Innovation in Nanomedicine through Materials Nanoarchitectonics

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Innovation in Nanomedicine through Materials Nanoarchitectonics Francoise M Winnik, and Piotr Kujawa Langmuir, Just Accepted Manuscript • DOI: 10.1021/la4014619 • Publication Date (Web): 23 Apr 2013 Downloaded from http://pubs.acs.org on May 3, 2013

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Innovation in Nanomedicine through Materials Nanoarchitectonics Piotr Kujawa1 and Françoise M. Winnik1,2,* 1

World Premier International (WPI) Research Center Initiative, International Center for

Materials Nanoarchitectonics (MANA) and National Institute for Materials Science (NIMS), 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan 2

Faculté de Pharmacie and Département de Chimie, Université de Montréal, CP 6128

Succursale Centre Ville, Montréal, QC, H3C 3J7, Canada, [email protected]

KEYWORDS:self-assembly, interfaces, theranostics, drug delivery, bioimaging, diagnostics

ACS Paragon Plus Environment

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ABSTRACT Materials nanoarchitectonics has led to important innovations in the design and construction of systems in nanoelectronics, nanomachinery, and energy conversion. Recent publications point to the fact that the same approach may be applied successfully to other fields. In this perspective, we define the key features of materials nanoarchitectonics and examine how they can be used to address current challenges in nanomedicine, placing emphasis on colloidal agents for therapeutic and diagnostic applications.


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Introduction The term materials nanoarchitectonics was coined at the dawn of the 21st century to describe a strategy that would stir innovation in nanotechnology and facilitate the necessary paradigm shifts of classical material science as it is faced with the challenge of converting the new properties of individual nano-objects into functional and, eventually, commercial materials and devices.1 The approach shuns the conventional analytical aspects of nanotechnology in favor of a synthetic view conducive to innovation. It is intended to lead to integrated assemblies that display concerted functions by virtue of mutual interactions among their units. It is achieved through the use of five “technologies”: self-organization, chemical nanomanipulation, field-induced interactions, new atom/molecule manipulations, and theoretical modeling (Figure 1). This set of tools was designed originally for the bottom-up assembly of atoms into integrated assemblies, such as atomic switches.

It was extended later to the functionality-driven design of

molecular/supramolecular systems and devices, with significant success in areas such as nanoelectronics, synaptic electronics, energy conversion systems, and molecular machinery. In this perspective, we examine how materials nanoarchitectonics can trigger innovation in the design nanomaterials for therapy and diagnostics. Nanoparticulate formulations are in clinical use, especially in oncology where liposome-based formulations exhibit outstanding therapeutic efficacies.2

Yet, nearly 20 years after FDA-

approval of the first liposomal formulation, actual implementation of nanoscience in clinical medicine remains modest.

It has been suggested that synergistic combinations of several

nanoparticle components or structural features can spur the development of more effective delivery systems.3 Of particular note is the emergence of multifunctional nanomaterials for combination drug therapy that takes advantage of the synergistic effect of “drug cocktails”.4


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Similarly, substantial enhancement of the specificity of in-vivo delivery towards pathological sites was achieved by controlling simultaneously the particle size, shape, and chemical targeting ability.5 Another thrust in research, known as “theranostics”, exploits the use of nanoparticles that combine therapeutic and diagnostic functions, in a single formulation and on the nanoscale.6 Site-specific activated release of therapeutics remains a major challenge in nanomaterials engineering. Strategies towards this goal rely on “responsive” nanomaterials that release their cargo as they sense a specific feature of the target site, such as its pH, redox balance, temperature or the presence of specific enzyme. Alternatively, an external stimulus (heat, radiation, etc… ) can be focused on nanoparticles as they reach their targeted site loaded with therapeutic or imaging agents.7-9 Issues related to the safety of nanomaterials cannot be ignored. They should be integrated throughout the process of nanoparticle design, preparation and implementation .10 In this perspective we define the five technologies of nanoarchitectonics and relate them to manipulations effected during the elaboration or in-vitro/in-vivo implementation of nanomaterials. We examine how the synergistic deployment of several technologies inherent to the nanoarchitectonics concept can promote nanotechnology in the biomedical arena. Examples were chosen for their didactic value and for their relevance to current challenges in nanomedicine. This necessarily brief and focused perspective is by no means comprehensive. In order to get a broader view on the implementation of nanoarchitectonics in current materials science, the reader is encouraged to read excellent recent reviews on specific aspects of nanomaterials in contemporary medicine and to consult special issues on materials nanoarchitectonics published by various journals (e.g. Sci. Technol. Adv. Mater. 2011, 12(4) and Adv. Mater. 2012, 24(2)).


