DOI QR코드

DOI QR Code

Poly(ethylene glycol-block-L-lactide-block-N-isopropylacrylamide) 삼중 블록 공중합체의 합성과 약물 방출성

Synthesis and Drug Release Property of Poly(ethylene glycol-block-L-lactide-block-N-isopropylacrylamide) Triblock Copolymer

  • 정수진 ((주)타우피엔유메디칼) ;
  • 김홍성 (부산대학교 바이오소재과학과)
  • 투고 : 2020.09.28
  • 심사 : 2020.10.11
  • 발행 : 2020.10.31

초록

Herein, novel linear block copolymers have been synthesized for use as a drug-eluting coating material in vascular grafts. Poly(ethylene glycol-block-L-lactide-block-N-isopropylacrylamide) triblock copolymers were prepared by stepwise polymerization from methoxy-terminated polyethylene glycol, i.e., anionic ring-opening polymerization of L-lactide followed by quasi-living polymerization of N-isopropylacrylamide. The chemical structures of the triblock copolymers were analyzed by FT-IR spectroscopy, 1H-NMR spectroscopy, and WAXD. The surface adhesion of triblock copolymers was evaluated for the substrate and model proteins. The drug release behavior of antiproliferative methotrexate was investigated according to the block ratio of the triblock copolymers. Viscosity increased significantly with increasing proportion of poly(N-isopropylacrylamide) block, whereas protein adhesion decreased with decreasing proportion of poly(L-lactide) block. Furthermore, methotrexate release increased with decreasing proportion of poly(L-lactide) block, and both the initial and sustained release increased with increasing proportion of poly(N-isopropyl acrylamide) block. This triblock copolymer can adjust the ratio of blocks to design effective drug release for specific applications.

키워드

과제정보

이 과제는 부산대학교 기본연구지원사업(2년)에 의하여 연구되었음.

