Stimuli-Responsive Polymers and Their Applications in Nanomedicine

This review focuses on smart nano-materials built of stimuli-responsive (SR) polymers and will discuss their numerous applications in the biomedical field. The authors will first provide an overview of different stimuli and their corresponding, responsive polymers. By introducing myriad functionalities, SR polymers present a wide range of possibilities in the design of stimuli-responsive devices, making use of virtually all types of polymer constructs, from self-assembled structures (micelles, vesicles) to surfaces (polymer brushes, films) as described in the second section of the review. In the last section of this review the authors report on some of the most promising applications of stimuli-responsive polymers in nanomedicine. In particular, we will discuss applications pertaining to diagnosis, where SR polymers are used to construct sensors capable of selective recognition and quantification of analytes and physical variables, as well as imaging devices. We will also highlight some examples of responsive systems used for therapeutic applications, including smart drug delivery systems (micelles, vesicles, dendrimers …) and surfaces for regenerative medicine.

[1]  Milan Mrksich,et al.  Dynamic interfaces between cells and surfaces: electroactive substrates that sequentially release and attach cells. , 2003, Journal of the American Chemical Society.

[2]  J. Corpart,et al.  Aqueous solution properties of ampholytic copolymers prepared in microemulsions , 1993 .

[3]  N. Rapoport,et al.  Acoustic activation of drug delivery from polymeric micelles: effect of pulsed ultrasound. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[4]  R. Hamers,et al.  Electrically Addressable Biomolecular Functionalization of Carbon Nanotube and Carbon Nanofiber Electrodes , 2004 .

[5]  Yen Wei,et al.  Photoresponsive nanocarriers based on PAMAM dendrimers with a o‐nitrobenzyl shell , 2010 .

[6]  D. Schmaljohann Thermo- and pH-responsive polymers in drug delivery. , 2006, Advanced drug delivery reviews.

[7]  Naoki Kanayama,et al.  Lactose-conjugated polyion complex micelles incorporating plasmid DNA as a targetable gene vector system: their preparation and gene transfecting efficiency against cultured HepG2 cells. , 2004, Journal of Controlled Release.

[8]  Li Lin,et al.  UV-Responsive Behavior of Azopyridine-Containing Diblock Copolymeric Vesicles: Photoinduced Fusion, Disintegration and Rearrangement. , 2009, Macromolecular rapid communications.

[9]  K. Kataoka,et al.  Biosignal-sensitive polyion complex micelles for the delivery of biopharmaceuticals , 2009 .

[10]  K. Nebesny,et al.  Polymer-coated ferromagnetic colloids from well-defined macromolecular surfactants and assembly into nanoparticle chains. , 2006, Journal of the American Chemical Society.

[11]  B. Mattiasson,et al.  Smart polymers: Physical forms and bioengineering applications , 2007 .

[12]  Lei Yu,et al.  An acid-labile block copolymer of PDMAEMA and PEG as potential carrier for intelligent gene delivery systems. , 2008, Biomacromolecules.

[13]  N. Peppas,et al.  Oral insulin delivery using P(MAA-g-EG) hydrogels: effects of network morphology on insulin delivery characteristics. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[14]  V. Bulmus,et al.  Acid-labile core cross-linked micelles for pH-triggered release of antitumor drugs. , 2008, Biomacromolecules.

[15]  Jeffrey A Hubbell,et al.  Glucose-oxidase based self-destructing polymeric vesicles. , 2004, Langmuir : the ACS journal of surfaces and colloids.

[16]  R. Advíncula,et al.  Homopolymer and Block Copolymer Brushes on Gold by Living Anionic Surface-Initiated Polymerization in a Polar Solvent , 2006 .

[17]  Malar A. Azagarsamy,et al.  Enzyme-triggered disassembly of dendrimer-based amphiphilic nanocontainers. , 2009, Journal of the American Chemical Society.

[18]  Jung Hyun Kim,et al.  Preparation of thermally denatured albumin gel and its pH-sensitive swelling , 1998 .

[19]  William B. Liechty,et al.  Polymers for drug delivery systems. , 2010, Annual review of chemical and biomolecular engineering.

[20]  J. Gong,et al.  Electrokinetic Modeling of the Contractile Phenomena of Polyelectrolyte Gels. One-Dimensional Capillary Model , 1994 .

[21]  Evgeny Katz,et al.  Switchable selectivity for gating ion transport with mixed polyelectrolyte brushes: approaching ‘smart’ drug delivery systems , 2009, Nanotechnology.

[22]  R. Advíncula,et al.  Surface-initiated polymerization , 2006 .

[23]  Kunihiro Ichimura,et al.  Reversible change in alignment mode of nematic liquid crystals regulated photochemically by command surfaces modified with an azobenzene monolayer , 1988 .

[24]  R. Zhuo,et al.  Synthesis of Thermo-Sensitive Micellar Aggregates Self-Assembled from Biotinylated PNAS-b-PNIPAAm-b-PCL Triblock Copolymers for Tumor Targeting , 2009 .

[25]  J. Zou,et al.  Synthesis and thermally responsive characteristics of dendritic poly(ether-amide) grafting with PNIPAAm and PEG , 2007 .

