SIOC English
化学学报
高级检索

化学学报 >

2012 , Vol. 70 >Issue 23: 2445 - 2450

DOI: https://doi.org/10.6023/A12080496

研究论文

PLGA-PEG共聚物负载多西紫杉醇的药物输运体系的计算机模拟

  • 刘红艳 ,
  • 郭泓雨 ,
  • 周健
展开
  • 华南理工大学化学与化工学院 广东省绿色化学产品技术重点实验室 广州 510640

收稿日期: 2012-08-03

  网络出版日期: 2012-10-25

基金资助

项目受教育部新世纪优秀人才支持计划(No. NCET-07-0313);国家自然科学基金(No. 20876052)及广东省自然科学基金(No. S2011010002078)资助.

收起

Computer Simulations on the Anticancer Drug Delivery System of Docetaxel and PLGA-PEG Copolymer

  • Liu Hongyan ,
  • Guo Hongyu ,
  • Zhou Jian
Expand
  • School of Chemistry and Chemical Engineering, Guangdong Provincial Key Lab for Green Chemical Product Technology, South China University of Technology, Guangzhou 510640

Received date: 2012-08-03

  Online published: 2012-10-25

Supported by

Project supported by Program for New Century Excellent Talents in Universities, Ministry of Education, China (No. NCET-07-0313), National Natural Science Foundation of China (No. 20876052) and Guangdong Natural Science Foundation (No. S2011010002078).

Fold

摘要

采用耗散粒子动力学模拟的方法研究了抗癌药物输运体系多西紫杉醇与聚乙丙交酯与聚乙二醇的共聚物(PLGA-PEG)的自组装形态, 考察了共聚物浓度、共聚物组成和药物含量等对自组装形态的影响. 模拟结果表明, 不同浓度的PLGA-PEG能够和多西紫杉醇自组装成球状、柱状、层状等结构; 一定的浓度下, 亲水的PEG嵌段将疏水的PLGA嵌段包裹起来形成核壳结构, 可用于疏水药物输运应用. 在比较低的浓度下, 不同组成的PLGA-PEG均会形成球状核壳结构, PEG嵌段较多时壳层较厚核尺寸较小, PLGA嵌段较多时核的尺寸较大但壳层较薄, 综合考虑载药量和稳定性, 模拟结果中PEG嵌段的摩尔分数为60%即PLGA40-PEG60作为载体时性能较佳. 药物的含量对自组装结构也有影响, 药物含量较小时形成球状结构, 药物含量较大时, 则会形成柱状结构. 对PLGA40-PEG60体系, 模拟结果显示药物、聚合物和水的最佳配比为5:10:90. 本工作可为共聚物载药体系的设计与开发提供参考.

关键词： 药物输运体系; 计算机模拟; 自组装; 嵌段共聚物; 核壳结构

本文引用格式

刘红艳 , 郭泓雨 , 周健 . PLGA-PEG共聚物负载多西紫杉醇的药物输运体系的计算机模拟[J]. 化学学报, 2012 , 70(23) : 2445 -2450 . DOI: 10.6023/A12080496

Abstract

Molecular dynamics (MD) and dissipative particle dynamics (DPD) simulations were integrated to study the morphologies of the drug delivery system self-assembled by amphiphilic block copolymer poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-PEG) and anticancer drug docetaxel. In this work, the solubility parameters used in DPD simulations were calculated by MD simulations. In DPD simulations, the effects of copolymer concentration, copolymer composition and drug content on self-assembled morphologies were investigated. Simulation results show that the morphologies self-assembled by PLGA-PEG and docetaxel (Dtx) undergo the transition from spherical to cylindrical and finally to lamellar micelles when increasing the copolymer concentration from 10% to 50% while maintaining the mass ratio of copolymer to drug as 5:1. In all cases, core-shell structures were obtained with the hydrophobic PLGA as the core and the hydrophilic PEG as the shell. It is found that PLGA-PEG copolymer with the composition of PEG block ranging from 10% to 90% (the total number of the blocks of PLGA-PEG is kept as 100) self-assembles into spherical core-shell structures in aqueous solutions without drug when the copolymer concentration is 10%. When the mole fraction of PEG in PLGA-PEG copolymer is less than 20%, PEG is unable to pack PLGA completely. With the increase of mole fraction of PEG, the PEG shell becomes thicker and the size of the core becomes smaller. In order to moderate the micelle’s drug loading efficiency (a small PLGA core will load small amount of hydrophobic anticancer drug Dtx) and stability (a thin PEG shell may make the core-shell micelle unstable), PLGA-PEG copolymer with the molar ratio of PEG to PLGA as 40:60 is considered to be the best drug carrier candidate. Besides, the simulation results show that the content of drugs also affects the self-assembled structure. When the drug content is under a certain value, spherical core-shell structures are gained and the size of them grows up with the increase of the drug content. When the drug content is above that value, the spherical structures will connect each other to form cylindrical structures. Considering the advantage of spherical core-shell structures in drug delivery, the optimal mass ratio of docetaxel, PLGA40-PEG60 copolymer and water is 5:10:90. This work is expected to provide some guidance for the design and development of drug delivery systems.

