Click Chemistry with Polymers, Dendrimers, and Hydrogels for Drug Delivery

Abstract

During the last decades, great efforts have been devoted to design polymers for reducing the toxicity, increasing the absorption, and improving the release profile of drugs. Advantage has been also taken from the inherent multivalency of polymers and dendrimers for the incorporation of diverse functional molecules of interest in targeting and diagnosis. In addition, polymeric hydrogels with the ability to encapsulate drugs and cells have been developed for drug delivery and tissue engineering applications. In the long road to this successful story, pharmaceutical sciences have been accompanied by parallel advances in synthetic methodologies allowing the preparation of precise polymeric materials with enhanced properties. In this context, the introduction of the click concept by Sharpless and coworkers in 2001 focusing the attention on modularity and orthogonality has greatly benefited polymer synthesis, an area where reaction efficiency and product purity are significantly challenged. The purpose of this Expert Review is to discuss the impact of click chemistry in the preparation and functionalization of polymers, dendrimers, and hydrogels of interest in drug delivery.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Fig. 15
Fig. 16

Abbreviations

AIBN:

azobisisobutyronitrile

ATRP:

atom transfer radical polymerization

bis-MPA:

2,2-bis(hydroxymethyl)propionic acid

BPDS:

bathophenanthroline disulphonated disodium salt

CA:

contrast agent

CL:

caprolactone

ConA:

Concanavalin A

CPT:

camptothecin

CuAAC:

Cu(I)-catalyzed azide-alkyne cycloaddition

DBU:

1,8-diazabicyclo[5.4.0]undec-7-ene

DDS:

drug delivery system

DIPEA:

N,N-diisopropylethylamine

DMPA:

2,2-dimethoxy-2-phenylacetophenone

DOX:

doxorubicin

EPR:

enhanced permeability and retention

GATG:

gallic acid-triethylene glycol

LCST:

lower critical solution temperature

LRP:

living radical polymerization

MAPC:

methacryloyloxyethyl phosphorylcholine

MMP:

matrix metalloproteinase

MRI:

magnetic resonance imaging

MSC:

mesenchymal stem cells

NMP:

N-methyl-2-pyrrolidone

PAMAM:

poly(amido amine)

PEG:

poly(ethylene glycol)

PEI:

poly(ethylene imine)

PEO:

poly(ethylene oxide)

PIC:

polyion complex

PLL:

poly-L-lysine

PMA:

propargyl methacrylate

PMDETA:

N,N,N′,N′,N″-pentamethyldiethylenetriamine

PMMA:

poly(methyl methacrylate)

PNIPAM:

poly(N-isopropylacrylamide)

POEGA:

poly(oligo(ethylene glycol) acrylate)

PPI:

poly(propylene imine)

PS:

poly(styrene)

PVA:

poly(vinyl alcohol)

RAFT:

reversible addition-fragmentation chain transfer

RGD:

Arg-Gly-Asp

ROMP:

ring-opening methathesis polymerization

ROS:

reactive oxygen species

SPAAC:

strain-promoted azide-alkyne cycloaddition

SPR:

surface plasmon resonance

TBTA:

tris(benzyltriazolylmethyl)amine

TEC:

thiol-ene coupling

THPTA:

tris(hydroxypropyltriazolylmethyl)amine

TMS:

trimethylsilyl

TYC:

thiol-yne coupling

References

  1. 1.

    Hoffman AS. The origins and evolution of “controlled” drug delivery systems. J Contr Rel. 2008;132:153–63.

    Article  CAS  Google Scholar 

  2. 2.

    Trost BM. Basic aspects of organic synthesis with transition metals. In (eds.), Wiley-VCH Verlag GmbH, 2008, pp. 2-14

  3. 3.

    Kolb HC, Finn MG, Sharpless KB. Click chemistry: diverse chemical function from a few good reactions. Angew Chem, Int Ed. 2001;40:2004–21.

    Article  CAS  Google Scholar 

  4. 4.

    Wu P, Fokin VV. Catalytic azide-alkyne cycloaddition: Reactivity and applications. Aldrichimica Acta. 2007;40:7–17.

    CAS  Google Scholar 

  5. 5.