[26]  J. F. Stoddart,et al.  Electrochemically controllable conjugation of proteins on surfaces. , 2007, Bioconjugate chemistry.

[27]  O. Ikkala,et al.  Architecturally induced multiresponsive vesicles from well-defined polypeptides: formation of gene vehicles. , 2007, Biomacromolecules.

[28]  S. Thayumanavan,et al.  Selective sensing of metalloproteins from nonselective binding using a fluorogenic amphiphilic polymer. , 2006, Journal of the American Chemical Society.

[29]  Toshiyuki Kanamori,et al.  In situ control of cell adhesion using photoresponsive culture surface. , 2005, Biomacromolecules.

[30]  B. Sumerlin,et al.  Responsive Polymer‐Protein Bioconjugates Prepared by RAFT Polymerization and Copper‐Catalyzed Azide‐Alkyne Click Chemistry , 2008 .

[31]  D E Ingber,et al.  Electrically conducting polymers can noninvasively control the shape and growth of mammalian cells. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[32]  R. Lai,et al.  The therapeutic response to multifunctional polymeric nano-conjugates in the targeted cellular and subcellular delivery of doxorubicin. , 2010, Biomaterials.

[33]  Xiangrong Chen,et al.  Thermosensitive cross-linked polymer vesicles for controlled release system , 2006 .

[34]  Kwangmeyung Kim,et al.  A near-infrared fluorescence-based optical thermosensor. , 2009, Chemistry.

[35]  C. Barrett,et al.  pH-responsive properties of multilayered poly(L-lysine)/hyaluronic acid surfaces. , 2003, Biomacromolecules.

[36]  Atsushi Harada,et al.  Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. , 2003, Angewandte Chemie.

[37]  R. Langer,et al.  Poly(Ethylene Oxide)-Modified Poly(β-Amino Ester) Nanoparticles as a pH-Sensitive System for Tumor-Targeted Delivery of Hydrophobic Drugs: Part 2. In Vivo Distribution and Tumor Localization Studies , 2005, Pharmaceutical Research.

[38]  Miklós Zrínyi,et al.  Shape Transition of Magnetic Field Sensitive Polymer Gels , 1998 .

[39]  Karl Fischer,et al.  Temperature triggered self-assembly of polypeptides into multivalent spherical micelles. , 2008, Journal of the American Chemical Society.

[40]  Su-Hyang Kim,et al.  Chondrogenic differentiation of human mesenchymal stem cells using a thermosensitive poly(N-isopropylacrylamide) and water-soluble chitosan copolymer. , 2004, Biomaterials.

[41]  Paul M. George,et al.  Electrically Controlled Drug Delivery from Biotin‐Doped Conductive Polypyrrole , 2006 .

[42]  Y. Bae,et al.  Novel pH-sensitive polymers containing sulfonamide groups , 1999 .

[43]  Ashutosh Chilkoti,et al.  Fabrication of a reversible protein array directly from cell lysate using a stimuli-responsive polypeptide. , 2003, Analytical chemistry.

[44]  E. Rofstad,et al.  Acidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude mice. , 2006, Cancer research.

[45]  F. Szoka,et al.  A single dose of doxorubicin-functionalized bow-tie dendrimer cures mice bearing C-26 colon carcinomas , 2006, Proceedings of the National Academy of Sciences.

[46]  Yongfeng Zhou,et al.  Temperature-responsive phase transition of polymer vesicles: real-time morphology observation and molecular mechanism. , 2007, The journal of physical chemistry. B.

[47]  S. Armes,et al.  pH-sensitive vesicles based on a biocompatible zwitterionic diblock copolymer. , 2005, Journal of the American Chemical Society.

[48]  S. Minko Responsive Polymer Brushes , 2006 .

[49]  J. Kopeček,et al.  Novel pH-sensitive hydrogels with adjustable swelling kinetics. , 1998, Biomaterials.

[50]  A. Downard,et al.  Reversible Photoregulation of Binding of α-Chymotrypsin to a Gold Surface , 2007 .

[51]  S. Armes,et al.  Tailoring Macromolecular Expression at Polymersome Surfaces , 2009 .

[52]  S. Lecommandoux,et al.  Temperature responsive poly(trimethylene carbonate)-block-poly(L-glutamic acid) copolymer: polymersomes fusion and fission , 2010 .

[53]  S. Cho,et al.  Dendrimers Derived from Polyphosphazene-Poly(propyleneimine) Systems: Encapsulation and Triggered Release of Hydrophobic Guest Molecules , 2007 .

[54]  Jinming Hu,et al.  Hg2+-reactive double hydrophilic block copolymer assemblies as novel multifunctional fluorescent probes with improved performance. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[55]  H. Klok,et al.  From supramolecular polymersomes to stimuli-responsive nano-capsules based on poly(diene-b-peptide) diblock copolymers , 2003, The European physical journal. E, Soft matter.

