Year 2018, Volume 5 , Issue 3, Pages 1327 - 1336 2018-09-01

In situ Crosslinkable Thiol-ene Hydrogels Based on PEGylated Chitosan and β-Cyclodextrin

Mehmet ARSLAN [1] , Tolga YİRMİBESOGLU [2] , Mithat CELEBİ [3]


Novel β-Cyclodextrin incorporated injectable hydrogels employing PEGylated chitosan as bio-based hydrophilic matrix have been fabricated via thiol-ene reaction. As thiol bearing polymer counterpart of hydrogel precursors, native chitosan was firstly modified with polyethylene glycol groups to increase its water solubility and bioinertness and then decorated with thiol groups to facilitate thiol-ene crosslinking with acryloyl-modified β-cyclodextrin. A series of hydrogels with varying amounts of acryloyl β-CD and PEGylated chitosan feed were synthesized with high efficiency under mild aqueous conditions. The resulting hydrogels were characterized by equilibrium swelling, structural morphology and rheology. These materials were investigated as controlled drug release platforms by employing a poorly water soluble anti-inflammatory drug diclofenac as model compound. Benefiting from the inclusion complex formation of the drug with β-CD groups in gel interior, prolonged release profiles were maintained. The total drug absorption and release of hydrogels were shown to be dependent on the amount of β-CD in gel matrix. These hydrogels combined efficient crosslinking and β-CD incorporation into clinically important chitosan scaffold and might have potential applications as injectable drug reservoirs such as in regenerative tissue engineering.  