    Meldal M, Tornøe CW. Cu-Catalyzed azide-alkyne cycloaddition. Chem Rev. 2008;108:2952–3015.

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Iha RK, Wooley KL, Nyström AM, Burke DJ, Kade MJ, Hawker CJ. Applications of orthogonal “click” chemistries in the synthesis of functional soft materials. Chem Rev. 2009;109:5620–86.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    van Dijk M, Rijkers DTS, Liskamp RMJ, van Nostrum CF, Hennink WE. Synthesis and applications of biomedical and pharmaceutical polymers via click chemistry methodologies. Bioconjugate Chem. 2009;20:2001–16.

    Article  Google Scholar 

  8. 8.

    Lallana E, Sousa-Herves A, Fernandez-Trillo F, Riguera R, Fernandez-Megia E. Click chemistry for drug delivery nanosystems. Pharm. Res. 2012;29:1–34.

    Google Scholar 

  9. 9.

    Tornøe CW, Christensen C, Meldal M. Peptidotriazoles on solid phase: [1,2,3]-Triazoles by regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. J Org Chem. 2002;67:3057–64.

    PubMed  Article  Google Scholar 

  10. 10.

    Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. A stepwise Huisgen cycloaddition process: Copper(I)-catalyzed regioselective “ligation” of azides and terminal alkynes. Angew Chem, Int Ed. 2002;41:2596–9.

    Article  CAS  Google Scholar 

  11. 11.

    Agard NJ, Prescher JA, Bertozzi CR. A strain-promoted [3 + 2] azide-alkyne cycloaddition for covalent modification of biomolecules in living systems. J Am Chem Soc. 2004;126:15046–7.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Lallana E, Riguera R, Fernandez-Megia E. Reliable and efficient procedures for the conjugation of biomolecules through Huisgen azide–alkyne cycloadditions. Angew Chem Int Ed. 2011;50:8794–804.

    Article  CAS  Google Scholar 

  13. 13.

    Kwon GS. Polymeric drug delivery systems. Taylor & Francis, 2005.

  14. 14.

    Barner-Kowollik C, DuPrez FE, Espeel P, Hawker CJ, Junkers T, Schlaad H, et al. “Clicking” polymers or just efficient linking: What is the difference? Angew Chem Int Ed. 2011;50:60–2.

    Article  CAS  Google Scholar 

  15. 15.

    Astruc D, Boisselier E, Ornelas C. Dendrimers designed for functions: From physical, photophysical, and supramolecular properties to applications in sensing, catalysis, molecular electronics, photonics, and nanomedicine. Chem Rev. 2010;110:1857–959.

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Lee CC, MacKay JA, Fréchet JMJ, Szoka FC. Designing dendrimers for biological applications. Nat Biotechnol. 2005;23:1517–26.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Tomalia DA, Baker H, Dewald J, Hall M, Kallos G, Martin S, et al. A new class of polymers: Starburst-dendritic macromolecules. Polym J. 1985;17:117–32.

    Article  CAS  Google Scholar 

  18. 18.

    de Brabander-van den Berg EMM, Meijer EW. Poly(propylene imine) dendrimers: Large-scale synthesis by hetereogeneously catalyzed hydrogenations. Angew Chem, Int Ed. 1993;32:1308–11.

    Article  Google Scholar 

  19. 19.

    Haag R, Sunder A, Stumbe J-F. An approach to glycerol dendrimers and pseudo-dendritic polyglycerols. J Am Chem Soc. 2000;122:2954–5.

    Article  CAS  Google Scholar 

  20. 20.

    Wu P, Feldman AK, Nugent AK, Hawker CJ, Scheel A, Voit B, et al. Efficiency and fidelity in a click-chemistry route to triazole dendrimers by the copper(I)-catalyzed ligation of azides and alkynes. Angew Chem, Int Ed. 2004;43:3928–32.

    Article  CAS  Google Scholar 

  21. 21.

    Hawker CJ, Fréchet JMJ. Preparation of polymers with controlled molecular architecture. A new convergent approach to dendritic macromolecules. J Am Chem Soc. 1990;112:7638–47.

    Article  CAS  Google Scholar 

  22. 22.