[56]  Kwang Hee Lee,et al.  Biodegradable thermo-sensitive nanoparticles from poly(L-lactic acid)/poly(ethylene glycol) alternating multi-block copolymer for potential anti-cancer drug carrier. , 2006, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[57]  Zengqian Shi,et al.  Facile Fabrication of pH-Responsive and Size-Controllable Polymer Vesicles From a Commercially Available Hyperbranched Polyester , 2008 .

[58]  Ronald P. Manginell,et al.  Programmed Adsorption and Release of Proteins in a Microfluidic Device , 2003, Science.

[59]  A. Hoffman,et al.  Controlling the aggregation of conjugates of streptavidin with smart block copolymers prepared via the RAFT copolymerization technique. , 2006, Biomacromolecules.

[60]  Mark Hayes,et al.  Photo-, thermally, and pH-responsive microgels. , 2007, Langmuir : the ACS journal of surfaces and colloids.

[61]  Ichimura,et al.  Light-driven motion of liquids on a photoresponsive surface , 2000, Science.

[62]  Paula M Mendes,et al.  Stimuli-responsive surfaces for bio-applications. , 2008, Chemical Society reviews.

[63]  A. Sabot,et al.  Biosensor based on enzyme-catalysed degradation of thin polymer films. , 2001, Biosensors & bioelectronics.

[64]  Yuichi Yamasaki,et al.  Block catiomer polyplexes with regulated densities of charge and disulfide cross-linking directed to enhance gene expression. , 2004, Journal of the American Chemical Society.

[65]  P. Gupta,et al.  Hydrogels: from controlled release to pH-responsive drug delivery. , 2002, Drug discovery today.

[66]  Daniel Cohn,et al.  Ethoxysilane-capped PEO-PPO-PEO triblocks: a new family of reverse thermo-responsive polymers. , 2004, Biomaterials.

[67]  Wei Chen,et al.  Unusual pH-Dependent Polarity Changes in PAMAM Dendrimers:  Evidence for pH-Responsive Conformational Changes , 2000 .

[68]  T. Okano,et al.  Thermo‐responsive polymeric surfaces; control of attachment and detachment of cultured cells , 1990 .

[69]  Haixiang Sun,et al.  Cellulose nitrate membrane formation via phase separation induced by penetration of nonsolvent from vapor phase , 2007 .

[70]  Evgeny Katz,et al.  Polymer Brush-Modified Electrode with Switchable and Tunable Redox Activity for Bioelectronic Applications , 2008 .

[71]  A. Chilkoti,et al.  Thermodynamically reversible addressing of a stimuli responsive fusion protein onto a patterned surface template , 2003 .

[72]  M. Kostiainen,et al.  Low-molecular-weight dendrons for DNA binding and release by reduction-triggered degradation of multivalent interactions. , 2009, Chemistry.

[73]  Sang Cheon Lee,et al.  Thermo‐responsive injectable hydrogel system based on poly(N‐isopropylacrylamide‐co‐vinylphosphonic acid). I. Biomineralization and protein delivery , 2009 .

[74]  H. Möhwald,et al.  Stimuli-responsive LbL capsules and nanoshells for drug delivery. , 2011, Advanced drug delivery reviews.

[75]  W. Hennink,et al.  In situ gelling hydrogels for pharmaceutical and biomedical applications. , 2008, International journal of pharmaceutics.

[76]  T. Okano,et al.  Temperature-responsive cell culture surfaces enable "on-off" affinity control between cell integrins and RGDS ligands. , 2004, Biomacromolecules.

[77]  Jyh-Ping Chen,et al.  Thermo-responsive chitosan-graft-poly(N-isopropylacrylamide) injectable hydrogel for cultivation of chondrocytes and meniscus cells. , 2006, Macromolecular bioscience.

[78]  Kinam Park,et al.  Environment-sensitive hydrogels for drug delivery , 2001 .

[79]  A. Bausch,et al.  Photoswitched cell adhesion on surfaces with RGD peptides. , 2005, Journal of the American Chemical Society.

[80]  Dzmitry G. Shcharbin,et al.  Dendrimers in gene transfection , 2009, Biochemistry (Moscow).

[81]  K. Ulbrich,et al.  Novel vectors for gene delivery formed by self-assembly of DNA with poly(L-lysine) grafted with hydrophilic polymers. , 1998, Biochimica et biophysica acta.

[82]  Yuichi Mori,et al.  Cell Culture on a Thermo-Responsive Polymer Surface , 1990, Bio/Technology.

[83]  J. Mano,et al.  Thermally Responsive Biomineralization on Biodegradable Substrates , 2007 .

[84]  Zhiyuan Zhong,et al.  Reversibly crosslinked temperature-responsive nano-sized polymersomes: synthesis and triggered drug release , 2009 .

[85]  Kazunori Kataoka,et al.  A protein nanocarrier from charge-conversion polymer in response to endosomal pH. , 2007, Journal of the American Chemical Society.

[86]  J. Rodríguez-Hernández,et al.  pH-responsive micelles and vesicles nanocapsules based on polypeptide diblock copolymers. , 2007, Biomolecular engineering.

[87]  R. Yoshida,et al.  New intelligent polymer gels: a self-oscillating gel with pacemaking and actuating functions , 1999, Journal of Artificial Organs.