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The five technologies of materials nanoarchitectonics Self-organization is the driving force for the formation and stability of polymeric nanoparticles, liposomes, or nanoemulsions with sizes in the 20 to 200 nm range useful for cell-internalization and in-vivo applications.11 Within the framework of nanoarchitectonics, this technology reaches far beyond the elaboration of simple monofunctional passive delivery and diagnostics agents. For instance, DNA or its fragments can be building blocks, either alone as described by Howarka in this issue of Langmuir12 or as the polar headgroup of polymeric amphiphiles. Thus, diblock copolymers consisting of a DNA block and a hydrophobic block self-assemble into discrete nanoparticles presenting a densely packed DNA corona.13

Further hybridization of

complementary oligonucleotides is readily achieved, yielding nanoparticles resistant to nuclease degradation. The nanoparticles, which are expected to allow targeted delivery (in-vitro and invivo) of intact hybridization-competent nucleic acids, may constitute a new generation of gene delivery agents, moving away from ill-defined and often cytotoxic polyplexed transfection agents.14 Tunable surface assemblies of guanine derivatives that can be deposited from aqueous solution were described by Kumar et al.15 They formed nanosized banding structures of tunable size by systematic tailoring of the molecular structure of the monomers. This concept was extended to the design of scaffolds obtained by supramolecular grafting of PEG groups onto the surface of highly oriented pyrolytic graphite (HOPG). The grafted assemblies were stable in biologically relevant temperatures and showed the ability to reduce static platelet adhesion. Protein-only self-assembled nanoparticles are assessed as carriers of therapeutic nucleic acids. For instance, Unzueta et al. were able to induce protein self-organization into nanoparticles by displaying arginine-rich cationic peptides, the “architectonic tags”, on histidine-tagged proteins.16 The resulting nanoparticles can serve as peptide carriers or as delivery systems for protein drugs.


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Other novel self-organized nanoparticles are built on liposome architectures rendered functional by incorporation of amphiphilic cyclodextrins17 or channel proteins.18 Molecular biorecognition is a particular form of self-organization. It underlies all biological processes. Biorecognition between α-fetoprotein, a tumor-specific marker glycoprotein, and its two ligands, antibody and lectin (Concavalin A), was used to actuate gels that recognize tumorspecific markers and shrink/expand according to the concentration of the protein.19

This

approach enabled the accurate detection and recognition of tumor-specific marker glycoproteins. It may lead to new sensors and devices for molecular diagnostics. Biorecognition between two oppositely-charged peptide fragments that results in physical crosslinking has also been used in the design of hybrid in-situ gelling hydrogels that may find use in biomaterials, biosensors and nanoreactors.20 Similar systems were used to induce cell apoptosis.21 Antibodies modified with peptide fragments were first attached to tumor cell surface via antigen-antibody biorecognition. Then, a polymer decorated with peptide fragments that can interact with antibody-peptide conjugates was introduced to the system and crosslinked on the cell surface via formation of heterodimeric coiled coils peptidic domains. Cell death occurred as result of simultaneous biorecognition and crosslinking, (see Fig. 2 for details).

Chemical manipulations are intrinsic part of the construction and fate of therapeutic nanoparticles. Nanomaterials can be functionalized with proteins, antibodies, or other biomolecules by various strategies in order to target specific or overexpressed receptors in diseased cells.22, 23 However, the targeting ability of functionalized nanomaterials is often muted in biological environments due to the adsorption of serum proteins on the nanomaterial surface,


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as demonstrated in the case of transferrin-conjugated nanoparticles, for which proteins in the media prevented transferrin from binding to either target cell receptors or soluble transferrin receptors.24