    Joralemon MJ, O’Reilly RK, Matson JB, Nugent AK, Hawker CJ, Wooley KL. Dendrimers clicked together divergently. Macromolecules. 2005;38:5436–43.

    Article  CAS  Google Scholar 

  23. 23.

    Wu P, Malkoch M, Hunt JN, Vestberg R, Kaltgrad E, Finn MG, Fokin VV, Sharpless KB, Hawker CJ. Multivalent, bifunctional dendrimers prepared by click chemistry. Chem. Commun. 5775–5777 (2005).

  24. 24.

    Kose MM, Yesilbag G, Sanyal A. Segment block dendrimers via Diels-Alder cycloaddition. Org Lett. 2008;10:2353–6.

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Antoni P, Hed Y, Nordberg A, Nyström D, von Holst H, Hult A, Malkoch M. Bifunctional dendrimers: From robust synthesis and accelerated one-pot postfunctionalization strategy to potential applications. Angew Chem, Int Ed. 2009;48:2126–30.

    Article  CAS  Google Scholar 

  26. 26.

    Killops KL, Campos LM, Hawker CJ. Robust, efficient, and orthogonal synthesis of dendrimers via thiol-ene “click” chemistry. J Am Chem Soc. 2008;130:5062–4.

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Chen G, Kumar J, Gregory A, Stenzel MH. Efficient synthesis of dendrimers via a thiol-yne and esterification process and their potential application in the delivery of platinum anti-cancer drugs. Chem. Commun. 6291–6293 (2009).

  28. 28.

    Kang T, Amir RJ, Khan A, Ohshimizu K, Hunt JN, Sivanandan K, et al. Facile access to internally functionalized dendrimers through efficient and orthogonal click reactions. Chem Commun. 2010;46:1556–8.

    Article  CAS  Google Scholar 

  29. 29.

    Amir RJ, Albertazzi L, Willis J, Khan A, Kang T, Hawker CJ. Multifunctional trackable dendritic scaffolds and delivery agents. Angew Chem Int Ed. 2011;50:3425–9.

    Article  CAS  Google Scholar 

  30. 30.

    Brauge L, Magro G, Caminade AM, Majoral JP. First divergent strategy using two AB2 unprotected monomers for the rapid synthesis of dendrimers. J Am Chem Soc. 2001;123:6698–9.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Maraval V, Caminade AM, Majoral JP, Blais JC. Dendrimer design: How to circumvent the dilemma of a reduction of steps or an increase of function multiplicity? Angew Chem Int Ed. 2003;42:1822–6.

    Article  CAS  Google Scholar 

  32. 32.

    Antoni P, Nyström D, Hawker CJ, Hult A, Malkoch M. A chemoselective approach for the accelerated synthesis of well-defined dendritic architectures. Chem. Commun. 2249–2251 (2007).

  33. 33.

    Vieyres A, Lam T, Gillet R, Franc G, Castonguay A, Kakkar A. Combined CuI-catalysed alkyne-azide cycloaddition and furan-maleimide Diels-Alder “click” chemistry approach to thermoresponsive dendrimers. Chem Commun. 2010;46:1875–7.

    Article  CAS  Google Scholar 

  34. 34.

    Antoni P, Robb MJ, Campos L, Montanez M, Hult A, Malmström E, et al. Pushing the limits for thiol-ene and CuAAC reactions: Synthesis of a 6th generation dendrimer in a single day. Macromolecules. 2010;43:6625–31.

    Article  CAS  Google Scholar 

  35. 35.

    Malkoch M, Schleicher K, Drockenmuller E, Hawker CJ, Russell TP, Wu P, et al. Structurally diverse dendritic libraries: A highly efficient functionalization approach using click chemistry. Macromolecules. 2005;38:3663–78.

    Article  CAS  Google Scholar 

  36. 36.

    Gabius H-J. The sugar code: fundamentals of glycosciences. Weinheim: Wiley-Blackwell; 2009.

    Google Scholar 

  37. 37.

    Imberty A, Chabre YM, Roy R. Glycomimetics and glycodendrimers as high affinity microbial anti-adhesins. Chem Eur J. 2008;14:7490–9.