[88]  Zhiyuan Zhong,et al.  Stimuli-responsive polymersomes for programmed drug delivery. , 2009, Biomacromolecules.

[89]  Vanessa Schmidt,et al.  Nanocontainers formed by self-assembly of poly(ethylene oxide)-b-poly(glycerol monomethacrylate)-drug conjugates , 2007 .

[90]  E. Gil,et al.  Stimuli-reponsive polymers and their bioconjugates , 2004 .

[91]  J. Kopeček,et al.  HPMA copolymer-bound doxorubicin induces apoptosis in ovarian carcinoma cells by the disruption of mitochondrial function. , 2006, Molecular pharmaceutics.

[92]  S. MacNeil,et al.  Biomimetic pH Sensitive Polymersomes for Efficient DNA Encapsulation and Delivery , 2007 .

[93]  A. R. Kulkarni,et al.  Chemically modified polyacrylamide-g-guar gum-based crosslinked anionic microgels as pH-sensitive drug delivery systems: preparation and characterization. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[94]  S. Kannan,et al.  Dendrimer-drug conjugates for tailored intracellular drug release based on glutathione levels. , 2008, Bioconjugate chemistry.

[95]  Toyoichi Tanaka,et al.  Collapse of Gels in an Electric Field , 1982, Science.

[96]  N. K. Jain,et al.  Dendritic systems in drug delivery applications , 2007, Expert opinion on drug delivery.

[97]  Patrick Keller,et al.  Stimuli-responsive polymer vesicles , 2009 .

[98]  P. Okunieff,et al.  Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. , 1989, Cancer research.

[99]  S. MacNeil,et al.  Non-cytotoxic polymer vesicles for rapid and efficient intracellular delivery. , 2008, Faraday discussions.

[100]  Michiya Matsusaki,et al.  Enzyme-responsive release of encapsulated proteins from biodegradable hollow capsules. , 2006, Biomacromolecules.

[101]  Zhiyuan Zhong,et al.  Polymersomes Spanning from Nano- to Microscales: Advanced Vehicles for Controlled Drug Delivery and Robust Vesicles for Virus and Cell Mimicking , 2011 .

[102]  Kazunori Kataoka,et al.  Polymeric micelles for nano-scale drug delivery , 2011 .

[103]  Joan W. Miller,et al.  Addendum to “Photosensitizer delivery for photodynamic therapy of choroidal neovascularization” , 2001 .

[104]  M. Stamm,et al.  Polymer surfaces and interfaces : characterization, modification and applications , 2008 .

[105]  H. Uludaǧ,et al.  Virus-mimetic polymeric micelles for targeted siRNA delivery. , 2010, Biomaterials.

[106]  Y. Lee,et al.  Preparation of pH/temperature responsive polymer membrane by plasma polymerization and its riboflavin permeation , 1997 .

[107]  N. Nishiyama,et al.  A Photo-Activated Targeting Chemotherapy Using Glutathione Sensitive Camptothecin-Loaded Polymeric Micelles , 2008, Pharmaceutical Research.

[108]  J. N. Russell,et al.  Electrically Addressable Biomolecular Functionalization of Conductive Nanocrystalline Diamond Thin Films , 2005 .

[109]  Adam E. Smith,et al.  Schizophrenic Self-Assembly of Block Copolymers Synthesized via Aqueous RAFT Polymerization: From Micelles to Vesicles , 2010 .

[110]  A. M. Vinogradov,et al.  Ultrasonically Controlled Release of Ciprofloxacin from Self-Assembled Coatings on Poly(2-Hydroxyethyl Methacrylate) Hydrogels for Pseudomonas aeruginosa Biofilm Prevention , 2005, Antimicrobial Agents and Chemotherapy.

[111]  A. P. de Silva,et al.  Fluorescent polymeric AND logic gate with temperature and pH as inputs. , 2004, Journal of the American Chemical Society.

[112]  Lei Jiang,et al.  Reversible switching between superhydrophilicity and superhydrophobicity. , 2004, Angewandte Chemie.

[113]  K. Kono,et al.  Rendering poly(amidoamine) or poly(propylenimine) dendrimers temperature sensitive. , 2004, Journal of the American Chemical Society.

[114]  T. Okano,et al.  A novel recovery system for cultured cells using plasma-treated polystyrene dishes grafted with poly(N-isopropylacrylamide). , 1993, Journal of biomedical materials research.

[115]  Roeland J. M. Nolte,et al.  A Polymersome Nanoreactor with Controllable Permeability Induced by Stimuli‐Responsive Block Copolymers , 2009 .

[116]  C. Palivan,et al.  Photoresponsive polymersomes as smart, triggerable nanocarriers , 2011 .

[117]  F. Manvi,et al.  In situ-forming hydrogels for sustained ophthalmic drug delivery. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[118]  X. Qian,et al.  Novel heterogeneous PET fluorescent sensors selective for transition metal ions or protons: polymers regularly labelled with naphthalimide , 2002 .

[119]  S. Kannan,et al.  Poly(amidoamine) dendrimer-drug conjugates with disulfide linkages for intracellular drug delivery. , 2009, Biomaterials.

