Click Chemistry for Drug Delivery Nanosystems

ABSTRACTThe purpose of this Expert Review is to discuss the impact of click chemistry in nanosized drug delivery systems. Since the introduction of the click concept by Sharpless and coworkers in 2001, numerous examples of click reactions have been reported for the preparation and functionalization of polymeric micelles and nanoparticles, liposomes and polymersomes, capsules, microspheres, metal and silica nanoparticles, carbon nanotubes and fullerenes, or bionanoparticles. Among these click processes, Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) has attracted most attention based on its high orthogonality, reliability, and experimental simplicity for non-specialists. A renewed interest in the use of efficient classical transformations has been also observed (e.g., thiol-ene coupling, Michael addition, Diels-Alder). Special emphasis is also devoted to critically discuss the click concept, as well as practical aspects of application of CuAAC to ensure efficient and harmless bioconjugation.

[1]  S. Gambhir,et al.  Quantum Dots for Live Cells, in Vivo Imaging, and Diagnostics , 2005, Science.

[2]  A. Tsourkas,et al.  An intein-mediated site-specific click conjugation strategy for improved tumor targeting of nanoparticle systems. , 2010, Small.

[3]  Trevor Douglas,et al.  Synthesis of a cross-linked branched polymer network in the interior of a protein cage. , 2009, Journal of the American Chemical Society.

[4]  Kui Yu,et al.  Soluble Stoichiometric Complexes from Poly(N-ethyl-4-vinylpyridinium) Cations and Poly(ethylene oxide)-block-polymethacrylate Anions , 1996 .

[5]  P. Friedl,et al.  Readily Accessible Bicyclononynes for Bioorthogonal Labeling and Three-Dimensional Imaging of Living Cells , 2010, Angewandte Chemie.

[6]  Li Liu,et al.  Bioconjugated Janus Particles Prepared by in Situ Click Chemistry , 2009 .

[7]  Lisa Brannon-Peppas,et al.  Active targeting schemes for nanoparticle systems in cancer therapeutics. , 2008, Advanced drug delivery reviews.

[8]  S. Nguyen,et al.  "Clickable" polymer-caged nanobins as a modular drug delivery platform. , 2009, Journal of the American Chemical Society.

[9]  F. Beyer,et al.  Thermally Driven Assembly of Nanoparticles in Polymer Matrices , 2007 .

[10]  M. Young,et al.  A click chemistry based coordination polymer inside small heat shock protein. , 2010, Chemical communications.

[11]  T. Brown,et al.  Template-directed oligonucleotide strand ligation, covalent intramolecular DNA circularization and catenation using click chemistry. , 2007, Journal of the American Chemical Society.

[12]  Brian G. Trewyn,et al.  Mesoporous Silica Nanoparticles for Drug Delivery and Biosensing Applications , 2007 .

[13]  M. Finn,et al.  Virus-glycopolymer conjugates by copper(I) catalysis of atom transfer radical polymerization and azide-alkyne cycloaddition. , 2005, Chemical communications.

[14]  Toshinobu Yogo,et al.  High-frequency, magnetic-field-responsive drug release from magnetic nanoparticle/organic hybrid based on hyperthermic effect. , 2010, ACS applied materials & interfaces.

[15]  K. Sharpless,et al.  Polytriazoles as copper(I)-stabilizing ligands in catalysis. , 2004, Organic letters.

[16]  S. Nguyen,et al.  Polymer-caged lipsomes: a pH-responsive delivery system with high stability. , 2007, Journal of the American Chemical Society.

[17]  W. Brittain,et al.  Tandem RAFT polymerization and click chemistry : An efficient approach to surface modification , 2007 .

[18]  Songming Peng,et al.  Synthesis and Characterization of Linear-Dendron-like Poly(ε-caprolactone)-b-poly(ethylene oxide) Copolymers via the Combination of Ring-Opening Polymerization and Click Chemistry , 2008 .

[19]  E. Gillies,et al.  Surface functionalization of nanomaterials with dendritic groups: toward enhanced binding to biological targets. , 2009, Journal of the American Chemical Society.