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Joosten JAF, Tholen NTH, Ait El Maate F, Brouwer AJ, Wilma Van Esse G, Rijkers DTS, et al. High-yielding microwave-assisted synthesis of triazole-linked glycodendrimers by copper-catalyzed [3+2] cycloaddition. Eur J Org Chem. 2005;70:3182–5.

    Article  Google Scholar 

  39. 39.

    Fernandez-Megia E, Correa J, Rodríguez-Meizoso I, Riguera R. A click approach to unprotected glycodendrimers. Macromolecules. 2006;39:2113–20.

    Article  CAS  Google Scholar 

  40. 40.

    Fernandez-Megia E, Correa J, Riguera R. “Clickable” PEG-dendritic block copolymers. Biomacromolecules. 2006;7:3104–11.

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Munoz EM, Correa J, Fernandez-Megia E, Riguera R. Probing the relevance of lectin clustering for the reliable evaluation of multivalent carbohydrate recognition. J Am Chem Soc. 2009;131:17765–7.

    PubMed  Article  Google Scholar 

  42. 42.

    Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2010;10:9–22.

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Rijkers DTS, Van Esse GW, Merkx R, Brouwer AJ, Jacobs HJF, Pieters RJ, Liskamp RMJ. Efficient microwave-assisted synthesis of multivalent dendrimeric peptides using cycloaddition reaction (click) chemistry. Chem. Commun. 4581-4583 (2005).

  44. 44.

    Dijkgraaf I, Rijnders AY, Soede A, Dechesne AC, van Esse GW, Brouwer AJ, et al. Synthesis of DOTA-conjugated multivalent cyclic-RGD peptide dendrimers via 1,3-dipolar cycloaddition and their biological evaluation: Implications for tumor targeting and tumor imaging purposes. Org Biomol Chem. 2007;5:935–44.

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Pieters RJ, Rijkers DTS, Liskamp RMJ. Application of the 1,3-dipolar cycloaddition reaction in chemical biology: Approaches toward multivalent carbohydrates and peptides and peptide-based polymers. QSAR & Combinatorial Science. 2007;26:1181–90.

    Article  CAS  Google Scholar 

  46. 46.

    de Castro S, Maruoka H, Hong K, Kilbey SM, Costanzi S, Hechler B, et al. Functionalized congeners of P2Y1 receptor antagonists: 2-Alkynyl (N)-methanocarba 2′-deoxyadenosine 3′,5′-bisphosphate analogues and conjugation to a polyamidoamine (PAMAM) dendrimer carrier. Bioconjugate Chem. 2010;21:1190–205.

    Article  Google Scholar 

  47. 47.

    Tosh DK, Yoo LS, Chinn M, Hong K, Kilbey II SM, Barrett MO, et al. Polyamidoamine (PAMAM) dendrimer conjugates of “clickable” agonists of the A3 adenosine receptor and coactivation of the P2Y14 receptor by a tethered nucleotide. Bioconjugate Chem. 2010;21:372–84.

    Article  CAS  Google Scholar 

  48. 48.

    Dufès C, Uchegbu IF, Schätzlein AG. Dendrimers in gene delivery. Adv Drug Del Rev. 2005;57:2177–202.

    Article  Google Scholar 

  49. 49.

    Volpi N. Therapeutic applications of glycosaminoglycans. Curr Med Chem. 2006;13(15):1799–810.

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Lee Y, Kataoka K. Biosignal-sensitive polyion complex micelles for the delivery of biopharmaceuticals. Soft Matter. 2009;5:3810–7.

    Article  CAS  Google Scholar 

  51. 51.

    Sousa-Hervés A, Fernandez-Megia E, Riguera R. Synthesis and supramolecular assembly of clicked anionic dendritic polymers into polyion complex micelles. Chem. Commun. 3136–3138 (2008).

  52. 52.

    Weinhart M, Gröger D, Enders S, Dernedde J, Haag R. Synthesis of dendritic polyglycerol anions and their efficiency toward L-selectin inhibition. Biomacromolecules. 2011;12:2502–11.

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Villaraza AJL, Bumb A, Brechbiel MW. Macromolecules, dendrimers, and nanomaterials in magnetic resonance imaging: the interplay between size, function, and pharmacokinetics. Chem Rev. 2010;110:2921–59.