[120]  Sergiy Minko,et al.  Nanosensors based on responsive polymer brushes and gold nanoparticle enhanced transmission surface plasmon resonance spectroscopy. , 2004, Journal of the American Chemical Society.

[121]  John R. Reynolds,et al.  Use of Conducting Electroactive Polymers for Drug Delivery and Sensing of Bioactive Molecules. A Redox Chemistry Approach , 2000 .

[122]  K. Ulbrich,et al.  Antibody-targeted Polymer–doxorubicin Conjugates with pH-controlled Activation , 2004, Journal of drug targeting.

[123]  K. L. Mittal,et al.  Polymer surfaces and interfaces : characterization, modification and applicaiton , 1997 .

[124]  Masayuki Yamato,et al.  Thermally responsive polymer-grafted surfaces facilitate patterned cell seeding and co-culture. , 2002, Biomaterials.

[125]  Jinho Hyun,et al.  Capture and release of proteins on the nanoscale by stimuli-responsive elastin-like polypeptide "switches". , 2004, Journal of the American Chemical Society.

[126]  R. Pelton,et al.  Temperature-sensitive aqueous microgels. , 2000, Advances in colloid and interface science.

[127]  Frank Bates,et al.  Biodegradable polymersomes loaded with both paclitaxel and doxorubicin permeate and shrink tumors, inducing apoptosis in proportion to accumulated drug. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[128]  R. Satchi‐Fainaro,et al.  Enhanced cytotoxicity of a polymer-drug conjugate with triple payload of paclitaxel. , 2009, Bioorganic & medicinal chemistry.

[129]  A. Higuchi,et al.  Photon-modulated changes of cell attachments on poly(spiropyran-co-methyl methacrylate) membranes. , 2004, Biomacromolecules.

[130]  Yue Zhao,et al.  How can azobenzene block copolymer vesicles be dissociated and reformed by light? , 2005, The journal of physical chemistry. B.

[131]  Dennis E Discher,et al.  Polymersome carriers: from self-assembly to siRNA and protein therapeutics. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[132]  Venkata Krishna Kotharangannagari,et al.  Photoresponsive Reversible Aggregation and Dissolution of Rod–Coil Polypeptide Diblock Copolymers , 2011 .

[133]  A. Watterson,et al.  Aqueous salt absorption by ampholytic polysaccharides , 1985 .

[134]  Jinming Hu,et al.  Responsive Polymers for Detection and Sensing Applications: Current Status and Future Developments , 2010 .

[135]  T. Okano,et al.  Intelligent thermoresponsive polymeric stationary phases for aqueous chromatography of biological compounds , 2002 .

[136]  Donald E. Chickering,et al.  Biologically erodable microspheres as potential oral drug delivery systems , 1997, Nature.

[137]  L. Yu,et al.  Poly(N-isopropylacrylamide)-chitosan as thermosensitive in situ gel-forming system for ocular drug delivery. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[138]  E. Lobel,et al.  A novel in situ-forming ophthalmic drug delivery system from alginates undergoing gelation in the eye , 1997 .

[139]  J. Dissemond,et al.  pH-Wert des Milieus chronischer Wunden , 2003, Der Hautarzt.

[140]  K. Kono,et al.  Control of Temperature-Sensitive Properties of Poly(amidoamine) Dendrimers Using Peripheral Modification with Various Alkylamide Groups , 2006 .

[141]  Nobuhiko Yui,et al.  Gelatin/dextran intelligent hydrogels for drug delivery : dual-stimuli-responsive degradation in relation to miscibility in interpenetrating polymer networks , 1998 .

[142]  C. Ahn,et al.  Synthesis of a PEGylated polymeric pH sensor and its pH sensitivity by fluorescence resonance energy transfer , 2006 .

[143]  D. Wise Electrical and optical polymer systems , 1998 .

[144]  Kazuo Yamaguchi,et al.  Photoactivation of a substrate for cell adhesion under standard fluorescence microscopes. , 2004, Journal of the American Chemical Society.

[145]  Y. Sugiyama,et al.  Novel cisplatin-incorporated polymeric micelles can eradicate solid tumors in mice. , 2003, Cancer research.

[146]  W. R. Taylor,et al.  In vivo imaging of hydrogen peroxide with chemiluminescent nanoparticles. , 2007, Nature materials.

[147]  D. Mukhopadhyay,et al.  Inhibition of vessel permeability by TNP-470 and its polymer conjugate, caplostatin. , 2005, Cancer cell.

[148]  T. Xu,et al.  Dendrimers as drug carriers: applications in different routes of drug administration. , 2008, Journal of pharmaceutical sciences.

[149]  Nicholas A Kotov,et al.  Quantum dot on a rope. , 2002, Journal of the American Chemical Society.

[150]  R. McCarley,et al.  Chemically and Electrochemically Mediated Release of Dendrimer End Groups , 2006 .

[151]  T. Okano,et al.  Inner core segment design for drug delivery control of thermo-responsive polymeric micelles. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[152]  R Langer,et al.  Stimulation of neurite outgrowth using an electrically conducting polymer. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[153]  Niels Bent Larsen,et al.  Studies of spin-coated polymer films , 2005 .

