W.; MacEwan, M. R.; Bridgman, P. C.; Xia, Y. Neurite Outgrowth on Electrospun Nanofibers with Uniaxial Alignment: The Effects of Fiber Density, Surface Coating, and Supporting Substrate ACS Nano 2014, 8, 1878– 1885
      66
      Neurite Outgrowth on Electrospun Nanofibers with Uniaxial Alignment: The Effects of Fiber Density, Surface Coating, and Supporting Substrate
      Xie, Jingwei; Liu, Wenying; MacEwan, Matthew R.; Bridgman, Paul C.; Xia, Younan
      ACS Nano (2014), 8 (2), 1878-1885CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Electrospun nanofibers with uniaxial alignment have recently gained its popularity as scaffolds for neural tissue engineering. Many studies have demonstrated that the nanofibers could guide the neurites to extend along the direction of alignment, resembling the native hierarchy of the nerve tissue. However, the contact cues provided by the nanofibers can be far more complicated than just guiding the neurites to extend along them. In the current study, we used dorsal root ganglia as a model system to systematically investigate the interactions between neurites and uniaxially aligned nanofibers. We demonstrated, for the first time, that the neurites could not only project along the nanofibers, but also be directed to grow along a direction perpendicular to the aligned nanofibers, depending on the following parameters: (i) the d. of nanofibers, (ii) the protein deposited on the surfaces of the nanofibers, and (iii) surface properties of the substrate on which the nanofibers were supported. We also investigated the pharmacol. effect of myosin II inhibition on the nanofiber-guided growth of neurites by adding blebbistatin to the culture medium. Our findings offer new insights into the design of nanofiber-based scaffolds for nerve injury repair and will provide new guidelines for the construction of well-defined neuronal network architecture (the so-called neural circuits).
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    67. 67
      Smith, L.; Xia, Y.; Galatz, L. M.; Genin, G. M.; Thomopoulos, S. Tissue-Engineering Strategies for the Tendon/Ligament-to-Bone Insertion Connect. Tissue Res. 2012, 53, 95– 105
      67
      Tissue-Engineering Strategies for the Tendon/Ligament-to-Bone Insertion
      Smith, Lester; Xia, Younan; Galatz, Leesa M.; Genin, Guy M.; Thomopoulos, Stavros
      Connective Tissue Research (2012), 53 (2), 95-105CODEN: CVTRBC; ISSN:0300-8207. (Informa Healthcare)
      A review. Injuries to connective tissues are painful and disabling and result in costly medical expenses. These injuries often require reattachment of an unmineralized connective tissue to bone. The uninjured tendon/ligament-to-bone insertion (enthesis) is a functionally graded material that exhibits a gradual transition from soft tissue (i.e., tendon or ligament) to hard tissue (i.e., mineralized bone) through a fibrocartilaginous transition region. This transition is believed to facilitate force transmission between the two dissimilar tissues by ameliorating potentially damaging interfacial stress concns. The transition region is impaired or lost upon tendon/ligament injury and is not regenerated following surgical repair or natural healing, exposing the tissue to risk of reinjury. The need to regenerate a robust tendon-to-bone insertion has led a no. of tissue engineering repair strategies. This review treats the tendon-to-bone insertion site as a tissue structure whose primary role is mech. and discusses current and emerging strategies for engineering the tendon/ligament-to-bone insertion in this context. The focus lies on strategies for producing mech. structures that can guide and subsequently sustain a graded tissue structure and the assocd. cell populations.
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    68. 68
      Xie, J.; MacEwan, M. R.; Ray, W. Z.; Liu, W.; Siewe, D. Y.; Xia, Y. Radially Aligned, Electrospun Nanofibers as Dural Substitutes for Wound Closure and Tissue Regeneration Applications ACS Nano 2010, 4, 5027– 5036
      There is no corresponding record for this reference.