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Fernández-Trillo F, Pacheco-Torres J, Correa J, Ballesteros P, Lopez-Larrubia P, Cerdán S, et al. Dendritic MRI contrast agents: An efficient prelabeling approach based on CuAAC. Biomacromolecules. 2011;12:2902–7.

    PubMed  Article  Google Scholar 

  55. 55.

    Veronese FM, Pasut G. PEGylation, successful approach to drug delivery. Drug Discovery Today. 2005;10:1451–8.

    PubMed  Article  CAS  Google Scholar 

  56. 56.

    Gopin A, Ebner S, Attali B, Shabat D. Enzymatic activation of second-generation dendritic prodrugs: Conjugation of self-immolative dendrimers with poly(ethylene glycol) via click chemistry. Bioconjugate Chem. 2006;17:1432–40.

    Article  CAS  Google Scholar 

  57. 57.

    Amir RJ, Danieli E, Shabat D. Receiver-amplifier, self-immolative dendritic device. Chem Eur J. 2007;13:812–21.

    PubMed  Article  CAS  Google Scholar 

  58. 58.

    Ornelas C, Broichhagen J, Weck M. Strain-promoted alkyne azide cycloaddition for the functionalization of poly(amide)-based dendrons and dendrimers. J Am Chem Soc. 2010;132:3923–31.

    PubMed  Article  CAS  Google Scholar 

  59. 59.

    Lee CC, Gillies ER, Fox ME, Guillaudeu SJ, Fréchet JMJ, Dy EE, et al. A single dose of doxorubicin-functionalized bow-tie dendrimer cures mice bearing C-26 colon carcinomas. Proc Natl Acad Sci USA. 2006;103:16649–54.

    PubMed  Article  CAS  Google Scholar 

  60. 60.

    Calderón M, Graeser R, Kratz F, Haag R. Development of enzymatically cleavable prodrugs derived from dendritic polyglycerol. Bioorg Med Chem Lett. 2009;19:3725–8.

    PubMed  Article  Google Scholar 

  61. 61.

    Diaz DD, Punna S, Holzer P, McPherson AK, Sharpless KB, Fokin VV, et al. Click chemistry in materials synthesis. 1. Adhesive polymers from copper-catalyzed azide-alkyne cycloaddition. J Polym Sci, Part A: Polym Sci. 2004;42:4392–403.

    Article  CAS  Google Scholar 

  62. 62.

    Steenis DJVCv, David ORP, Strijdonck GPFv, Maarseveen JHv, Reek JNH. Click-chemistry as an efficient synthetic tool for the preparation of novel conjugated polymers. Chem. Commun. 4333–4335 (2005).

  63. 63.

    Angelo NG, Arora PS. Nonpeptidic foldamers from amino acids: synthesis and characterization of 1,3-substituted triazole oligomers. J Am Chem Soc. 2005;127:17134–5.

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    Angell YL, Burgess K. Peptidomimetics via copper-catalyzed azide-alkyne cycloadditions. Chem Soc Rev. 2007;36:1674–89.

    PubMed  Article  CAS  Google Scholar 

  65. 65.

    Srinivasachari S, Liu Y, Zhang G, Prevette L, Reineke TM. Trehalose click polymers inhibit nanoparticle aggregation and promote pDNA delivery in serum. J Am Chem Soc. 2006;128:8176–84.

    PubMed  Article  CAS  Google Scholar 

  66. 66.

    Srinivasachari S, Liu Y, Prevette LE, Reineke TM. Effects of trehalose click polymer length on pDNA complex stability and delivery efficacy. Biomaterials. 2007;28:2885–98.

    PubMed  Article  CAS  Google Scholar 

  67. 67.

    Srinivasachari S, Reineke TM. Versatile supramolecular pDNA vehicles via “click polymerization” of β-cyclodextrin with oligoethyleneamines. Biomaterials. 2009;30:928–38.

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Prevette LE, Lynch ML, Kizjakina K, Reineke TM. Correlation of amine number and pDNA binding mechanism for trehalose-based polycations. Langmuir. 2008;24:8090–101.

    PubMed  Article  CAS  Google Scholar 

  69. 69.