[154]  Takehisa Matsuda,et al.  The potential of poly(N-isopropylacrylamide) (PNIPAM)-grafted hyaluronan and PNIPAM-grafted gelatin in the control of post-surgical tissue adhesions. , 2005, Biomaterials.

[155]  Tao Wu,et al.  Fabrication of Photoswitchable and Thermotunable Multicolor Fluorescent Hybrid Silica Nanoparticles Coated with Dye-Labeled Poly(N-isopropylacrylamide) Brushes , 2009 .

[156]  J. Folkman,et al.  Malignant progression and blockade of angiogenesis in a murine transgenic model of neuroblastoma. , 2007, Cancer research.

[157]  T. Swager,et al.  A fluorescent self-amplifying wavelength-responsive sensory polymer for fluoride ions. , 2003, Angewandte Chemie.

[158]  S. Kannan,et al.  Stimuli-responsive star poly(ethylene glycol) drug conjugates for improved intracellular delivery of the drug in neuroinflammation. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[159]  L. White,et al.  Water-Soluble Polymers .73. Electrolyte- and pH-Responsive Zwitterionic Copolymers of 4-[(2-acrylamido-2-methylpropyl)Dimethylammonio]butanoate with 3-[(2-acrylamido-2-methylpropyl)dimethylammonio]propanesulfonate , 1997 .

[160]  K. Kataoka,et al.  pH-responsive oligodeoxynucleotide (ODN)-poly(ethylene glycol) conjugate through acid-labile beta-thiopropionate linkage: preparation and polyion complex micelle formation. , 2003, Biomacromolecules.

[161]  Jing Zhang,et al.  Synthesis and Characterization of pH- and Temperature-Sensitive Poly(methacrylic acid)/Poly(N-isopropylacrylamide) Interpenetrating Polymeric Networks , 2000 .

[162]  A. P. de Silva,et al.  Fluorescent molecular thermometers based on polymers showing temperature-induced phase transitions and labeled with polarity-responsive benzofurazans. , 2003, Analytical chemistry.

[163]  C. Alexander,et al.  Thermoresponsive Surface-Grafted Poly(N−isopropylacrylamide) Copolymers: Effect of Phase Transitions on Protein and Bacterial Attachment , 2003 .

[164]  I. El-Sherbiny,et al.  Chitosan-based interpolymeric pH-responsive hydrogels for in vitro drug release , 2007 .

[165]  Francis C Szoka,et al.  Designing dendrimers for biological applications , 2005, Nature Biotechnology.

[166]  Ashutosh Chilkoti,et al.  Stimulus-responsive macromolecules and nanoparticles for cancer drug delivery. , 2010, Nanomedicine.

[167]  K. Kontturi,et al.  Modeling of the Salt and pH Effects on the Permeability of Grafted Porous Membranes , 1996 .

[168]  Axel H. E. Müller,et al.  Thermosensitive water-soluble copolymers with doubly responsive reversibly interacting entities , 2007 .

[169]  W. Meier,et al.  Stimuli-responsive polymersomes as nanocarriers for drug and gene delivery. , 2009, Macromolecular bioscience.

[170]  T. Vandamme,et al.  The use of polysaccharides to target drugs to the colon , 2002 .

[171]  E. Harth,et al.  Molecular dendritic transporter nanoparticle vectors provide efficient intracellular delivery of peptides. , 2009, ACS nano.

[172]  E. Simanek,et al.  Design, synthesis, characterization, and biological evaluation of triazine dendrimers bearing paclitaxel using ester and ester/disulfide linkages. , 2009, Bioconjugate chemistry.

[173]  Y. Yoshioka,et al.  Design of a pH-Sensitive Polymeric Carrier for Drug Release and Its Application in Cancer Therapy , 2004, Clinical Cancer Research.

[174]  T. Park,et al.  Founder's Award, Society for Biomaterials. Sixth World Biomaterials Congress 2000, Kamuela, HI,May 15-20, 2000. Really smart bioconjugates of smart polymers and receptor proteins. , 2000, Journal of biomedical materials research.

[175]  Seon Jeong Kim,et al.  Synthesis and characteristics of interpenetrating polymer network hydrogel composed of chitosan and poly(acrylic acid) , 1999 .

[176]  Younan Xia,et al.  Gold nanocages covered by smart polymers for controlled release with near-infrared light , 2009, Nature materials.

[177]  Malar A. Azagarsamy,et al.  Disassembly of dendritic micellar containers due to protein binding. , 2010, Journal of the American Chemical Society.

[178]  T. Okano,et al.  Decrease in culture temperature releases monolayer endothelial cell sheets together with deposited fibronectin matrix from temperature-responsive culture surfaces. , 1999, Journal of biomedical materials research.

[179]  Dennis E. Discher,et al.  Temperature‐Controlled Assembly and Release from Polymer Vesicles of Poly(ethylene oxide)‐block‐ poly(N‐isopropylacrylamide) , 2006 .

[180]  B Mattiasson,et al.  'Smart' polymers and what they could do in biotechnology and medicine. , 1999, Trends in biotechnology.