The nanoparticles were still able to enter cells, but they lost their targeting

specificity. Thus great care should be taken when designing the optimal strategy to functionalize nanomaterials for cell- or tissue–specific targeting .9 Although the PEG corona is necessary to ensure long blood circulation time, there are indications that it hinders extracellular or intracellular drug release and prevents binding of the nanoparticle targeting groups onto cell membrane receptors.25-27 Shedding the non-fouling coating may enhance the drug release and particle internalization, as schematically shown in Fig. 3. The un-zipping of the protective coat necessitates the cleavage of the covalent bond linking the PEG moieties to the nanoparticles.28 Suitable chemical reactions have been reviewed recently.29, 30 The polymeric components of functionalized nanomaterials, also, need to be designed with care, keeping in mind that they must undergo self-assembly and also contain all the functionalities required in order to minimize or better, eliminate, the need of nanomaterial postmodification. Gu et al. demonstrated this approach for nanoparticles targeted to prostate cancer cells.31 The polymeric building block selected consisted of (i) a poly(D,L-lactide-co-glycolide) (PLGA) block as controlled release hydrophobic moiety, (ii) a polyethylene glycol (PEG) block with antifouling properties, and (iii) a RNA aptamer as targeting agent that binds to a prostate specific membrane antigen. The triblock copolymer spontaneously self-assembles in a single step into targeted non-fouling nanoparticles.

This approach can be used to formulate distinct

nanoparticles that vary narrowly from each other, for example by incorporation of non-targeted PLGA-b-PEG copolymers.


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New atom/molecule manipulation, the third technology of materials nanoarchitectonics, is extended here to manipulations of biopolymers and cell components of relevance to biological systems. From this viewpoint, the layer-by-layer (LBL) polymer assemblies, also known as polyelectrolyte multilayers (PEM), are ubiquitous manipulations in the design of biomaterials and sensors. Two examples of their application can be found in this issue of Langmuir.32,33 For a comprehensive review of the field, the readers are referred to recent books edited by Decher and Schlenoff.34 Recent new applications of PME in therapeutics abound. For instance they are central to the design of an intradermal DNA vaccine programmed to release DNA progressively after implantation into epidermis.35 Microneedles coated with releasable polymer multilayers containing vaccine DNA, immune-stimulatory nucleic acids, and biodegradable polycations were employed as efficient, reproducible and pain-free delivery devices for DNA vaccines (see Fig. 4. for details). These ‘multilayer tattoo’ DNA vaccines induced immune responses against a model HIV antigen, enhanced memory T-cell generation, and elicited 140-fold higher gene expression in non-human primate skin, compared to intradermal DNA injection. PEM constructs have been used extensively as coatings of live cells to protect them against stressful situations,32 to camouflage foreign cells against the host autoimmune response,36 and to produce three dimensional tissue-like cell multilayers with nanometer-sized extracellular matrix films.37 Conversely, synthetic nanoparticles were camouflaged for in-vivo applications using cellular components. This strategy was demonstrated in a recent study where nanoporous silica particles were coated with purified cellular membranes obtained from leukocytes.38 In-vitro and in-vivo studies established that the resulting hybrid cell membrane/silica nanoparticles were able to elude the immune system, communicate with endothelial cells, accumulate in tumor sites, and release entrapped drug.


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Important advances in the applications of multilayered complexes are complemented by recent developments in the methods of their preparation.

By using simultaneous spraying, fast

preparation of uniform nanocoatings on large surfaces is now possible.39 A reverse phase LbL process using organic solvents and a water-soluble sacrificial template was employed to construct systems where accurate control over concentration of encapsulated material is essential and minute losses of the expensive biomacromolecular cargo should be precluded.40 These approaches open new opportunities for the preparation of materials that, so far, were inaccessible via traditional aqueous deposition methods. A new molecule manipulation based on the “dynamic bond” has emerged recently as a powerful means to access a new class of responsive and structurally dynamic polymers. The dynamic bond can be defined as any class of bond able to undergo reversible breaking and reformation under equilibrium conditions.41 Dynamic bonds may involve reversible supramolecular interactions or dynamic covalent bonds. In concert with other nanoarchitectonics technologies, they can provide routes to new classes of programmable responsive biomaterials, as discussed below. Field-induced interactions, in the context of nanoarchitectonics, are stimuli or physical forces implicated in the fabrication or function of nanodevices. Fields, such as heat or redox potential, are involved in the synthesis of most nanoparticles for therapeutics or diagnostics. Surface energy coupled with hydrophobicity-induced transfer is not used as frequently, although it is a simple and mild field-driven strategy to promote ligand exchange via nanoparticle transfer from an organic water-immiscible solvent to water.42 Fields are applied also to stimulate a specific function of nanoparticles or devices in their application site,43, 44 and to control the release of hydrophobic guests entrapped in nanoparticles, as demonstrated in the case of non-covalently bound photodynamic therapy agents loaded onto PEGylated gold nanoparticles.45