[20]  Yin Ren,et al.  In vivo tumor cell targeting with "click" nanoparticles. , 2008, Bioconjugate chemistry.

[21]  Beyond electrostatics. , 2007, Lab on a chip.

[22]  Gaojian Chen,et al.  Macromolecular cobalt carbonyl complexes encapsulated in a click-cross-linked micelle structure as a nanoparticle to deliver cobalt pharmaceuticals. , 2009, Biomacromolecules.

[23]  W. Sakamoto,et al.  Chemoselective Synthesis of Folic Acid−Functionalized Magnetite Nanoparticles via Click Chemistry for Magnetic Hyperthermia , 2009 .

[24]  S. Nguyen,et al.  "Clickable" polymer nanoparticles: a modular scaffold for surface functionalization. , 2010, Chemical communications.

[25]  C. van Nostrum,et al.  Synthesis and applications of biomedical and pharmaceutical polymers via click chemistry methodologies. , 2009, Bioconjugate chemistry.

[26]  Hua-ming Li,et al.  Functionalization of single-walled carbon nanotubes with well-defined polystyrene by "click" coupling. , 2005, Journal of the American Chemical Society.

[27]  C. Cai,et al.  "Clickable", polymerized liposomes as a versatile and stable platform for rapid optimization of their peripheral compositions. , 2010, Chemical communications.

[28]  W. Binder,et al.  Surface-modified nanoparticles via thermal and Cu(I)-mediated “click” chemistry: Generation of luminescent CdSe nanoparticles with polar ligands guiding supramolecular recognition , 2007 .

[29]  R. Weissleder,et al.  Hybrid PET-optical imaging using targeted probes , 2010, Proceedings of the National Academy of Sciences.

[30]  Allan Svendsen,et al.  Bionanoconjugation via click chemistry: The creation of functional hybrids of lipases and gold nanoparticles. , 2006, Bioconjugate chemistry.

[31]  Elodie Boisselier,et al.  Gold nanoparticles in nanomedicine: preparations, imaging, diagnostics, therapies and toxicity. , 2009, Chemical Society reviews.

[32]  Jaime Ruiz,et al.  How to very efficiently functionalize gold nanoparticles by "click" chemistry. , 2008, Chemical communications.

[33]  E. Gillies,et al.  Multivalent polymer vesicles via surface functionalization. , 2007, Chemical communications.

[34]  É. Duguet,et al.  Magnetic nanoparticle design for medical diagnosis and therapy , 2004 .

[35]  S. Schmid,et al.  Multivalent Display and Receptor‐Mediated Endocytosis of Transferrin on Virus‐Like Particles , 2010, Chembiochem : a European journal of chemical biology.

[36]  Li Liu,et al.  Bioconjugation of biotin to the interfaces of polymeric micelles via in situ click chemistry. , 2009, Langmuir : the ACS journal of surfaces and colloids.

[37]  Andrei A. Poloukhtine,et al.  Selective labeling of living cells by a photo-triggered click reaction. , 2009, Journal of the American Chemical Society.

[38]  Po-Chiao Lin,et al.  Site-specific protein modification through Cu(I)-catalyzed 1,2,3-triazole formation and its implementation in protein microarray fabrication. , 2006, Angewandte Chemie.

[39]  O. Wolfbeis,et al.  Probing the Activity of Matrix Metalloproteinase II with a Sequentially Click‐Labeled Silica Nanoparticle FRET Probe , 2009, Chembiochem : a European journal of chemical biology.

[40]  Nicholas J Turro,et al.  Toward the syntheses of universal ligands for metal oxide surfaces: controlling surface functionality through click chemistry. , 2007, Journal of the American Chemical Society.

[41]  F. Caruso,et al.  Low-fouling, biofunctionalized, and biodegradable click capsules. , 2008, Biomacromolecules.

[42]  C. Bertozzi,et al.  Rapid Cu-Free Click Chemistry with Readily Synthesized Biarylazacyclooctynones , 2010, Journal of the American Chemical Society.