Key words： drug delivery system; computer simulation; self-assembly; block copolymer; core-shell structure

参考文献

[1] Immordino, M. L.; Brusa, P.; Arpicco, S.; Stella, B.; Dosio, F.; Cattel, L. J. Controlled Release 2003, 91(3), 417.
[2] Yang, Y.; Wang, J.-C.; Zhang, X.; Lu, W.-L.; Zhang, Q. J. Controlled Release 2009, 135(2), 175.
[3] Straubinger, R. M.; Balasubramanian, S. V. Methods in Enzymology, Vol. 391, 2005, p. 97.
[4] Chen, Y.; Zhao, Y.; Liu, Q.-Q.; Zou, J. China Pharmacy 2011, 22(2), 130. (陈瑶, 赵银, 刘青青, 邹俊, 中国药房, 2011, 22(2), 130.)
[5] Gaucher, G.; Dufresne, M. H.; Sant, V. P.; Kang, N.; Maysinger, D.; Leroux, J. C. J. Controlled Release 2005, 109(1-3), 169.
[6] Yu, S.-F.; Gu, X.; Wu, G.-L.; Wang, Z.; Wang, Y.-N.; Gao, H.; Ma, J.-B. Acta Chim. Sinica 2012, 70(2), 177. (于树芳, 顾鑫, 伍国琳, 王铮, 王亦农, 高辉, 马建标, 化学学报, 2012, 70(2), 177.)
[7] Zheng, X.-L.; Ding, A.-S.; Luo, D.; Gao, H.-S. Acta Chim. Sinica 2012, 70(1), 92. (郑兴良, 丁爱顺, 罗丹, 高鸿盛, 化学学报, 2012, 70(1), 92.).
[8] Yang, Z.-L.; Li, X.-R.; Yang, K.-W.; Liu, Y. Acta Chim. Sinica 2007, 65(19), 2169. (杨卓理, 李馨汝, 杨可伟, 刘艳, 化学学报, 2007, 65(19), 2169.)
[9] Mao, J.; Gan, Z.-H. Chem. J. Chin. Univ. 2009, 30(11), 2291. (毛静, 甘志华, 高等学校化学学报, 2009, 30(11), 2291.).
[10] Tran, V. T.; Karam, J. P.; Garric, X.; Coudane, J.; Benoit, J. P.; Montero-Menei, C. N.; Venier-Julienne, M. C. Eur. J. Pharm. Sci. 2012, 45(1-2), 128.
[11] Vey, E.; Rodger, C.; Meehan, L.; Booth, J.; Claybourn, M.; Miller, A. F.; Saiani, A. Polym. Degrad. Stab. 2012, 97(3), 358.
[12] Alconcel, S. N. S.; Baas, A. S.; Maynard, H. D. Polym. Chem. 2011, 2(7), 1442.
[13] Menz, B.; Knerr, R.; Gopferich, A.; Steinem, C. Biomaterials 2005, 26(20), 4237.
[14] Bluemmel, J.; Perschmann, N.; Aydin, D.; Drinjakovic, J.; Surrey, T.; Lopez-Garcia, M.; Kessler, H.; Spatz, J. P. Biomaterials 2007, 28(32), 4739.
[15] Xie, Y.; Liu, M.-F.; Zhou, J. Appl. Surf. Sci. 2012, 258(20), 8153.
[16] Gref, R.; Minamitake, Y.; Peracchia, M. T.; Trubetskoy, V.; Torchilin, V.; Langer, R. Science 1994, 263(5153), 1600.