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Oncological drug delivery systems often rely on heat-responsive nanoparticles that release their cargo within tumor sites, which are slightly warmer than normal tissues. The drug release mechanism

exploits

the

property

of

thermo-sensitive

polymers,

such

as

poly(N-

isopropylacrylamide) (PNIPAM), that dehydrate, contract, and phase-separate from water as their aqueous solution (or suspension) temperature exceeds a value in the vicinity of body temperature. Changes in temperature are also actuators for stimuli-responsive gate-keepers or valves that control the release of guests entrapped in porous materials, such as mesoporous silica. For instance, Schlossbauer et al. covered porous silica nanoparticles with a shell of streptavidindecorated DNA double stands that block the outer silica pores. The valve opens when the nanoparticle environment exceeds the melting temperature of the DNA strand encoded in the DNA sequence. Higher levels of responsiveness can be attained with particles tunable via two (or more) fields. This design was demonstrated by Morimoto et al., who prepared nanogels responsive to changes in both temperature and redox conditions.46 The nanogels were obtained via reactive addition fragmentation termination grafting of NIPAM onto pullulan bearing sulfanylthiocarbonylsulfanyl (STS) groups, followed by aminolysis of the STS groups to generate thiols. PNIPAM-grafted pullulans dissolve molecularly in cold water; they form nanoparticles in warm water (T > 35 oC). Intra-particle disulfide links form in the presence of an oxidant; the crosslinked particles swell upon cooling but do not dissolve in water; their integrity in preserved until contact with a reducing agent, which readily unzip the nanoparticles and regenerate soluble polymers (Fig. 5). Incorporation of superparamagnetic iron oxide (SPION) nanoparticles and gold nanorods into dextran-poly(methacrylic acid)-PNIPAM-thiol nanogels further expands the functionality of the nanoparticles.47 These nanocomposites are responsive to (i) pH, via the poly(methacrylic acid)


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chains, (ii) heat via synergistic responses of PNIPAM and gold nanorods; (iii) magnetic fields, via the SPION nanoparticles, and (iv) near-IR irradiation, via the gold nanorods. A study of dual-responsive nanocomposites is presented in this issue by Kim et al.48 The nanoparticles are sensitive to heat, due to the presence of PNIPAM, and to the application of a magnetic field, as they SPION nanoparticles. A drug (doxorubicin) loaded in the nanocomposites was released at physiological temperature upon magnetic heating.

The iron oxide nanoparticles also

demonstrated MRI contrast enhancement enabling MRI imaging of the nanoparticles. Molecular recognition in synergy with changes in pH was used recently to reproduce the muscle-like synchronized action of myosin and actin filaments.49

Very high molecular weight

supramolecular polymers were constructed via dynamic bonds between a secondary dialkylammonium ion and a [24]crown-8 motif involving two self-complementary monomers. The bonds were deactivated upon deprotonation of the ammonium group triggering a macroscopic contraction of the polymer.

Protonation of the dialkyl amine reestablished

supramolecular recognition among complementary motifs, accompanied by polymer expansion. Current biosensors often rely on synergistic combinations of self-assembly and application of several fields. For instance, electrically contacted glycoenzyme electrodes were constructed by using ionic self-assembly and biorecognition principles.50 First, an electroactive polymer containing carbohydrate moieties was coated on an electrode via ionic self-assembly. Subsequently,

the

lectin

Concavalin

A

(Con

A)

was

bound

to

the

film

via

complexation/recognition of the carbohydrate residues. The resulting Con A layer facilitates the attachment of a glycoenzyme (horseradish peroxidase) while preserving the enzymatic activity and the electro-conductivity of the construct.