[43]  F. Du,et al.  Synthesis of Amphiphilic Biodegradable Glycocopolymers Based on Poly(ε-caprolactone) by Ring-Opening Polymerization and Click Chemistry , 2009 .

[44]  Hongkun He,et al.  'Clicked' magnetic nanohybrids with a soft polymer interlayer. , 2009, Chemical communications.

[45]  J. Lutz,et al.  In Situ Functionalization of Thermoresponsive Polymeric Micelles using the “Click” Cycloaddition of Azides and Alkynes , 2007 .

[46]  Qian Wang,et al.  Adaptations of nanoscale viruses and other protein cages for medical applications. , 2006, Nanomedicine : nanotechnology, biology, and medicine.

[47]  P. Krusic,et al.  Addition of alkylthiyl and alkoxy radicals to C60 studied by ESR , 1993 .

[48]  J. Nierengarten,et al.  A click-click approach for the preparation of functionalized [5:1]-hexaadducts of C60. , 2009, Chemistry.

[49]  B. Frisch,et al.  Targeted liposomes: convenient coupling of ligands to preformed vesicles using "click chemistry". , 2006, Bioconjugate chemistry.

[50]  John E. Johnson,et al.  Potato virus X as a novel platform for potential biomedical applications. , 2010, Nano letters.

[51]  P. Couvreur,et al.  Synthesis of poly(alkyl cyanoacrylate)-based colloidal nanomedicines. , 2009, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[52]  M. Shoichet,et al.  Click chemistry functionalized polymeric nanoparticles target corneal epithelial cells through RGD-cell surface receptors. , 2009, Bioconjugate chemistry.

[53]  D. Pang,et al.  Clickable gold nanoparticles as the building block of nanobioprobes. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[54]  S. Pati,et al.  Semiconductor to metal transition in SWNTs caused by interaction with gold and platinum nanoparticles , 2008, 0803.3368.

[55]  J. V. van Hest,et al.  "Clickable" polymersomes. , 2007, Chemical communications.

[56]  Xuesi Chen,et al.  Hemoglobin conjugated micelles based on triblock biodegradable polymers as artificial oxygen carriers. , 2009, Biomaterials.

[57]  Siqi Li,et al.  Chemoselective derivatization of a bionanoparticle by click reaction and ATRP reaction. , 2007, Chemical communications.

[58]  J. Guillet,et al.  Drug Delivery Systems , 1995 .

[59]  Dirk M Guldi,et al.  Multifunctional molecular carbon materials--from fullerenes to carbon nanotubes. , 2006, Chemical Society reviews.

[60]  D. Werz,et al.  Synthesis of fullerene glycoconjugates via a copper-catalyzed Huisgen cycloaddition reaction. , 2007, Organic letters.

[61]  Johann Kecht,et al.  A programmable DNA-based molecular valve for colloidal mesoporous silica. , 2010, Angewandte Chemie.

[62]  Luke G Green,et al.  A stepwise huisgen cycloaddition process: copper(I)-catalyzed regioselective "ligation" of azides and terminal alkynes. , 2002, Angewandte Chemie.

[63]  S. Fry.  Oxidative scission of plant cell wall polysaccharides by ascorbate-induced hydroxyl radicals. , 1998, The Biochemical journal.

[64]  W. Brittain,et al.  Combination of Living Radical Polymerization and Click Chemistry for Surface Modification , 2007 .

[65]  É. Drockenmuller,et al.  Efficient Approaches for the Surface Modification of Platinum Nanoparticles via Click Chemistry , 2010 .

[66]  P. Mahadevan,et al.  An overview , 2007, Journal of Biosciences.

[67]  Jeremiah A. Johnson,et al.  Toward the Syntheses of Universal Ligands for Metal Oxide Surfaces: Controlling Surface Functionality through Click Chemistry , 2006 .

[68]  Frank Caruso,et al.  Targeting of cancer cells using click-functionalized polymer capsules. , 2010, Journal of the American Chemical Society.

[69]  F. Caruso,et al.  Ultrathin, responsive polymer click capsules. , 2007, Nano letters.