    Barua S, Joshi A, Banerjee A, Matthews D, Sharfstein ST, Cramer SM, et al. Parallel synthesis and screening of polymers for non-viral gene delivery. Mol Pharmaceutics. 2008;6:86–97.

    Article  Google Scholar 

  70. 70.

    Binder WH, Kluger C. Combining ring-opening metathesis polymerization (ROMP) with Sharpless-type ‘click’ reactions: An easy method for the preparation of side chain functionalized poly(oxynorbornenes). Macromolecules. 2004;37:9321–30.

    Article  CAS  Google Scholar 

  71. 71.

    Parrish B, Breitenkamp RB, Emrick T. PEG- and peptide-grafted aliphatic polyesters by click chemistry. J Am Chem Soc. 2005;127:7404–10.

    PubMed  Article  CAS  Google Scholar 

  72. 72.

    Sumerlin BS, Tsarevsky NV, Louche G, Lee RY, Matyjaszewski K. Highly efficient “click” functionalization of poly(3-azidopropyl methacrylate) prepared by ATRP. Macromolecules. 2005;38:7540–5.

    Article  CAS  Google Scholar 

  73. 73.

    Ladmiral V, Mantovani G, Clarkson GJ, Cauet S, Irwin JL, Haddleton DM. Synthesis of neoglycopolymers by a combination of “click chemistry” and living radical polymerization. J Am Chem Soc. 2006;128:4823–30.

    PubMed  Article  CAS  Google Scholar 

  74. 74.

    Zhang X, Lian X, Liu L, Zhang J, Zhao H. Synthesis of comb copolymers with pendant chromophore groups based on RAFT polymerization and click chemistry and formation of electron donor-acceptor supramolecules. Macromolecules. 2008;41:7863–9.

    Article  CAS  Google Scholar 

  75. 75.

    Zhang W, Zhang W, Zhang Z, Zhu J, Zhu X. SET-RAFT polymerization of progargyl methacrylate and a one-pot/one-step preparation of side-chain functionalized polymers via combination of SET-RAFT and click chemistry. Macromol Rapid Commun. 2010;31:1354–8.

    PubMed  Article  CAS  Google Scholar 

  76. 76.

    Geng J, Lindqvist J, Mantovani G, Haddleton DM. Simultaneous copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) and living radical polymerization. Angew Chem, Int Ed. 2008;47:4180–3.

    Article  CAS  Google Scholar 

  77. 77.

    Chen X, McRae S, Parelkar S, Emrick T. Polymeric phosphorylcholine-camptothecin conjugates prepared by controlled free radical polymerization and click chemistry. Bioconjugate Chem. 2009;20:2331–41.

    Article  CAS  Google Scholar 

  78. 78.

    Mather BD, Viswanathan K, Miller KM, Long TE. Michael addition reactions in macromolecular design for emerging technologies. Prog Polym Sci. 2006;31:487–531.

    Article  CAS  Google Scholar 

  79. 79.

    Ulbrich K, Subr V. Polymeric anticancer drugs with pH-controlled activation. Adv Drug Del Rev. 2004;56:1023–50.

    Article  CAS  Google Scholar 

  80. 80.

    Gress A, Volkel A, Schlaad H. Thio-click modification of poly[2-(3-butenyl)-2-oxazoline]. Macromolecules. 2007;40:7928–33.

    Article  CAS  Google Scholar 

  81. 81.

    Malkoch M, Thibault RJ, Drockenmuller E, Messerschmidt M, Voit B, Russell TP, et al. Orthogonal approaches to the simultaneous and cascade functionalization of macromolecules using click chemistry. J Am Chem Soc. 2005;127:14942–9.

    PubMed  Article  CAS  Google Scholar 

  82. 82.

    Yang SK, Weck M. Modular covalent multifunctionalization of copolymers. Macromolecules. 2007;40:346–51.

    Google Scholar 

  83. 83.

    Taton D, Gnanou Y. Guidelines for synthesizing block copolymers. In (eds.), Wiley-VCH Verlag GmbH & Co., 2008, pp. 9–38

  84. 84.

    Opsteen JA, van Hest JCM. Modular synthesis of block copolymers via cycloaddition of terminal azide and alkyne functionalized polymers. Chem. Commun. 57–59 (2005).

  85. 85.