    69. 69
      Lang, N.; Pereira, M. J.; Lee, Y.; Friehs, I.; Vasilyev, N. V.; Feins, E. N.; Ablasser, K.; O’Cearbhaill, E. D.; Xu, C.; Fabozzo, A. A Blood-Resistant Surgical Glue for Minimally Invasive Repair of Vessels and Heart Defects Sci. Transl. Med. 2014, 6, 218ra6
      There is no corresponding record for this reference.
    70. 70
      Yang, S. Y.; O’Cearbhaill, E. D.; Sisk, G. C.; Park, K. M.; Cho, W. K.; Villiger, M.; Bouma, B. E.; Pomahac, B.; Karp, J. M. A Bio-Inspired Swellable Microneedle Adhesive for Mechanical Interlocking with Tissue Nat. Commun. 2013, 4, 1702
      70
      A bio-inspired swellable microneedle adhesive for mechanical interlocking with tissue
      Yang Seung Yun; O'Cearbhaill Eoin D; Sisk Geoffroy C; Park Kyeng Min; Cho Woo Kyung; Villiger Martin; Bouma Brett E; Pomahac Bohdan; Karp Jeffrey M
      Nature communications (2013), 4 (), 1702 ISSN:.
      Achieving significant adhesion to soft tissues while minimizing tissue damage poses a considerable clinical challenge. Chemical-based adhesives require tissue-specific reactive chemistry, typically inducing a significant inflammatory response. Staples are fraught with limitations including high-localized tissue stress and increased risk of infection, and nerve and blood vessel damage. Here inspired by the endoparasite Pomphorhynchus laevis, which swells its proboscis to attach to its host's intestinal wall, we have developed a biphasic microneedle array that mechanically interlocks with tissue through swellable microneedle tips, achieving ~3.5-fold increase in adhesion strength compared with staples in skin graft fixation, and removal force of ~4.5 N cm(-2) from intestinal mucosal tissue. Comprising a poly(styrene)-block-poly(acrylic acid) swellable tip and non-swellable polystyrene core, conical microneedles penetrate tissue with minimal insertion force and depth, yet high adhesion strength in their swollen state. Uniquely, this design provides universal soft tissue adhesion with minimal damage, less traumatic removal, reduced risk of infection and delivery of bioactive therapeutics.
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    71. 71
      Cho, W. K.; Ankrum, J. A.; Guo, D.; Chester, S. A.; Yang, S. Y.; Kashyap, A.; Campbell, G. A.; Wood, R. J.; Rijal, R. K.; Karnik, R. Microstructured Barbs on the North American Porcupine Quill Enable Easy Tissue Penetration and Difficult Removal Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 21289– 21294
      There is no corresponding record for this reference.
    72. 72
      Liu, Y.; Lim, J.; Teoh, S.-H. Review: Development of Clinically Relevant Scaffolds for Vascularised Bone Tissue Engineering Biotechnol. Adv. 2013, 31, 688– 705
      There is no corresponding record for this reference.
    73. 73
      Lim, J.; Chong, M. S. K.; Chan, J. K. Y.; Teoh, S. H. Polymer Powder Processing of Cryomilled Polycaprolactone for Solvent-Free Generation of Homogeneous Bioactive Tissue Engineering Scaffolds Small 2014, 10, 2495– 2502
      There is no corresponding record for this reference.
    74. 74
      Peer, D.; Karp, J. M.; Hong, S.; Farokhzad, O. C.; Margalit, R.; Langer, R. Nanocarriers as an Emerging Platform for Cancer Therapy Nat. Nanotechnol. 2007, 2, 751– 760
      74
      Nanocarriers as an emerging platform for cancer therapy
      Peer, Dan; Karp, Jeffrey M.; Hong, Seungpyo; Farokhzad, Omid C.; Margalit, Rimona; Langer, Robert
      Nature Nanotechnology (2007), 2 (12), 751-760CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
      A review. Nanotechnol. has the potential to revolutionize cancer diagnosis and therapy. Advances in protein engineering and materials science have contributed to novel nanoscale targeting approaches that may bring new hope to cancer patients. Several therapeutic nanocarriers were approved for clin. use. However, to date, there are only a few clin. approved nanocarriers that incorporate mols. to selectively bind and target cancer cells. This review examines some of the approved formulations and discusses the challenges in translating basic research to the clinic. The authors detail the arsenal of nanocarriers and mols. available for selective tumor targeting, and emphasize the challenges in cancer treatment.