[70]  C. Hawker,et al.  Preparation of orthogonally-functionalized core Click cross-linked nanoparticles , 2007 .

[71]  P. Jégou,et al.  Efficient functionalization of carbon nanotubes with porphyrin dendrons via click chemistry. , 2009, Journal of the American Chemical Society.

[72]  F. Caruso,et al.  Stabilization and Functionalization of Polymer Multilayers and Capsules via Thiol-Ene Click Chemistry , 2009 .

[73]  D. Maysinger,et al.  Tailoring the efficacy of nimodipine drug delivery using nanocarriers based on A2B miktoarm star polymers. , 2010, Biomaterials.

[74]  B. Halliwell,et al.  Role of free radicals and catalytic metal ions in human disease: an overview. , 1990, Methods in enzymology.

[75]  Hiroshi Maeda,et al.  Tumor-selective delivery of macromolecular drugs via the EPR effect: background and future prospects. , 2010, Bioconjugate chemistry.

[76]  V. Chechik,et al.  Shell cross-linked Au nanoparticles. , 2006, Langmuir : the ACS journal of surfaces and colloids.

[77]  G. Stucky,et al.  Heterofunctional polymers and core-shell nanoparticles via cascade aminolysis/Michael addition and alkyne-azide click reaction of RAFT polymers. , 2008, Chemical communications.

[78]  D. Hammer,et al.  Polymersomes: tough vesicles made from diblock copolymers. , 1999, Science.

[79]  Morten Meldal,et al.  Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. , 2002, The Journal of organic chemistry.

[80]  O. Wolfbeis,et al.  Dual labeling of biomolecules by using click chemistry: a sequential approach. , 2009, Angewandte Chemie.

[81]  N. Steinmetz,et al.  Buckyballs meet viral nanoparticles: candidates for biomedicine. , 2009, Journal of the American Chemical Society.

[82]  D. Pine,et al.  Functionalization of polymer microspheres using click chemistry. , 2009, Langmuir : the ACS journal of surfaces and colloids.

[83]  Marianne Manchester,et al.  Folic acid-mediated targeting of cowpea mosaic virus particles to tumor cells. , 2007, Chemistry & biology.

[84]  Carolyn R Bertozzi,et al.  Biocompatible carbon nanotubes generated by functionalization with glycodendrimers. , 2008, Angewandte Chemie.

[85]  Paul Anastas,et al.  Green chemistry: principles and practice. , 2010, Chemical Society reviews.

[86]  M. Wolfert,et al.  Visualizing metabolically labeled glycoconjugates of living cells by copper-free and fast huisgen cycloadditions. , 2008, Angewandte Chemie.

[87]  F. Caruso,et al.  Biodegradable click capsules with engineered drug-loaded multilayers. , 2010, ACS nano.

[88]  A. Heise,et al.  Glaser coupling of polymers : side-reaction in huisgens "Click" coupling reaction and opportunity for polymers with focal diacetylene units in combination with ATRP , 2009 .

[89]  F. Caruso,et al.  Next generation, sequentially assembled ultrathin films: beyond electrostatics. , 2007, Chemical Society reviews.

[90]  T. Carell,et al.  Chain-like assembly of gold nanoparticles on artificial DNA templates via 'click chemistry'. , 2008, Chemical communications.

[91]  Morten Meldal,et al.  Cu-catalyzed azide-alkyne cycloaddition. , 2008, Chemical reviews.

[92]  Duane E. Prasuhn,et al.  Viral MRI contrast agents: coordination of Gd by native virions and attachment of Gd complexes by azide-alkyne cycloaddition. , 2007, Chemical communications.

[93]  Chi‐Huey Wong,et al.  The chemistry of amine-azide interconversion: catalytic diazotransfer and regioselective azide reduction. , 2002, Journal of the American Chemical Society.

[94]  M. Shoichet,et al.  Doxorubicin‐Conjugated Immuno‐Nanoparticles for Intracellular Anticancer Drug Delivery , 2009 .