[181]  D. Shabat,et al.  Molecular probe for enzymatic activity with dual output. , 2007, Bioorganic & medicinal chemistry.

[182]  Robert Langer,et al.  Controlled Delivery Systems for Proteins Based on Poly(Lactic/Glycolic Acid) Microspheres , 1991, Pharmaceutical Research.

[183]  R. Haag,et al.  Photoresponsive crosslinked hyperbranched polyglycerols as smart nanocarriers for guest binding and controlled release. , 2009, Small.

[184]  T. Xu,et al.  Controlled release of ionic drug through the positively charged temperature-responsive membranes , 2006 .

[185]  Yuting Li,et al.  Thermally responsive vesicles and their structural "locking" through polyelectrolyte complex formation. , 2006, Angewandte Chemie.

[186]  Mauro Ferrari,et al.  Seven challenges for nanomedicine. , 2008, Nature nanotechnology.

[187]  Jianhua Zhou,et al.  Temperature- and pH-responsive star amphiphilic block copolymer prepared by a combining strategy of ring-opening polymerization and reversible addition–fragmentation transfer polymerization , 2010 .

[188]  Bin Zhao,et al.  Multiple Micellization and Dissociation Transitions of Thermo- and Light-Sensitive Poly(ethylene oxide)-b-poly(ethoxytri(ethylene glycol) acrylate-co-o-nitrobenzyl acrylate) in Water , 2008 .

[189]  Neutral and charged polymers at interfaces , 2002, cond-mat/0203364.

[190]  Bruce C. Bunker,et al.  Reversible switching of interfacial interactions , 2008 .

[191]  Daniel T Kamei,et al.  Polyarginine segments in block copolypeptides drive both vesicular assembly and intracellular delivery. , 2007, Nature materials.

[192]  I. Fischer,et al.  In vitro analysis of PNIPAAm-PEG, a novel, injectable scaffold for spinal cord repair. , 2009, Acta biomaterialia.

[193]  Lifen Zhang,et al.  Thermo and pH sensitive fluorescent polymer sensor for metal cations in aqueous solution , 2008 .

[194]  W. Huck,et al.  Effect of nanoconfinement on the collapse transition of responsive polymer brushes. , 2008, Nano letters.

[195]  Photoregulation of a peptide-RNA interaction on a gold surface. , 2007, Journal of the American Chemical Society.

[196]  L. Miller,et al.  Poly(N-methylpyrrolylium) poly(styrenesulfonate) - a conductive, electrically switchable cation exchanger that cathodically binds and anodically releases dopamine , 1987 .

[197]  É. Boisselier,et al.  Dendrimers designed for functions: from physical, photophysical, and supramolecular properties to applications in sensing, catalysis, molecular electronics, photonics, and nanomedicine. , 2010, Chemical reviews.

[198]  D. S. Lee,et al.  Controlled release of human growth hormone from a biodegradable pH/temperature-sensitive hydrogel system , 2011 .

[199]  Christian Blum,et al.  Temperature-modulated quenching of quantum dots covalently coupled to chain ends of poly(N-isopropyl acrylamide) brushes on gold , 2009, Nanotechnology.

[200]  G. Kwon,et al.  Polymeric micelles for the pH-dependent controlled, continuous low dose release of paclitaxel. , 2010, Biomaterials.

[201]  Tokuji Miyashita,et al.  Nanoscale actuation of thermoreversible polymer brushes coupled with localized surface plasmon resonance of gold nanoparticles. , 2007, Langmuir : the ACS journal of surfaces and colloids.

[202]  Stimuli-induced Pulsatile or Triggered Release Delivery Systems for Bioactive Compounds , 2007 .

[203]  K. Kataoka,et al.  Biodegradable nanogels prepared by atom transfer radical polymerization as potential drug delivery carriers: synthesis, biodegradation, in vitro release, and bioconjugation. , 2007, Journal of the American Chemical Society.

[204]  Jiahai Zhang,et al.  Host-guest chemistry of dendrimer-drug complexes. 6. Fully acetylated dendrimers as biocompatible drug vehicles using dexamethasone 21-phosphate as a model drug. , 2011, The journal of physical chemistry. B.

[205]  J. Mano Stimuli‐Responsive Polymeric Systems for Biomedical Applications , 2008 .

[206]  Z. Sideratou,et al.  Quaternized Poly(propylene imine) Dendrimers as Novel pH-Sensitive Controlled-Release Systems , 2000 .

[207]  Xenophon Papademetris,et al.  Self-assembly of pH-responsive fluorinated dendrimer-based particulates for drug delivery and noninvasive imaging. , 2009, Biomaterials.

[208]  T. Koyama,et al.  Synthesis and Characterization of Photo-Responsive Carbosilane Dendrimers , 2009, Molecules.

[209]  Kinam Park,et al.  Smart Polymeric Gels: Redefining the Limits of Biomedical Devices. , 2007, Progress in polymer science.

[210]  M. C. Stuart,et al.  Emerging applications of stimuli-responsive polymer materials. , 2010, Nature materials.