    Quémener D, Davis TP, Barner-Kowollik C, Stenzel MH. RAFT and click chemistry: A versatile approach to well-defined block copolymers. Chem. Commun. 5051–5053 (2006).

  86. 86.

    Agut W, Taton D, Lecommandoux S. A versatile synthetic approach to polypeptide based rod-coil block copolymers by click chemistry. Macromolecules. 2007;40:5653–61.

    Article  CAS  Google Scholar 

  87. 87.

    Lutz JF, Börner HG, Weichenhan K. Combining ATRP and “click” chemistry: A promising platform toward functional biocompatible polymers and polymer bioconjugates. Macromolecules. 2006;39:6376–83.

    Article  CAS  Google Scholar 

  88. 88.

    Narumi A, Fuchise K, Kakuchi R, Toda A, Satoh T, Kawaguchi S, et al. A versatile method for adjusting thermoresponsivity: Synthesis and “click” reaction of an azido end-functionalized poly(N-isopropylacrylamide). Macromol Rapid Commun. 2008;29:1126–33.

    Article  CAS  Google Scholar 

  89. 89.

    Campos LM, Killops KL, Sakai R, Paulusse JMJ, Damiron D, Drockenmuller E, et al. Development of thermal and photochemical strategies for thiol-ene click polymer functionalization. Macromolecules. 2008;41:7063–70.

    Article  CAS  Google Scholar 

  90. 90.

    Yu B, Chan JW, Hoyle CE, Lowe AB. Sequential thiol-ene/thiol-ene and thiol-ene/thiol-yne reactions as a route to well-defined mono and bis end-functionalized poly(N-isopropylacrylamide). J Polym Sci, Part A: Polym Sci. 2009;47:3544–57.

    Article  CAS  Google Scholar 

  91. 91.

    Durmaz H, Dag A, Altintas O, Erdogan T, Hizal G, Tunca U. One-pot synthesis of ABC type triblock copolymers via in situ click [3+2] and Diels-Alder [4+2] reactions. Macromolecules. 2007;40:191–8.

    Article  CAS  Google Scholar 

  92. 92.

    Gungor E, Hizal G, Tunca U. One-pot double click reactions for the preparation of H-shaped ABCDE-type quintopolymer. J Polym Sci, Part A: Polym Sci. 2009;47:3409–18.

    Article  CAS  Google Scholar 

  93. 93.

    Nasongkla N, Chen B, Macaraeg N, Fox ME, Fréchet JMJ, Szoka FC. Dependence of pharmacokinetics and biodistribution on polymer architecture: Effect of cyclic versus linear polymers. J Am Chem Soc. 2009;131:3842–3.

    PubMed  Article  CAS  Google Scholar 

  94. 94.

    Tsarevsky NV, Sumerlin BS, Matyjaszewski K. Step-growth “click” coupling of telechelic polymers prepared by atom transfer radical polymerization. Macromolecules. 2005;38:3558–61.

    Article  CAS  Google Scholar 

  95. 95.

    Laurent BA, Grayson SM. An efficient route to well-defined macrocyclic polymers via “click” cyclization. J Am Chem Soc. 2006;128:4238–9.

    PubMed  Article  CAS  Google Scholar 

  96. 96.

    Lonsdale DE, Bell CA, Monteiro MJ. Strategy for rapid and high-purity monocyclic polymers by CuAAC “click” reactions. Macromolecules. 2010;43:3331–9.

    Article  CAS  Google Scholar 

  97. 97.

    Ge Z, Zhou Y, Xu J, Liu H, Chen D, Liu S. High-efficiency preparation of macrocyclic diblock copolymers via selective click reaction in micellar media. J Am Chem Soc. 2009;131:1628–9.

    PubMed  Article  CAS  Google Scholar 

  98. 98.

    Hoare TR, Kohane DS. Hydrogels in drug delivery: Progress and challenges. Polymer. 2008;49:1993–2007.

    Article  CAS  Google Scholar 

  99. 99.

    Elbert DL, Pratt AB, Lutolf MP, Halstenberg S, Hubbell JA. Protein delivery from materials formed by self-selective conjugate addition reactions. J Contr Rel. 2001;76:11–25.

    Article  CAS  Google Scholar 

  100. 100.