[95]  Andrew K. Udit,et al.  Electrochemically Protected Copper(I)‐Catalyzed Azide–Alkyne Cycloaddition , 2008, Chembiochem : a European journal of chemical biology.

[96]  Po-Chiao Lin,et al.  Surface modification of magnetic nanoparticle via Cu(I)-catalyzed alkyne-azide [2 + 3] cycloaddition. , 2007, Organic letters.

[97]  M. Debets,et al.  Azide: A Unique Dipole for Metal‐Free Bioorthogonal Ligations , 2010, Chembiochem : a European journal of chemical biology.

[98]  M. Prato,et al.  Biomedical applications of functionalised carbon nanotubes. , 2005, Chemical communications.

[99]  Cynthia L. Warner,et al.  Thiol-ene induced diphosphonic acid functionalization of superparamagnetic iron oxide nanoparticles. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[100]  Eunju Kim,et al.  Direct synthesis of polymer nanocapsules: self-assembly of polymer hollow spheres through irreversible covalent bond formation. , 2010, Journal of the American Chemical Society.

[101]  R. Riguera,et al.  Surpassing the use of copper in the click functionalization of polymeric nanostructures: a strain-promoted approach. , 2009, Journal of the American Chemical Society.

[102]  M. G. Finn,et al.  Click Chemistry: Diverse Chemical Function from a Few Good Reactions. , 2001, Angewandte Chemie.

[103]  N. Steinmetz,et al.  Labeling live cells by copper-catalyzed alkyne--azide click chemistry. , 2010, Bioconjugate chemistry.

[104]  C. Mirkin,et al.  Polyvalent oligonucleotide iron oxide nanoparticle "click" conjugates. , 2010, Nano letters.

[105]  A. Müller,et al.  Clickable, biocompatible, and fluorescent hybrid nanoparticles for intracellular delivery and optical imaging. , 2010, Biomacromolecules.

[106]  Gaojian Chen,et al.  Synthesis of thiol-linked neoglycopolymers and thermo-responsive glycomicelles as potential drug carrier. , 2009, Chemical communications.

[107]  Chi‐Huey Wong,et al.  Anti‐Carbohydrate Antibodies Elicited by Polyvalent Display on a Viral Scaffold , 2007, Chembiochem : a European journal of chemical biology.

[108]  S. Armes,et al.  Recent Advances in Shell Cross-Linked Micelles , 2007 .

[109]  Demei Tian,et al.  Cooperative binding of bifunctionalized and click-synthesized silver nanoparticles for colorimetric co(2+) sensing. , 2010, ACS applied materials & interfaces.

[110]  Qian Wang,et al.  Bioconjugation by copper(I)-catalyzed azide-alkyne [3 + 2] cycloaddition. , 2003, Journal of the American Chemical Society.

[111]  D. Prosperi,et al.  One-step bioengineering of magnetic nanoparticles via a surface diazo transfer/azide-alkyne click reaction sequence. , 2008, Chemical communications.

[112]  Peng Wu,et al.  Catalytic Azide—Alkyne Cycloaddition: Reactivity and Applications , 2007 .

[113]  Daniel J. Burke,et al.  Applications of orthogonal "click" chemistries in the synthesis of functional soft materials. , 2009, Chemical reviews.

[114]  P. Couvreur,et al.  Synthesis of Highly Functionalized Poly(alkyl cyanoacrylate) Nanoparticles by Means of Click Chemistry , 2008 .

[115]  Zhishen Ge,et al.  Polyion Complex Micelles Possessing Thermoresponsive Coronas and Their Covalent Core Stabilization via “Click” Chemistry , 2008 .

[116]  Mansoor M. Amiji,et al.  Poly(ethylene glycol)-modified Nanocarriers for Tumor-targeted and Intracellular Delivery , 2007, Pharmaceutical Research.

[117]  X. Jiang,et al.  Facile preparation of core-crosslinked micelles from azide-containing thermoresponsive double hydrophilic diblock copolymer via click chemistry , 2008 .