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    75. 75
      Chow, E. K.-H.; Ho, D. Cancer Nanomedicine: From Drug Delivery to Imaging Sci. Transl. Med. 2013, 5, 216rv4
      There is no corresponding record for this reference.
    76. 76
      Godwin, H.; Nameth, C.; Avery, D.; Bergeson, L. L.; Bernard, D.; Beryt, E.; Boyes, W.; Brown, S.; Clippinger, A. J.; Cohen, Y. Nanomaterial Categorization for Assessing Risk Potential to Facilitate Regulatory Decision-Making ACS Nano 2015, 9, 3409– 3417
      There is no corresponding record for this reference.
    77. 77
      Mura, S.; Nicolas, J.; Couvreur, P. Stimuli-Responsive Nanocarriers for Drug Delivery Nat. Mater. 2013, 12, 991– 1003
      77
      Stimuli-responsive nanocarriers for drug delivery
      Mura, Simona; Nicolas, Julien; Couvreur, Patrick
      Nature Materials (2013), 12 (11), 991-1003CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
      A review. Spurred by recent progress in materials chem. and drug delivery, stimuli-responsive devices that deliver a drug in spatial-, temporal- and dosage-controlled fashions have become possible. Implementation of such devices requires the use of biocompatible materials that are susceptible to a specific phys. incitement or that, in response to a specific stimulus, undergo a protonation, a hydrolytic cleavage or a (supra)mol. conformational change. In this Review, we discuss recent advances in the design of nanoscale stimuli-responsive systems that are able to control drug biodistribution in response to specific stimuli, either exogenous (variations in temp., magnetic field, ultrasound intensity, light or elec. pulses) or endogenous (changes in pH, enzyme concn. or redox gradients).
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    78. 78
      Pacardo, D. B.; Ligler, F. S.; Gu, Z. Programmable Nanomedicine: Synergistic and Sequential Drug Delivery Systems Nanoscale 2015, 7, 3381– 3391
      There is no corresponding record for this reference.
    79. 79
      Lu, Y.; Sun, W.; Gu, Z. Stimuli-Responsive Nanomaterials for Therapeutic Protein Delivery J. Controlled Release 2014, 194, 1– 19
      79
      Stimuli-responsive nanomaterials for therapeutic protein delivery
      Lu, Yue; Sun, Wujin; Gu, Zhen
      Journal of Controlled Release (2014), 194 (), 1-19CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
      A review. Protein therapeutics have emerged as a significant role in treatment of a broad spectrum of diseases, including cancer, metabolic disorders and autoimmune diseases. The efficacy of protein therapeutics, however, is limited by their instability, immunogenicity and short half-life. In order to overcome these barriers, tremendous efforts have recently been made in developing controlled protein delivery systems. Stimuli-triggered release is an appealing and promising approach for protein delivery and has made protein delivery with both spatiotemporal- and dosage-controlled manners possible. This review surveys recent advances in controlled protein delivery of proteins or peptides using stimuli-responsive nanomaterials. Strategies utilizing both physiol. and external stimuli are introduced and discussed.
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    80. 80
      Gu, Z.; Aimetti, A. A.; Wang, Q.; Dang, T. T.; Zhang, Y.; Veiseh, O.; Cheng, H.; Langer, R. S.; Anderson, D. G. Injectable Nano-network for Glucose-Mediated Insulin Delivery ACS Nano 2013, 7, 4194– 4201
      80
      Injectable Nano-Network for Glucose-Mediated Insulin Delivery
      Gu, Zhen; Aimetti, Alex A.; Wang, Qun; Dang, Tram T.; Zhang, Yunlong; Veiseh, Omid; Cheng, Hao; Langer, Robert S.; Anderson, Daniel G.
