화학공학소재연구정보센터
홈 로그인 로그아웃 연락처 사이트맵
Macromolecular Research, Vol.20, No.3, 292-301, March, 2012
DOI10.1007/s13233-012-0051-0  Export Citation
pH-Responsive Drug Delivery Systems Based on Clickable Poly(L-glutamic acid)-Grafted Comb Copolymers
Jianxun Ding1, 2, Chaoliang He1, 3, Chunsheng Xiao1, 2, Jie Chen1, 3, Xiuli Zhuang1, 3, and Xuesi Chen1, 3, †
  • 1Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
  • 2Graduate University of Chinese Academy of Sciences, Beijing, 100039, P. R. China
  • 3, China
E-mail:
Five pH-responsive alkyne-poly(2-aminoethyl methacrylate)-graft-poly(L-glutamic acid) (alkyne- PAMA-g-PLGA) comb copolymers were synthesized through the ring-opening polymerization (ROP) of γ-benzyl-L-glutamate N-carboxyanhydride (BLG NCA) and the subsequent deprotection of benzyl group from BLG unit. The chemical structures of copolymers were confirmed by proton nuclear magnetic resonance spectra (1H NMR) and Fourier transform infrared spectroscopy (FTIR). The pyrene-probe-based fluorescence technique and transmission electron microscopy (TEM) measurements revealed that the comb copolymers could spontaneously self-assemble into micellar or vesicular nanoparticles in phosphate buffered saline (PBS) at pH 7.4. Doxorubicin (DOX), an anthracycline anticancer drug, was loaded into nanoparticles as a model anticancer drug. The in vitro release results showed that the release behaviors could be altered by adjusting the composition of the comb copolymer and pH of the release medium. In vitro methyl thiazolyl tetrazolium (MTT) assays demonstrated that the copolymers were biocompatible, and DOX-loaded nanoparticles showed effective inhibition of cellular proliferation. Hemolysis tests indicated that the copolymers were also hemocompatible, and that the presence of the copolymers could reduce the hemolysis ratio (HR) of the DOX significantly. In addition, the comb copolymers could be modified through versatile Cu(I)-catalyzed “click chemistry” between the terminal alkyne group and azide-modified functional agents. These properties indicate that the pH-responsive clickable comb copolymers are promising candidates for multifunctional nanocarriers in cancer diagnosis and therapy.
Keywords:comb copolymer;drug delivery;nanoparticle;pH-responsive;polypeptide.
  1. Huynh VT, de Souza P, Stenzel MH, Macromolecules, 44(20), 7888 (2011)
  2. Shen Z, Wei W, Tanaka H, Kohama K, Ma G, Dobashi T, Maki Y, Wang H, Bi J, Dai S, Pharmacol. Res., 64, 410 (2011)
  3. Thambi T, Yoon HY, Kim K, Kwon IC, Yoo CK, Park JH, Bioconjug. Chem., 22, 1924 (2011)
  4. Wang W, Ding JX, Xiao CS, Tang ZH, Li D, Chen J, Zhuang XL, Chen XS, Biomacromolecules, 12(7), 2466 (2011)
  5. Cha EJ, Kim JE, Ahn CH, Macromol. Res., 18(7), 686 (2010)
  6. Han JK, Kim MS, Lee DS, Kim YS, Park RW, Kim KM, Kwon IC, Macromol. Res., 17(2), 99 (2009)
  7. Hwang SJ, Kim MS, Han JK, Lee DS, Kim BS, Choi EK, Park HJ, Kim JS, Macromol. Res., 15(5), 437 (2007)
  8. Cheng J, Ding JX, Wang YC, Wang J, Polymer, 49(22), 4784 (2008)
  9. Chang GT, Li C, Lu WY, Ding JD, Macromol. Biosci., 10, 1248 (2010)
  10. Brown MD, Schatzlein A, Brownlie A, Jack V, Wang W, Tetley L, Gray AI, Uchegbu IF, Bioconjug. Chem., 11, 880 (2000)
  11. Ding JX, Xiao CS, He CL, Li MQ, Li D, Zhuang XL, Chen XS, Nanotechnology., 22, 494012 (2011)
  12. Fukushima S, Miyata K, Nishiyama N, Kanayama N, Yamasaki Y, Kataoka K, J. Am. Chem. Soc., 127(9), 2810 (2005)
  13. Wang W, Ding JX, Xiao CS, Tang ZH, Li D, Chen J, Zhuang XL, Chen XS, Biomacromolecules., 12, 2446 (2011)
  14. Licciardi M, Paolino D, Celia C, Giammona G, Cavallaro G, Fresto M, Biomaterials., 31, 7340 (2010)
  15. Maeng JH, Lee DH, Jung KH, Bae YH, Park IS, Jeong S, Jeon YS, Shim CK, Kim W, Kim J, Lee J, Lee YM, Kim JH, Kim WH, Hong SS, Biomaterials., 31, 4995 (2010)