[118]  Isabelle Texier,et al.  Copper-free click chemistry for highly luminescent quantum dot conjugates: application to in vivo metabolic imaging. , 2010, Bioconjugate chemistry.

[119]  J. Nierengarten,et al.  Click chemistry for the efficient preparation of functionalized [60]fullerene hexakis-adducts. , 2008, Chemical communications.

[120]  Duane E. Prasuhn,et al.  Unnatural amino acid incorporation into virus-like particles. , 2008, Bioconjugate chemistry.

[121]  D. A. Fleming,et al.  Triazole Cycloaddition as a General Route for Functionalization of Au Nanoparticles , 2006 .

[122]  M. Finn,et al.  Accelerated bioorthogonal conjugation: a practical method for the ligation of diverse functional molecules to a polyvalent virus scaffold. , 2005, Bioconjugate chemistry.

[123]  Xuesi Chen,et al.  Grafting BSA onto poly[(L-lactide)-co-carbonate] microspheres by click chemistry. , 2008, Macromolecular bioscience.

[124]  Greg M Thurber,et al.  18F labeled nanoparticles for in vivo PET-CT imaging. , 2009, Bioconjugate chemistry.

[125]  B. Sumerlin,et al.  Folate-conjugated thermoresponsive block copolymers: highly efficient conjugation and solution self-assembly. , 2008, Biomacromolecules.

[126]  Jodie L. Conyers,et al.  Biomedical applications of functionalized fullerene-based nanomaterials , 2009, International journal of nanomedicine.

[127]  M. Shoichet,et al.  Immuno-polymeric nanoparticles by Diels-Alder chemistry. , 2007, Angewandte Chemie.

[128]  Carolyn R. Bertozzi,et al.  Copper-free click chemistry for dynamic in vivo imaging , 2007, Proceedings of the National Academy of Sciences.

[129]  Vladimir P. Torchilin,et al.  Liposomes as ‘smart’ pharmaceutical nanocarriers , 2010 .

[130]  J. V. van Hest,et al.  Aza-dibenzocyclooctynes for fast and efficient enzyme PEGylation via copper-free (3+2) cycloaddition. , 2010, Chemical communications.

[131]  Hongkun He,et al.  Clickable Macroinitiator Strategy to Build Amphiphilic Polymer Brushes on Carbon Nanotubes , 2008 .

[132]  Giuseppe Battaglia,et al.  Polymersomes: nature inspired nanometer sized compartments , 2009 .

[133]  Yongsheng Chen,et al.  Covalently β-cyclodextrin modified single-walled carbon nanotubes: a novel artificial receptor synthesized by ‘click’ chemistry , 2008 .

[134]  K. Kataoka,et al.  Block copolymer micelles for drug delivery: design, characterization and biological significance. , 2001, Advanced drug delivery reviews.

[135]  Craig J Hawker,et al.  Cross-linked block copolymer micelles: functional nanostructures of great potential and versatility. , 2006, Chemical Society reviews.

[136]  R. Narain,et al.  Fabrication of two types of shell-cross-linked micelles with "inverted" structures in aqueous solution from schizophrenic water-soluble ABC triblock copolymer via click chemistry. , 2009, Langmuir : the ACS journal of surfaces and colloids.

[137]  Jennifer A. Prescher,et al.  A strain-promoted [3 + 2] azide-alkyne cycloaddition for covalent modification of biomolecules in living systems. , 2004, Journal of the American Chemical Society.

[138]  Jan Grimm,et al.  Drug/dye-loaded, multifunctional iron oxide nanoparticles for combined targeted cancer therapy and dual optical/magnetic resonance imaging. , 2009, Small.

[139]  Philippe Compain,et al.  Glycosidase inhibition with fullerene iminosugar balls: a dramatic multivalent effect. , 2010, Angewandte Chemie.

[140]  Xian‐Zheng Zhang,et al.  Core-shell nanosized assemblies mediated by the alpha-beta cyclodextrin dimer with a tumor-triggered targeting property. , 2010, ACS nano.

[141]  Atsushi Harada,et al.  Formation of Polyion Complex Micelles in an Aqueous Milieu from a Pair of Oppositely-Charged Block Copolymers with Poly(ethylene glycol) Segments , 1995 .