Drug releasing hydrogels, β-cyclodextrin, thiol-ene crosslinking, injectable gels
  • 1. Yang JA, Yeom J, Hwang BW, Hoffman AS, Hahn SK. In situ-forming injectable hydrogels for regenerative medicine. Progress in Polymer Science. 2014; 39(12): 1973-86.
  • 2. Drury JL, Mooney DJ. Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials. 2003; 24(24): 4337-51.
  • 3. Hunt JA, Chen R, Van Veen T, Bryan N. Hydrogels for tissue engineering and regenerative medicine. Journal of Materials Chemistry B. 2014; 2: 5319-38.
  • 4. Vermonden T, Censi R, Hennink WE. Hydrogels for protein delivery. Chemical Reviews. 2012; 112 (5): 2853–88.
  • 5. Yu F, Cao X, Li Y, Zeng L, Yuanab B, Chen X. An injectable hyaluronic acid/PEG hydrogel for cartilage tissue engineering formed by integrating enzymatic crosslinking and Diels–Alder “click chemistry”. Polymer Chemistry. 2014; 5: 1082-90.
  • 6. Takahashi A, Suzuki Y, Suhara T, Omichi K, Shimizu A, Hasegawa K, Kokudo N, Ohta S, Ito T. In situ cross-linkable hydrogel of hyaluronan produced via copper-free click chemistry. Biomacromolecules. 2013; 14(10): 3581-8.
  • 7. Ahadian S, Sadeghian RB, Salehi S, Ostrovidov S, Bae H, Ramalingam M, Khademhosseini A. Bioconjugated hydrogels for tissue engineering and regenerative medicine. Bioconjugate Chemistry. 2015; 26(10): 1984-01.
  • 8. Sivashanmugam A, Arun Kumar R, Vishnu Priya M, Nair S V., Jayakumar R. An overview of injectable polymeric hydrogels for tissue engineering. European Polymer Journal. 2015; 72: 543-65.
  • 9. Yan S, Wang T, Feng L, Zhu J, Zhang K, Chen X, Cui L, Yin J. Injectable in situ self-cross-linking hydrogels based on poly(l-glutamic acid) and alginate for cartilage tissue engineering. Biomacromolecules. 2014; 15(12): 4495-08.
  • 10. Xiao ZS, Ahmad S, Liu Y, Prestwich GD. Synthesis and evaluation of injectable, in situ crosslinkable synthetic extracellular matrices for tissue engineering. Journal of Biomedical Materials Research Part A. 2006; 79(4): 902-12. 11. Cai S, Liu Y, Zheng Shu X, Prestwich GD. Injectable glycosaminoglycan hydrogels for controlled release of human basic fibroblast growth factor. Biomaterials. 2005; 26(30): 6054-67.
  • 12. Tiller JC. Increasing the local concentration of drugs by hydrogel formation. Angewandte Chemie-International Edition. 2003; 42(27): 3072-75.
  • 13. Paul A, Hasan A, Kindi H Al, Gaharwar AK, Rao VTS, Nikkhah M, Shin SR, Krafft D, Dokmeci MR, Shum-Tim D, Khademhosseini A. Injectable graphene oxide/hydrogel-based angiogenic gene delivery system for vasculogenesis and cardiac repair. ACS Nano. 2014; 8(8): 8050-62. 14. Seliktar D. Designing cell-compatible hydrogels for biomedical applications. Science. 2012; 336(6085): 1124-8.
  • 15. Dash M, Chiellini F, Ottenbrite RM, Chiellini E. Chitosan- A versatile semi-synthetic polymer in biomedical applications. Progress in Polymer Science. 2011; 36(8): 981-14.
  • 16. Rinaudo M. Chitin and chitosan: Properties and applications. Progress in Polymer Science. 2006; 31(7): 603-32.
  • 17. Bhattarai N, Gunn J, Zhang M. Chitosan-based hydrogels for controlled, localized drug delivery. Advanced Drug Delivery Reviews. 2010; 62(1): 83-99.
  • 18. Ta HT, Dass CR, Dunstan DE. Injectable chitosan hydrogels for localised cancer therapy. Journal of Controlled Release. 2008;126(3): 205-16.
  • 19. Bhattarai N, Ramay HR, Gunn J, Matsen FA, Zhang M. PEG-grafted chitosan as an injectable thermosensitive hydrogel for sustained protein release. Journal of Controlled Release. 2005; 103(3): 609-24.
  • 20. Jin R, Moreira Teixeira LS, Dijkstra PJ, Karperien M, van Blitterswijk CA, Zhong ZY, Feijen J. Injectable chitosan-based hydrogels for cartilage tissue engineering. Biomaterials. 2009; 30(13): 2544-51.
  • 21. Sashiwa H, Aiba SI. Chemically modified chitin and chitosan as biomaterials. Progress in Polymer Science. 2004; 29(9): 887-08.
  • 22. Casettari L, Vllasaliu D, Castagnino E, Stolnik S, Howdle S, Illum L. PEGylated chitosan derivatives: Synthesis, characterizations and pharmaceutical applications. Progress in Polymer Science. 2012; 37(5): 659-85.
  • 23. Aydin D, Arslan M, Sanyal A, Sanyal R. Hooked on cryogels: A carbamate linker based depot for slow drug release. Bioconjugate Chemistry. 2017; 28(5): 1443-51.
  • 24. Van De Manakker F, Vermonden T, Van Nostrum CF, Hennink WE. Cyclodextrin-based polymeric materials: Synthesis, properties, and pharmaceutical/biomedical applications. Biomacromolecules. 2009; 10(12): 3157-75.
  • 25. Li J, Loh XJ. Cyclodextrin-based supramolecular architectures: Syntheses, structures, and applications for drug and gene delivery. Advanced Drug Delivery Reviews. 2008; 60(9): 1000-17.
  • 26. Arslan M, Gevrek TN, Sanyal A, Sanyal R. Cyclodextrin mediated polymer coupling via thiol-maleimide conjugation: Facile access to functionalizable hydrogels. RSC Advances. 2014; 4: 57834-41.
  • 27. Arslan M, Aydin D, Degirmenci A, Sanyal A, Sanyal R. Embedding well-defined responsive hydrogels with nanocontainers: Tunable materials from telechelic polymers and cyclodextrins. ACS Omega. 2017; 2(10): 6658-67.
  • 28. Arslan M, Gevrek TN, Sanyal R, Sanyal A. Fabrication of poly(ethylene glycol)-based cyclodextrin containing hydrogels via thiol-ene click reaction. European Polymer Journal. 2015; 62: 426-34.
  • 29. Arslan M, Sanyal R, Sanyal A. Cyclodextrin-containing hydrogel networks. In: Mishra M, editor. Encyclopedia of Biomedical Polymers and Polymeric Biomaterials. Taylor and Francis: New York; 2015. p.  2243-58. Available from: https://www.taylorfrancis.com/books/e/9781466501799/chapters/10.1081%2FE-EBPP-120050543