참고문헌

  1. G. E. Wnek and G. L. Bowlin, Ed., "Encyclopedia of Biomaterials and Biomedical Engineering", 2nd Ed., Informa Healthcare USA Inc., NY, Vol. 4, 2008, pp.2985-3011.
  2. W. H. Maisel, "Unanswered Questions - Drug-eluting Stents and the Risk of Late Thrombosis", N. Engl. J. Med., 2007, 356, 981-984. https://doi.org/10.1056/NEJMp068305
  3. S.-J. Kang, G. S. Mintz, D.-W. Park, S.-W. Lee, Y.-H. Kim, C. W. Lee, K.-H. Han, J.-J. Kim, S.-W. Park, and S.-J. Park, "Mechanisms of In-stent Restenosis after Drug-eluting Stent Implantation: Intravascular Ultrasound Analysis", Circ. Cardiovasc. Interv., 2011, 4, 9-14. https://doi.org/10.1161/CIRCINTERVENTIONS.110.940320
  4. B. S. Ki, "Drug Eluting Stent and Percutaneous Coronary Intervention", Korean Circ. J., 2003, 33, 857-860. https://doi.org/10.4070/kcj.2003.33.10.857
  5. T. Q. Dinh, R. J. Tuch, and R. S. Schwartz, "Drug Eluting Stent", US Patent, 5,591,227 (1997).
  6. R. Moreno, C. Fernandez, R. Hernandez, F. Alfonso, D. J. Angiolillo, M. Sabate, J. Escaned, C. Banuelos, A. Fernandez-Ortiz, and C. Macaya, "Drug-eluting Stent Thrombosis - Results from a Pooled Analysis Including 10 Randomized Studies", J. Am. Coll. Cardiol., 2008, 45, 954-959. https://doi.org/10.1016/j.jacc.2004.11.065
  7. X. Xu, X. Chen, Z. Wang, and X. Jing, "Ultrafine PEG-PLA Fibers Loaded with Both Paclitaxel and Doxorubicin Hydrochloride and Their in vitro Cytotoxicity", Eur. J. Pharm. Biopharm., 2009, 72, 18-25. https://doi.org/10.1016/j.ejpb.2008.10.015
  8. T. Xi, R. Gao, B. Xu, L. Chen, T. Luo, Y. Wei, and S. Zhong, "In vitro and in vivo Changes to PLGA/sirolimus Coating on DESs", Biomaterials, 2010, 31, 5151-5158. https://doi.org/10.1016/j.biomaterials.2010.02.003
  9. S. K. Hu, Y. L. Mitcho, A. L. Oronsky, and S. S. Kerwar, "Studies on the Effect of Methotrexate on Macrophage Function", J. Rheumatol., 1988, 15, 206-209.
  10. M. Cutolo, A. Sulli, C. Pizzorni, and B. Seriolo, "Anti-inflammatory Mechanisms of Methotrexate in Rheumatoid Arthritis", Ann. Rheum. Dis., 2001, 60, 729-735. https://doi.org/10.1136/ard.60.8.729
  11. M. K. Gupta, J. R. Martin, B. B. Dollinger, M. E. Hattaway, and C. L. Duvall, "Thermogelling, ABC Triblock Copolymer Platform for Resorbable Hydrogels with Tunable, Degradation-mediated Drug Release", Adv. Funct. Mater., 2017, 27, 1704107. https://doi.org/10.1002/adfm.201704107
  12. E. Konishcheva, D. Daubian, J. Gaitzsch, and W. Meier, "Synthesis of Linear ABC Triblock Copolymers and Their Self-assembly in Solution", Helv. Chim. Acta., 2018, 101, e1700287. https://doi.org/10.1002/hlca.201700287
  13. T. Jiang, L. Wang, S. Lin, J. Lin, and Y. Li, "Structural Evoluation of Multicompartment Micelles Self-assembled from Linear ABC Triblock Copolymer in Selective Solvents", Langmuir, 2011, 27, 6440-6448. https://doi.org/10.1021/la201080z
  14. J. Chen, M. Lin, H. Gong, Y. Huang, and C. Chen, "Synthesis and Self-assembly of Thermoresponsive PEG-b-PNIPAM-b-PCL ABC Triblock Copolymer Through the Combination of Atom Transfer Radical Polymerization, Ring-opening Polymerization, and Click Chemistry", J. Fhys. Chem. B, 2011, 115, 14947-14955. https://doi.org/10.1021/jp208494w
  15. M. K. Gupta, J. R. Martin, T. A. Werfel, T. Shen, J. M. Page, and C. L. Duvall, "Cell Protective, ABC Triblock Polymer-based Thermoresponsive Hydrogels with ROS-triggered Degradation and Drug Release", J. Am. Chem. Soc., 2014, 136, 14896-14902. https://doi.org/10.1021/ja507626y
  16. N. H. Hoang, C. Lim, T. Sim, and K. T. Oh, "Triblock Copolymers for Nano-sized Drug Delivery Systems", J. Pharm. Invest., 2017, 47, 27-35. https://doi.org/10.1007/s40005-016-0291-7
  17. F. Vohidov, L. E. Milling, Q. Chen, W. Zhang, S. Bhagchandani, H. V.-T. Nguyen, D. J. Irvine, and J. A. Johnson, "ABC triblock Bottlebrush Copolymer-based Injectable Hydrogels: Design, Synthesis, and Application to Expanding the Therapeutic Index of Cancer Immunochemotherapy", J. Chem. Sci., 2020, 11, 5974-5986. https://doi.org/10.1039/D0SC02611E
  18. H. Otsuka, Y. Nagasaki, and K. Kataoka, "PEGylated Nanoparticles for Biological and Pharmaceutical Applications", Adv. Drug Delivery Rev., 2003, 55, 403-419. https://doi.org/10.1016/S0169-409X(02)00226-0
  19. Y. Le and M. D. Scott, "Immunocamouflage: The Biophysical Basis of Immunoprotection by Grafted Methoxy Poly(ethylene glycol)(mPEG)", Acta Biomaterialia, 2010, 6, 2631-2641. https://doi.org/10.1016/j.actbio.2010.01.031
  20. M. J. Barthel, F. H. Schacher, and U. S. Schubert, "Poly(ethylene oxide)(PEO)-based ABC Triblock Terpolymers - Synthetic Complexity vs. Application Benefits", Polym. Chem., 2014, 5, 2647-2662. https://doi.org/10.1039/c3py01666h
  21. K. Yasugi, Y. Nagasaki, M. Kato, and K. Kataoka, "Preparation and Charaterization of Polymer Micelles from Poly(ethylene glycol)-poly(D,L-lactide) Block Copolymers as Potential Drug Carrier", J. Control. Release, 1999, 62, 89-100. https://doi.org/10.1016/S0168-3659(99)00028-0
  22. J. T. deFaria, A. M. deCampos, and E. L. Senna, "Preparation and Characterization of Poly(D,L-lactide) (PLA) and Poly (D,L-lactide)-poly(ethylene glycol) (PLA-PEG) Nanocapsules Containing Antitumoral Agent Methotrexate", Macromol. Symp., 2005, 229, 228-233.
  23. F. Kohori, K. Sakai, T. Aoyagi, M. Yokoyama, Y. Sakurai, and T. Okano, "Preparation and Characterization of Thermally Responsive Block Copolymer Micelles Comprising Poly(Nisopropylacrylamide-b-DL-lactide)", J. Control. Release, 1998, 55, 87-98. https://doi.org/10.1016/S0168-3659(98)00023-6
  24. R. Plummer, D. J. T. Hill, and A. K. Whittaker, "Solution Properties of Star and Linear Poly(N-isopropyl acrylamide)", Macromolecules, 2006, 39, 8379-8388. https://doi.org/10.1021/ma0614545
  25. Y. Liu, R.-Q. Wei, J. Wei, and X.-N. Liu, "Purification of Lactide by Recrystallization with Alternating Solvents and its Influence on Polymerization", J. Chem. Eng. Chinese Univ., 2008, 22, 1065-1070. https://doi.org/10.3321/j.issn:1003-9015.2008.06.027
  26. Y. You, C. Hong, W. Wang, W. Lu, and C. Pan, "Preparation and Characterization of Thermally Responsive and Biodegradable Block Copolymer Comprised of PNIPAAm and PLA by Combination of ROP and RAFT Method", Macromolecules, 2004, 37, 9761-9767. https://doi.org/10.1021/ma048444t
  27. M. L. Adams, A. Lavasanifar, and G. S. Kwon, "Amphiphilic Block Copolymers for Drug Delivery", J. Pharm. Sci., 2003, 92, 1343-1355. https://doi.org/10.1002/jps.10397
  28. U. V. Singh and N. Udupa, "In vitro Characterization of Methotrexate-Loaded Poly(lactic acid) Microspheres of Different Molecular Weights", Drug Delivery, 1998, 5, 57-61. https://doi.org/10.3109/10717549809052028
  29. S. Manna, A. M. Donnell, N. Kaval, M. F. Al-Rjoub, J. J. Augsburger, and R. K. Banerjee, "Improved Design and Characterization of PLGA/PLA-coated Chitosan Based Micro-implants for Controlled Release of Hydrophilic Drugs", Int. J. Pharm., 2018, 547, 122-132. https://doi.org/10.1016/j.ijpharm.2018.05.066