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Theory and simulations are intrinsic components of the nanoarchitectonics strategy. Computer simulations and molecular modeling provide precious insights into phenomena inaccessible by traditional experimental approach. Results of simulations indicate that the shape of a nanoparticle affects the nature of its interactions with the cell membrane.51 The penetrating capability of a nanoparticle across a membrane is determined by the contact area between the particle and the lipid bilayer and the local curvature of the particle at the contact point.52 Simulations of diffusion of nanoparticles decorated with ligands that are attached to a particle surface by dynamic bonds showed that the type of ligands and their grafting density affect penetration efficiency and translocation time.53 Vácha et al. reported a study of the release of nanoparticles from their lipid coating into the cytosol.54 The protective bilayer coating was detached by the changes in pH experienced by the nanoparticle. Shedding or the lipidic shell lowered the attraction between the nanoparticle and the membrane constituents, but only in the case of small or nonspherical nanoparticles. The release of large spherical nanoparticles, inside the cells only occurred when the pH-induced reduction of attraction was accompanied by exerting an additional tension on the membrane, e.g. via nanoparticle expansion. Soft matter physics coupled with nanoarchitectonics provide new insights into how soft tissues and tumors develop and spread on a “soft” surface.55 Analogies between tissue mechanics and dynamic phenomena involving liquid interfaces have been used to explain several ubiquitous tissue behaviors, including aggregation, fusion, and spreading on substrates of variable rigidity.56, 57

These advances in fundamental knowledge can be applied to understand cell differentiation

and cancer progression processes and to design new approaches in tissue engineering. Further modeling and theoretical efforts in this exciting field are needed to link physiological response of cells and tissues with physical phenomena occurring on different time and distance scales.


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Conclusions We have presented promising studies that use in synergy two or more inherent tools of materials nanoarchitectonics. Concepts of soft matter physics and simulations were linked to biological events such as cell migration and spreading and nanoparticle trafficking in and out of cells. Materials science and nanotechnology were combined with external fields to design polymer multilayer ”tattooing” devices for the delivery of DNA vaccines. Many other possibilities exist, as well as daunting challenges. For instance, it has become clear that biofunctionalization may not be the most efficient way to direct nanomaterials toward their targets in biological milieu. What will be the consequences of this observation on the design of multifunctional nanocarriers? Programmed in-vivo stability of nanodevices, also, needs to be addressed in the future. Nanoparticles should be stable enough to transport their cargo in the bloodstream and across the cellular membrane, but they should disintegrate in order to release their payload in the cytoplasm without release of toxic material. These questions, among many others, have motivated intensive research.

Nanoarchitectonics may bring some answers.

It can also be an inspiration for

innovative approaches outside current paradigms.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]. Tel: +1-514-340-5179. Funding Sources


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This work was supported by the Natural Sciences and Engineering Council of Canada-discovery program and the World Premier International Research Center Initiative (WPI) MEXT Japan. ACKNOWLEDGMENT The authors thank Dr. Masakazu Aono for insightful discussions and helpful comments on the manuscript.

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FIGURES

Figure 1. Materials nanoarchitectonics offer an integrated approach for the design, exploration, and fabrication of new nanomaterials for biology, medicine, and pharmaceutical applications, encompassed here in the term “Nano-Life”. It is based on five pillars: self-organization, chemical manipulation,

new

atom/molecule

manipulation,

field-induced

interaction,

and

theory/simulation. Selected examples for each area represented schematically in the figure are discussed in the text. Images are adapted with permission from: i) Self-organization: Dobrunz, D.; Toma, A. C.; Tanner, P.; Pfohl, T.; Palivan, C. G., Polymer Nanoreactors with Dual Functionality: Simultaneous Detoxification of Peroxynitrite and Oxygen Transport. Langmuir 2012, 28, 15889-15899. Copyright 2012 Americam Chemical Society. Kumar, A. M. S.;


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Sivakova, S.; Fox, J. D.; Green, J. E.; Marchant, R. E.; Rowan, S. J., Molecular Engineering of Supramolecular Scaffold Coatings that Can Reduce Static Platelet Adhesion. J. Am. Chem. Soc. 2008, 130, 1466-1476. Copyright 2008 American Chemical Society; ii) Chemical manipulation: Romberg, B.; Hennink, W.; Storm, G., Sheddable Coatings for Long-Circulating Nanoparticles. Pharm. Res. 2008, 25, 55-71. Copyright 2008 Springer Science and Business Media; iii) Fieldinduced interaction: Cortez, M. L.; Pallarola, D.; Ceolin, M.; Azzaroni, O.; Battaglini, F., Ionic self-assembly of electroactive biorecognizable units: electrical contacting of redox glycoenzymes made easy. Chem. Commun. 2012, 48, 10868-10870. Copyright 2012 Royal Society of Chemistry; iv) Theory: Ding, H. M.; Tian, W. D.; Ma, Y. Q., Designing Nanoparticle Translocation through Membranes by Computer Simulations. ACS Nano 2012, 6, 1230-1238. Copyright 2012 American Chemical Society; and v) New atom/molecule manipulation: Parodi, A.; Quattrocchi, N.; van de Ven, A. L.; Chiappini, C.; Evangelopoulos, M.; Martinez, J. O.; Brown, B. S.; Khaled, S. Z.; Yazdi, I. K.; Enzo, M. V.; Isenhart, L.; Ferrari, M.; Tasciotti, E., Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions. Nat. Nanotech. 2013, 8, 61-68. Copyright 2013 Macmillan Publishers Ltd.