  • 30. Gevrek, TN, Arslan, M, Sanyal, A. Design and synthesis of maleimide group containing polymeric materials via the Diels‐Alder/Retro Diels‐Alder strategy. In: Theato P and Klok H, editors. Functional Polymers by Post‐Polymerization Modification. Wiley‐VCH Verlag GmbH & Co.; 2013. p. 123-55. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/9783527655427.ch5
  • 31. Arslan, M, Gevrek, TN, Sanyal, A. Maleimide containing thiol-reactive polymers: Synthesis and functionalization. In. Shunmugam R, editor. Functional Polymers. Apple Academic Press: New York; 2017. Ch. 7. Available from: https://www.taylorfrancis.com/books/e/9781771882972/chapters/10.1201%2F9781315366524-17
  • 32. Arslan M, Tasdelen MA. Polymer nanocomposites via click chemistry reactions. Polymers. 2017; 9(10): 499.
  • 33. Arslan M, Gok O, Sanyal R, Sanyal A. Clickable poly(ethylene glycol)-based copolymers using azide-alkyne click cycloaddition-mediated step-growth polymerization. Macromolecular Chemistry and Physics. 2014; 215(22): 2237-47.
  • 34. Oz Y, Arslan M, Gevrek TN, Sanyal R, Sanyal A. Modular fabrication of polymer brush coated magnetic nanoparticles: Engineering the interface for targeted cellular imaging. ACS Applied Materials ans Interfaces. 2016; 8(30): 19813-26.
  • 35. Arslan M, Gevrek TN, Lyskawa J, Szunerits S, Boukherroub R, Sanyal R, Woisel P, Sanyal A. Bioinspired anchorable thiol-reactive polymers: Synthesis and applications toward surface functionalization of magnetic nanoparticles. Macromolecules. 2014; 47(15): 5124-34.
  • 36. Yilmaz II, Arslan M, Sanyal A. Design and synthesis of novel “orthogonally” functionalizable maleimide-based styrenic copolymers. Macromolecular Rapid Communications. 2012; 33(9): 856-62.
  • 37. Hoyle CE, Bowman CN. Thiol-ene click chemistry. Angewandte Chemie-International Edition. 2010; 49(9): 1540-73.
  • 38. Kharkar PM, Rehmann MS, Skeens KM, Maverakis E, Kloxin AM. Thiol-ene click hydrogels for therapeutic delivery. ACS Biomaterials Science and Engineering. 2016; 2(2): 165-79.
  • 39. Wang FP, Li, GF, Zhou QQ, Yang CX, Wang QZ. Removal of metal ions from aqueous solution with cyclodextrin-based hydrogels. 2016; 6(5): 394-02.
  • 40. Nishimura SI, Kohgo O, Kurita K, Kuzuhara H. Chemospecific manipulations of a rigid polysaccharide: Syntheses of novel chitosan derivatives with excellent solubility in common organic solvents by regioselective chemical modifications. Macromolecules. 1991; 24(17): 4745-48.
  • 41. Bentzen EL, Tomlinson ID, Mason J, Gresch P, Warnement MR, Wright D, Sanders-Bush E, Blakely R, Rosenthal SJ. Surface modification to reduce nonspecific binding of quantum dots in live cell assays. Bioconjugate Chemistry. 2005; 16(6): 1488-94.
  • 42. Sharpe JC, Mitchell JS, Lin L, Sedoglavich N, Blaikie RJ. Gold nanohole array substrates as immunobiosensors. Analiytcal Chemistry. 2008; 80(6): 2244–49.
  • 43. Ellman GL. Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics. 1959; 82(1): 70-77.
  • 44. Riddles PW, Blakeley RL, Zerner B. Reassessment of Ellman’s reagent. Methods in Enzymology. 1983; 91: 49-60.
  • 45. Kono H, Teshirogi T. Cyclodextrin-grafted chitosan hydrogels for controlled drug delivery. Int. J. Biol. Macromol. 72, 299-308 (2015).
  • 46. Dong ZQ, Cao Y, Yuan QJ, Wang YF, Li JH, Li BJ, Zhang S. Redox- and glucose-induced shape-memory polymers. Macromol. Rapid Commun. 34, 867–872 (2013).
  • 47. Siemoneit U, Schmitt C, Alvarez-Lorenzo C, Luzardo A, Otero-Espinar F, Concheiro A, Blanco-Méndez J. Acrylic/cyclodextrin hydrogels with enhanced drug loading and sustained release capability. International Journal of Pharmaceutics. 2006; 312(1-2): 66-74.
  • 48. Li R, Zhang X, Zhang Q, Liu H, Rong J, Tu M, Zeng R, Zhao J. b-cyclodextrin-conjugated hyaluronan hydrogel as a potential drug sustained delivery carrier for wound healing. Inc. J. Appl. Polym. Sci. 133, 43072 (2016).
  • 49. Jin R, Moreira Teixeira LS, Dijkstra PJ, Karperien M, van Blitterswijk CA, Zhong ZY, vd. Injectable chitosan-based hydrogels for cartilage tissue engineering. Biomaterials. May 2009;30(13):2544-51.
  • 50. Andrade-Vivero P, Fernandez-Gabriel E, Alvarez-Lorenzo C, Concheiro A. Improving the loading and release of NSAIDs from pHEMA hydrogels by copolymerization with functionalized monomers. Journal of Pharmaceutical Sciences. 2007; 96(4): 802-13.
  • 51. Das S, Subuddhi U. Studies on the complexation of diclofenac sodium with β-cyclodextrin: Influence of method of preparation. Journal of Molecular Structure. 2015; 1099: 482-89.
  • 52. Xu J, Li X, Sun F. Cyclodextrin-containing hydrogels for contact lenses as a platform for drug incorporation and release. Acta Biomaterialia. 2010; 6(2): 486-93.
Primary Language en
Subjects Engineering, Chemical
Published Date Fall
Journal Section Articles
Authors

Orcid: 0000-0003-3355-4045
Author: Mehmet ARSLAN (Primary Author)
Institution: YALOVA UNIVERSITY
Country: Turkey


Author: Tolga YİRMİBESOGLU
Institution: YALOVA UNIVERSITY

Author: Mithat CELEBİ
Institution: YALOVA UNIVERSITY

Dates

Application Date : September 15, 2018
Acceptance Date : November 22, 2018
Publication Date : September 1, 2018

Vancouver Arslan M , Yi̇rmi̇besoglu T , Celebi̇ M . In situ Crosslinkable Thiol-ene Hydrogels Based on PEGylated Chitosan and β-Cyclodextrin. Journal of the Turkish Chemical Society Section A: Chemistry. 2018; 1327-1336.