[211]  R Langer,et al.  Bioerodible polyanhydrides as drug-carrier matrices. I: Characterization, degradation, and release characteristics. , 1985, Journal of biomedical materials research.

[212]  M. Nowakowska,et al.  “Smart” polymeric nanospheres as new materials for possible biomedical applications , 2003, Journal of materials science. Materials in medicine.

[213]  F. Bates,et al.  Preparation, stability, and in vitro performance of vesicles made with diblock copolymers. , 2000, Biotechnology and bioengineering.

[214]  Kazuo Yamaguchi,et al.  Spatiotemporal control of migration of single cells on a photoactivatable cell microarray. , 2007, Journal of the American Chemical Society.

[215]  Martin Müller,et al.  Oxidation-responsive polymeric vesicles , 2004, Nature materials.

[216]  J. Wiedenmann,et al.  Polyelectrolyte-mediated protein adsorption: fluorescent protein binding to individual polyelectrolyte nanospheres. , 2005, The journal of physical chemistry. B.

[217]  Jeffrey A Hubbell,et al.  PEG-SS-PPS: reduction-sensitive disulfide block copolymer vesicles for intracellular drug delivery. , 2007, Biomacromolecules.

[218]  Sankaran Thayumanavan,et al.  Fluorescence patterns from supramolecular polymer assembly and disassembly for sensing metallo- and nonmetalloproteins. , 2009, Journal of the American Chemical Society.

[219]  D. Christensen,et al.  Ultrasound-triggered drug targeting of tumors in vitro and in vivo. , 2004, Ultrasonics.

[220]  B. Sumerlin,et al.  Future perspectives and recent advances in stimuli-responsive materials , 2010 .

[221]  Sakurai Yasuhisa,et al.  Regulated release of drug microspheres from inflammation responsive degradable matrices of crosslinked hyaluronic acid , 1993 .

[222]  P. Heegaard,et al.  Dendrimers in drug research. , 2004, Chemical Society reviews.

[223]  M. Akashi,et al.  Synthesis and functionalities of poly(N‐vinylalkylamide). V. Control of a lower critical solution temperature of poly(N‐vinylalkylamide) , 1997 .

[224]  G. Dupuis,et al.  Colon-specific drug delivery: Influence of solution reticulation properties upon pectin beads performance. , 2006, International journal of pharmaceutics.

[225]  N. Nishiyama,et al.  Environment-responsive block copolymer micelles with a disulfide cross-linked core for enhanced siRNA delivery. , 2009, Biomacromolecules.

[226]  M. Davies,et al.  Responsive hybrid block co-polymer conjugates of proteins–controlled architecture to modulate substrate specificity and solution behaviour , 2011 .

[227]  Anna Gutowska,et al.  Lessons from nature: stimuli-responsive polymers and their biomedical applications. , 2002, Trends in biotechnology.

[228]  A. Roggan,et al.  Optical Properties of Circulating Human Blood in the Wavelength Range 400-2500 nm. , 1999, Journal of biomedical optics.

[229]  V. Sinha,et al.  Polysaccharides in colon-specific drug delivery. , 2001, International journal of pharmaceutics.

[230]  Tae Gwan Park,et al.  Catechol-functionalized chitosan/pluronic hydrogels for tissue adhesives and hemostatic materials. , 2011, Biomacromolecules.

[231]  Anil K Patri,et al.  Dendritic polymer macromolecular carriers for drug delivery. , 2002, Current opinion in chemical biology.

[232]  W. Goddard,et al.  PAMAM dendrimers undergo pH responsive conformational changes without swelling. , 2009, Journal of the American Chemical Society.

[233]  Y. Bae,et al.  PEG-poly(amino acid) Block Copolymer Micelles for Tunable Drug Release , 2010, Pharmaceutical Research.

[234]  Taolei Sun,et al.  Biomimetic Smart Interface Materials for Biological Applications , 2011, Advanced materials.

[235]  J. Davies,et al.  Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470 , 2004, Nature Medicine.

[236]  M. Maeda,et al.  A polymer micelle responding to the protein kinase a signal , 2001 .

[237]  V. Pillay,et al.  A Review of Multi-Responsive Membranous Systems for Rate-Modulated Drug Delivery , 2010, AAPS PharmSciTech.

[238]  Jian Ji,et al.  Micelles and reverse micelles with a photo and thermo double‐responsive block copolymer , 2010 .

[239]  T. Okano,et al.  Creation of designed shape cell sheets that are noninvasively harvested and moved onto another surface. , 2000, Biomacromolecules.

[240]  Lei Jiang,et al.  Photoresponsive surfaces with controllable wettability , 2007 .

[241]  S. Thayumanavan,et al.  Disassembly of noncovalent amphiphilic polymers with proteins and utility in pattern sensing. , 2008, Journal of the American Chemical Society.

[242]  Dean P. Jones,et al.  Glutathione measurement in human plasma. Evaluation of sample collection, storage and derivatization conditions for analysis of dansyl derivatives by HPLC. , 1998, Clinica chimica acta; international journal of clinical chemistry.

[243]  F. Brochard-Wyart,et al.  Bursting of sensitive polymersomes induced by curling , 2009, Proceedings of the National Academy of Sciences.