[142]  Partha Sarathi Banerjee,et al.  Chemoselective attachment of small molecule effector functionality to human adenoviruses facilitates gene delivery to cancer cells. , 2010, Journal of the American Chemical Society.

[143]  Robert Langer,et al.  Impact of nanotechnology on drug delivery. , 2009, ACS nano.

[144]  Stephen Z. D. Cheng,et al.  Clicking Fullerene with Polymers : Synthesis of [60]Fullerene End-Capped Polystyrene , 2008 .

[145]  J. Nierengarten,et al.  Sequential copper catalyzed alkyne-azide and thiol-ene click reactions for the multiple functionalization of fullerene hexaadducts. , 2010, Chemical communications.

[146]  S. Nguyen,et al.  High-density doxorubicin-conjugated polymeric nanoparticles via ring-opening metathesis polymerization. , 2005, Chemical communications.

[147]  Leonie Barner,et al.  Surface Modification of Poly(divinylbenzene) Microspheres via Thiol-Ene Chemistry and Alkyne-Azide Click Reactions , 2009 .

[148]  S. Nguyen,et al.  Indomethacin-Containing Nanoparticles Derived from Amphiphilic Polynorbornene: A Model ROMP-Based Drug Encapsulation System , 2004 .

[149]  W. Hennink,et al.  Degradable Multilayer Films and Hollow Capsules via a 'Click' Strategy , 2008 .

[150]  Koichiro Hayashi,et al.  One-Pot Biofunctionalization of Magnetic Nanoparticles via Thiol−Ene Click Reaction for Magnetic Hyperthermia and Magnetic Resonance Imaging , 2010 .

[151]  Carolyn R. Bertozzi,et al.  Second-Generation Difluorinated Cyclooctynes for Copper-Free Click Chemistry , 2008, Journal of the American Chemical Society.

[152]  Cuiping Han,et al.  Triazole-ester modified silver nanoparticles: click synthesis and Cd2+ colorimetric sensing. , 2009, Chemical communications.

[153]  R. Weissleder,et al.  Development of a bioorthogonal and highly efficient conjugation method for quantum dots using tetrazine-norbornene cycloaddition. , 2010, Journal of the American Chemical Society.

[154]  W. Hennink,et al.  Biodegradable microcapsules designed via 'click' chemistry. , 2008, Chemical communications.

[155]  J. Ludden,et al.  Principles and Practice , 1998, Community-based Learning and Social Movements.

[156]  J. Dobson.  Magnetic nanoparticles for drug delivery , 2006 .

[157]  S. Das,et al.  Drug Delivery: Principles and Applications , 2006 .

[158]  R. Riguera,et al.  Synthesis and supramolecular assembly of clicked anionic dendritic polymers into polyion complex micelles. , 2008, Chemical communications.

[159]  A. Kros,et al.  The chemical modification of liposome surfaces via a copper-mediated [3 + 2] azide-alkyne cycloaddition monitored by a colorimetric assay. , 2006, Chemical communications.

[160]  C. Hawker,et al.  Shell click-crosslinked (SCC) nanoparticles: a new methodology for synthesis and orthogonal functionalization. , 2005, Journal of the American Chemical Society.

[161]  Allan S. Hoffman,et al.  The origins and evolution of "controlled" drug delivery systems. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[162]  M. Finn,et al.  Discovery and characterization of catalysts for azide-alkyne cycloaddition by fluorescence quenching. , 2004, Journal of the American Chemical Society.

[163]  C. Mirkin,et al.  Bioluminescent nanosensors for protease detection based upon gold nanoparticle-luciferase conjugates. , 2010, Chemical communications.

[164]  Xuesi Chen,et al.  The immobilization of proteins on biodegradable polymer fibers via click chemistry. , 2008, Biomaterials.

[165]  M. Finn,et al.  Analysis and optimization of copper-catalyzed azide-alkyne cycloaddition for bioconjugation. , 2009, Angewandte Chemie.