    Lei Y, Segura T. DNA delivery from matrix metalloproteinase degradable poly(ethylene glycol) hydrogels to mouse cloned mesenchymal stem cells. Biomaterials. 2009;30:254–65.

    PubMed  Article  CAS  Google Scholar 

  101. 101.

    Brochu ABW, Craig SL, Reichert WM. Self-healing biomaterials. J Biomed Mater Res, Part A. 2011;96A:492–506.

    Article  CAS  Google Scholar 

  102. 102.

    Chujo Y, Sada K, Saegusa T. Reversible gelation of polyoxazoline by means of Diels-Alder reaction. Macromolecules. 1990;23:2636–41.

    Article  CAS  Google Scholar 

  103. 103.

    Wei H-L, Yang Z, Zheng L-M, Shen Y-M. Thermosensitive hydrogels synthesized by fast Diels-Alder reaction in water. Polymer. 2009;50:2836–40.

    Article  CAS  Google Scholar 

  104. 104.

    Ossipov DA, Hilborn J. Poly(vinyl alcohol)-based hydrogels formed by “click chemistry”. Macromolecules. 2006;39:1709–18.

    Article  CAS  Google Scholar 

  105. 105.

    Malkoch M, Vestberg R, Gupta N, Mespouille L, Dubois P, Mason AF, Hedrick JL, Liao Q, Frank CW, Kingsbury K, Hawker CJ. Synthesis of well-defined hydrogel networks using click chemistry. Chem. Commun. 2774–2776 (2006).

  106. 106.

    Crescenzi V, Cornelio L, Di Meo C, Nardecchia S, Lamanna R. Novel hydrogels via click chemistry: Synthesis and potential biomedical applications. Biomacromolecules. 2007;8:1844–50.

    PubMed  Article  CAS  Google Scholar 

  107. 107.

    Testa G, Di Meo C, Nardecchia S, Capitani D, Mannina L, Lamanna R, et al. Influence of dialkyne structure on the properties of new click-gels based on hyaluronic acid. Int J Pharm. 2009;378:86–92.

    PubMed  Article  CAS  Google Scholar 

  108. 108.

    Johnson JA, Baskin JM, Bertozzi CR, Koberstein JT, Turro NJ. Copper-free click chemistry for the in situ crosslinking of photodegradable star polymers. Chem. Commun. 3064–3066 (2008).

  109. 109.

    Johnson JA, Lewis DR, Diaz DD, Finn MG, Koberstein JT, Turro NJ. Synthesis of degradable model networks via ATRP and click chemistry. J Am Chem Soc. 2006;128:6564–5.

    PubMed  Article  CAS  Google Scholar 

  110. 110.

    Johnson JA, Finn MG, Koberstein JT, Turro NJ. Synthesis of photocleavable linear macromonomers by ATRP and star macromonomers by a tandem ATRP-click reaction: Precursors to photodegradable model networks. Macromolecules. 2007;40:3589–98.

    Article  CAS  Google Scholar 

  111. 111.

    DeForest CA, Polizzotti BD, Anseth KS. Sequential click reactions for synthesizing and patterning three-dimensional cell microenvironments. Nat Mater. 2009;8:659–64.

    PubMed  Article  CAS  Google Scholar 

  112. 112.

    DeForest CA, Sims EA, Anseth KS. Peptide-functionalized click hydrogels with independently tunable mechanics and chemical functionality for 3D cell culture. Chem Mat. 2010;22:4783–90.

    Article  CAS  Google Scholar 

Download references

Acknowledgments & DISCLOSURES

This work was financially supported by the Spanish Ministry of Science and Innovation (CTQ2009-10963 and CTQ2009-14146-C02-02) and the Xunta de Galicia (10CSA209021PR and CN2011/037).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Eduardo Fernandez-Megia.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lallana, E., Fernandez-Trillo, F., Sousa-Herves, A. et al. Click Chemistry with Polymers, Dendrimers, and Hydrogels for Drug Delivery. Pharm Res 29, 902–921 (2012). https://doi.org/10.1007/s11095-012-0683-y

Download citation

Key Words

  • click chemistry
  • dendrimer
  • drug delivery
  • hydrogel
  • polymer