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Figure 2. Induction of apoptosis in B cells non-Hodgkin lymphoma by cross-linking of its CD20 antigens mediated by antiparallel coiled-coil formation at the cell surface. The cells were exposed first to Fab’ fragments of the 1F5 anti-CD20 antibody conjugated with CCE peptide. The exposure results in the decoration of the cell surface with multiple copies of the CCE peptide through antigen-antibody biorecognition. Further exposure of the decorated cells to the copolymer grafted with multiple copies of CCK peptide results in the formation of CCE–CCK coiled-coil heterodimers on the cell surface. This second biorecognition event induces the crosslinking of CD20 receptors and triggers the apoptosis of B cells. Copied with permission from Wu, K.; Liu, J.; Johnson, R. N.; Yang, J.; Kopeček, J., Drug-Free Macromolecular


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Therapeutics: Induction of Apoptosis by Coiled-Coil-Mediated Cross-Linking of Antigens on the Cell Surface. Angew. Chem. Int. Ed. 2010, 49, 1451-1455. Copyright 2010 John Wiley and Sons.

Figure 3. Interaction of a multifunctional nanocarrier with the target cell. Long protective PEG chains are attached to the nanoparticle via stimuli-sensitive sheddable bonds. Nanoparticle recognizes the targeted cell via interaction of the specific ligand (e.g. antibody) with its binding site. The protective PEG coating and the PEG-ligand conjugates are shedded from the nanoparticle upon the application of the stimulus. Adapted with permission from Sawant, R. M.; Hurley, J. P.; Salmaso, S.; Kale, A.; Tolcheva, E.; Levchenko, T. S.; Torchilin, V. P., “SMART” Drug Delivery Systems: Double-Targeted pH-Responsive Pharmaceutical Nanocarriers. Bioconj. Chem. 2006, 17, 943-949. Copyright 2006 American Chemical Society.


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Therapeutic layer

Microneedle Array

Release Layer Microneedle Surface

Anchoring layer

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Skin Film Implantation

Sustained Vaccine Release

Figure 4. Design and working principle of quick-release vaccine-loaded microneedle coatings. Microneedles are coated with a release layer film and a polyelectrolyte multilayer. The release layer film is initially organic-soluble, but upon UV exposure it is converted to a weak polyelectrolyte soluble in water at pH > 6.5. In order to ensure uniform charge distribution, an anchoring layer composed from protamine sulfate (black) and poly(styrene sulfonate) (gray) is deposited on top of the release layer. The therapeutic multilayer is composed of a DNA vaccine (yellow), an adjuvant (red) and a cationic biodegradable transfection agent (light gray). The multilayer film implantation depends on the release-layer dissolution. Implanted films provide sustained release of nucleic acids through hydrolytic degradation of the polycationic transfection agent and release of in situ-formed nucleic acid/polycation complexes. The released polyplexes mediate local transfection and immune modulation in the tissue. Adapted with permission from Macmillan Publishers Ltd: Nature Materials (DeMuth, P. C.; Min, Y.; Huang, B.; Kramer, J. A.; Miller, A. D.; Barouch, D. H.; Hammond, P. T.; Irvine, D. J., Polymer multilayer tattooing for enhanced DNA vaccination. Nat. Mater. 2013, 12, 367-376), copyright 2013.


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Figure 5. Schematic representation of transitions in an aqueous solution of temperature and redox-responsive PNIPAM-grafted polysaccharide nanogels. The polymer dissolves molecularly in cold water, but it self-assembles upon heating due to the dehydration and collapse of the grafyed chains. In the presence of an oxidant, intra-particle disulfide links are formed. Crosslinked particles swell upon cooling and can be disintegrated upon contact with a reducing agent, which unzips the nanoparticles and regenerate soluble polymer chains.


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TOC Graphic (for table of content)


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Innovation in Nanomedicine through Materials Nanoarchitectonics

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