      ACS Nano (2013), 7 (5), 4194-4201CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Diabetes mellitus, a disorder of glucose regulation, is a global burden affecting 366 million people across the world. An artificial "closed-loop" system able to mimic pancreas activity and release insulin in response to glucose level changes has the potential to improve patient compliance and health. Herein we develop a glucose-mediated release strategy for the self-regulated delivery of insulin using an injectable and acid-degradable polymeric network. Formed by electrostatic interaction between oppositely charged dextran nanoparticles loaded with insulin and glucose-specific enzymes, the nanocomposite-based porous architecture can be dissocd. and subsequently release insulin in a hyperglycemic state through the catalytic conversion of glucose into gluconic acid. In vitro insulin release can be modulated in a pulsatile profile in response to glucose concns. In vivo studies validated that these formulations provided improved glucose control in type 1 diabetic mice s.c. administered with a degradable nano-network. A single injection of the developed nano-network facilitated stabilization of the blood glucose levels in the normoglycemic state (<200 mg/dL) for up to 10 days.
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    81. 81
      Mo, R.; Jiang, T.; DiSanto, R.; Tai, W.; Gu, Z. ATP-Triggered Anticancer Drug Delivery Nat. Commun. 2014, 5, 3364
      81
      ATP-triggered anticancer drug delivery
      Mo Ran; Jiang Tianyue; DiSanto Rocco; Tai Wanyi; Gu Zhen
      Nature communications (2014), 5 (), 3364 ISSN:.
      Stimuli-triggered drug delivery systems have been increasingly used to promote physiological specificity and on-demand therapeutic efficacy of anticancer drugs. Here we utilize adenosine-5'-triphosphate (ATP) as a trigger for the controlled release of anticancer drugs. We demonstrate that polymeric nanocarriers functionalized with an ATP-binding aptamer-incorporated DNA motif can selectively release the intercalating doxorubicin via a conformational switch when in an ATP-rich environment. The half-maximal inhibitory concentration of ATP-responsive nanovehicles is 0.24 μM in MDA-MB-231 cells, a 3.6-fold increase in the cytotoxicity compared with that of non-ATP-responsive nanovehicles. Equipped with an outer shell crosslinked by hyaluronic acid, a specific tumour-targeting ligand, the ATP-responsive nanocarriers present an improvement in the chemotherapeutic inhibition of tumour growth using xenograft MDA-MB-231 tumour-bearing mice. This ATP-triggered drug release system provides a more sophisticated drug delivery system, which can differentiate ATP levels to facilitate the selective release of drugs.
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    82. 82
      Gu, Z.; Dang, T. T.; Ma, M.; Tang, B. C.; Cheng, H.; Jiang, S.; Dong, Y.; Zhang, Y.; Anderson, D. G. Glucose-Responsive Microgels Integrated with Enzyme Nanocapsules for Closed-Loop Insulin Delivery ACS Nano 2013, 7, 6758– 6766
      82
      Glucose-Responsive Microgels Integrated with Enzyme Nanocapsules for Closed-Loop Insulin Delivery
      Gu, Zhen; Dang, Tram T.; Ma, Minglin; Tang, Benjamin C.; Cheng, Hao; Jiang, Shan; Dong, Yizhou; Zhang, Yunlong; Anderson, Daniel G.
      ACS Nano (2013), 7 (8), 6758-6766CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      A glucose-responsive closed-loop insulin delivery system represents the ideal treatment of type 1 diabetes mellitus. In this study, we develop uniform injectable microgels for controlled glucose-responsive release of insulin. Monodisperse microgels (256 ± 18 μm), consisting of a pH-responsive chitosan matrix, enzyme nanocapsules, and recombinant human insulin, were fabricated through a one-step electrospray procedure. Glucose-specific enzymes were covalently encapsulated into the nanocapsules to improve enzymic stability by protecting from denaturation and immunogenicity as well as to minimize loss due to diffusion from the matrix. The microgel system swelled when subjected to hyperglycemic conditions, as a result of the enzymic conversion of glucose into gluconic acid and protonation of the chitosan network. Acting as a self-regulating valve system, microgels were adjusted to release insulin at basal release rates under normoglycemic conditions and at higher rates under hyperglycemic conditions. Finally, we demonstrated that these microgels with enzyme nanocapsules facilitate insulin release and result in a redn. of blood glucose levels in a mouse model of type 1 diabetes.