  16. Shen YQ, Jin EL, Zhang B, Murphy CJ, Sui MH, Zhao J, Wang JQ, Tang JB, Fan MH, Van Kirk E, Murdoch WJ, J. Am. Chem. Soc., 132(12), 4259 (2010)
  17. Smith B, Lyakhov I, Loomis K, Needle D, Baxa U, Yavlovich A, Capala J, Blumenthal R, Puri A, J. Control.Release., 153, 187 (2011)
  18. Ding J, Shi F, Xiao C, Lin L, Chen L, He C, Zhuang X, Chen X, Polym. Chem., 2, 2857 (2011)
  19. Ding J, Zhuang X, Xiao C, Cheng Y, Zhao L, He C, Tang Z, Chen X, J. Mater. Chem., 21, 11383 (2011)
  20. Lee SJ, Min KH, Lee HJ, Koo AN, Rim HP, Jeon BJ, Jeong SY, Heo JS, Lee SC, Biomacromolecules, 12(4), 1224 (2011)
  21. Chen KJ, Chiu YL, Chen YM, Ho YC, Sung HW, Biomaterials., 32, 2586 (2011)
  22. MacEwan SR, Callahan DJ, Chilkoti A, Nanomedicine., 5, 793 (2010)
  23. Thornton PD, Mart RJ, Ulijn RV, Adv. Mater., 19(9), 1252 (2007)
  24. Tang LY, Wang YC, Li Y, Du JZ, Wang J, Bioconjug.Chem., 20, 1095 (2009)
  25. Sanson C, Schatz C, Le Meins JF, Soum A, Thevenot J, Garanger E, Lecommandoux S, J. Control. Release., 147, 428 (2010)
  26. Rodriguez-Hernandez J, Gatti M, Klok HA, Biomacromolecules, 4(2), 249 (2003)
  27. Izunobi JU, Higginbotham CL, J. Mol. Struct., 977, 153 (2010)
  28. Deming TJ, Prog. Polym. Sci., 32, 858 (2007)
  29. Huang YC, Arham M, Jan JS, Soft Matter., 7, 3975 (2011)
  30. Sanson C, Diou O, Thevenot J, Ibarboure E, Soum A, Brulet A, Miraux S, Thiaudiere E, Tan S, Brisson A, Dupuis V, Sandre O, Lecommandoux S, ACS Nano., 5, 1122 (2011)
  31. Cho K, Wang X, Nie S, Chen Z, Shin DM, Clin. Cancer Res., 14, 1310 (2008)
  32. Ding JX, Xiao CS, Zhao L, Cheng YL, Ma LL, Tang ZH, Zhuang XL, Chen XS, J. Polym. Sci. A: Polym. Chem., 49(12), 2665 (2011)
  33. Ding J, Xiao C, Tang Z, Zhuang X, Chen X, Macromol.Biosci., 11, 192 (2011)
  34. Zhao CW, Zhuang XL, He P, Xiao CS, He CL, Sun JR, Chen XS, Jing XB, Polymer, 50(18), 4308 (2009)
  35. Xiao CS, Zhao CW, He P, Tang ZH, Chen XS, Jing XB, Macromol. Rapid Commun., 31(11), 991 (2010)
  36. Jabr Milane L, van Vlerken L, Devalapally H, Shenoy D, Komareddy S, Bhavsar M, Amiji M, J. Control. Release., 130, 121 (2008)
  37. Jabr Milane LS, van Vlerken LE, Yadav S, Amiji MM, Cancer Treat. Rev., 34, 592 (2008)
  38. He LH, Read ES, Armes SP, Adams DJ, Macromolecules, 40(13), 4429 (2007)
  39. Deng C, Rong GZ, Tian HY, Tang ZH, Chen XS, Jing XB, Polymer, 46(3), 653 (2005)
  40. Wei XY, Chen W, Chen XJ, Russell TP, Macromolecules, 43(14), 6234 (2010)
  41. Lin YS, Haynes CL, J. Am. Chem. Soc., 132(13), 4834 (2010)
  42. Xu FJ, Yang WT, Prog. Polym. Sci., 36, 1099 (2011)
  43. Tsarevsky NV, Matyjaszewski K, Chem. Rev., 107(6), 2270 (2007)
  44. Kricheldorf HR, Angew. Chem., Int. Ed., 45, 5752 (2006)
  45. He CL, Zhao CW, Guo XH, Guo ZJ, Chen XS, Zhuang XL, Liu SY, Jing XB, J. Polym. Sci. A: Polym. Chem., 46(12), 4140 (2008)
  46. Wang YC, Li Y, Yang XZ, Yuan YY, Yan LF, Wang J, Macromolecules, 42(8), 3026 (2009)
  47. Sun HL, Guo BN, Li XQ, Cheng R, Meng FH, Liu HY, Zhong ZY, Biomacromolecules, 11(4), 848 (2010)
  48. Wu J, Liu XQ, Wang YC, Wang J, J. Mater. Chem., 19, 7856 (2009)
  49. Upadhyay KK, Bhatt AN, Castro E, Mishra AK, Chuttani K, Dwarakanath BS, Schatz C, Le Meins JF, Misra A, Lecommandoux S, Macromol. Biosci., 10, 503 (2010)
  50. Kim SY, Cho SH, Lee YM, Chu LY, Macromol. Res., 15(7), 646 (2007)
  51. Lee JS, Hwang SJ, Lee DS, Kim SC, Kim DJ, Macromol. Res., 17(2), 72 (2009)
  52. Li L, Huh KM, Lee YK, Kim SY, Macromol. Res., 18(2), 153 (2010)
  53. Du JZ, Sun TM, Song WJ, Wu J, Wang J, Angew.Chem., Int. Ed., 49, 3621 (2010)
  54. Bae Y, Fukushima S, Harada A, Kataoka K, Angew.Chem., Int. Ed., 42, 4640 (2003)
  55. Bae Y, Nishiyama N, Fukushima S, Koyama H, Yasuhiro M, Kataoka K, Bioconjug. Chem., 16, 122 (2005)
  56. Sun HL, Guo BN, Cheng R, Meng FH, Liu HY, Zhong ZY, Biomaterials., 30, 6358 (2009)