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    83. 83
      Godwin, H.; Nameth, C.; Avery, D.; Bergeson, L. L.; Bernard, D.; Beryt, E.; Boyes, W.; Brown, S.; Clippinger, A. J.; Cohen, Y. Nanomaterial Categorization for Assessing Risk Potential to Facilitate Regulatory Decision-Making ACS Nano 2015, 9, 3409– 3417
      There is no corresponding record for this reference.
    84. 84
      Mitragotri, S.; Burke, P. A.; Langer, R. Overcoming the Challenges in Administering Biopharmaceuticals: Formulation and Delivery Strategies Nat. Rev. Drug Discovery 2014, 13, 655– 672
      84
      Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies
      Mitragotri, Samir; Burke, Paul A.; Langer, Robert
      Nature Reviews Drug Discovery (2014), 13 (9), 655-672CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
      The formulation and delivery of biopharmaceutical drugs, such as monoclonal antibodies and recombinant proteins, poses substantial challenges owing to their large size and susceptibility to degrdn. In this Review we highlight recent advances in formulation and delivery strategies - such as the use of microsphere-based controlled-release technologies, protein modification methods that make use of polyethylene glycol and other polymers, and genetic manipulation of biopharmaceutical drugs - and discuss their advantages and limitations. We also highlight current and emerging delivery routes that provide an alternative to injection, including transdermal, oral and pulmonary delivery routes. In addn., the potential of targeted and intracellular protein delivery is discussed.
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    85. 85
      Chertok, B.; Webber, M. J.; Succi, M. D.; Langer, R. Drug Delivery Interfaces in the 21st Century: From Science Fiction Ideas to Viable Technologies Mol. Pharmaceutics 2013, 10, 3531– 3543
      85
      Drug Delivery Interfaces in the 21st Century: From Science Fiction Ideas to Viable Technologies
      Chertok, Beata; Webber, Matthew J.; Succi, Marc D.; Langer, Robert
      Molecular Pharmaceutics (2013), 10 (10), 3531-3543CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      A review. Early science fiction envisioned the future of drug delivery as targeted micrometer-scale submarines and cyborg body parts. Here we describe the progression of the field toward technologies that are now beginning to capture aspects of this early vision. Specifically, we focus on the two most prominent types of systems in drug delivery: the intravascular micro/nano drug carriers for delivery to the site of pathol. and drug-loaded implantable devices that facilitate release with the predefined kinetics or in response to a specific cue. We discuss the unmet clin. needs that inspire these designs, the physiol. factors that pose difficult challenges for their realization, and viable technologies that promise robust solns. We also offer a perspective on where drug delivery may be in the next 50 years based on expected advances in material engineering and in the context of future diagnostics.
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    86. 86
      Hammond, P. T. A Growing Place for Nano in Medicine ACS Nano 2014, 8, 7551– 7552
      There is no corresponding record for this reference.
    87. 87
      Khademhosseini, A.; Peppas, N. A. Micro- and Nanoengineering of Biomaterials for Healthcare Applications Adv Healthc Mater 2013, 2, 10– 12
      87
      Micro- and Nanoengineering of Biomaterials for Healthcare Applications
      Khademhosseini, Ali; Peppas, Nicholas A.
      Advanced Healthcare Materials (2013), 2 (1), 10-12CODEN: AHMDBJ; ISSN:2192-2640. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review is given on the development and applications of micro- and nanoscale technologies for biomedicine. Engineered surface topog. of tissue engineering scaffolds, nanoparticles for siRNA and drug delivery, imaging, and biosensing, microfabricated structures to control tissue culture conditions, and biomaterials generate the biochem. and biomech. microenvironment for directing the differentiation of adult stem cells are included.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXkvVCgug%253D%253D&md5=a4fdea7811d7aba2402ad854a8a2d29f
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