[17] Ukawala, M.; Rajyaguru, T.; Chaudhari, K.; Manjappa, A. S.; Pimple, S.; Babbar, A. K.; Mathur, R.; Mishra, A. K.; Murthy, R. S. R. Drug Delivery 2012, 19(3), 155.
[18] Mothe, C. G.; Azevedo, A. D.; Drumond, W. S.; Wang, S. H.; Sinisterra, R. D. J. Therm. Anal. Calorim. 2011, 106(3), 671.
[19] Li, T.-H.; Han, R.-Y.; Wang, M.-Z.; Liu, C.-B.; Jing, X.-B.; Huang, Y.-B. Macromol. Biosci. 2011, 11(11), 1570.
[20] Zhang, W.-L.; Li, Y.-L.; Liu, L.-X.; Sun, Q.-Q.; Shuai, X.-T.; Zhu, W.; Chen, Y.-M. Biomacromolecules 2010, 11(5), 1331.
[21] Jain, R. A. Biomaterials 2000, 21(23), 2475.
[22] Veronese, F. M.; Pasut, G. Drug Discovery Today 2005, 10(21), 1451.
[23] Mallarde, D.; Boutignon, F.; Moine, F.; Barre, E.; David, S.; Touchet, H.; Ferruti, P.; Deghenghi, R. Int. J. Pharm. 2003, 261(1-2), 69.
[24] Davaran, S.; Rashidi, M. R.; Pourabbas, B.; Dadashzadeh, M.; Haghshenas, N. M. Int. J. Nanomed. 2006, 1(4), 535.
[25] Mo, S. M.; Oh, I. J. J. Nanosci. Nanotechnol. 2011, 11(2), 1795.
[26] Pamujula, S.; Hazari, S.; Bolden, G.; Graves, R. A.; Chinta, D. D.; Dash, S.; Kishore, V.; Mandal, T. K. J. Pharm. Pharmacol. 2012, 64(1), 61.
[27] Ashjari, M.; Khoee, S.; Mahdavian, A. R.; Rahmatolahzadeh, R. J. Mater. Sci.: Mater. Med. 2012, 23(4), 943.
[28] Liu, H.-L.; Hu, Y. CIESC J. 2003, 54(4), 440. (刘洪来, 胡英, 化工学报, 2003, 54(4), 440.)
[29] Feng, J.; Liu, H.-L.; Hu, Y. J. Nanjing Univ. Technol. 2005, 27(2), 105. (冯剑, 刘洪来, 胡英, 南京工业大学学报, 2005, 27(2), 105.)
[30] Xia, J.; Zhong, C.-L. Macromol. Rapid Commun. 2006, 27, 1110.
[31] Zhong, C.-L.; Liu, D.-H. Macromol. Theory Simul. 2007, 16, 141.
[32] Liu, D.-H.; Zhong, C.-L. Polymer 2008, 49(5), 1407.
[33] Xin, J.; Liu, D.-H.; Zhong, C.-L. J. Phys. Chem. B 2009, 113(28), 9364.
[34] Feng, J.; Ge, X.-T.; Shang, Y.-Z.; Zhou, L.-H.; Liu, H.-L.; Hu, Y. Fluid Phase Equilib. 2011, 302, 26.
[35] Guo, H.-Y.; Cui, J.-M.; Sun, D.-L.; Zhou, J. CIESC J. 2012, 11, 3707. (郭泓雨, 崔洁铭, 孙德林, 周健, 化工学报, 2012, 11, 3707.)
[36] Guo, X.-D.; Zhang, L.-J.; Qian, Y.; Zhou, J. Chem. Eng. J. 2007, 131, 195.
[37] Posocco, P.; Fermeglia, M.; Pricl, S. J. Mater. Chem. 2010, 20, 7742.
[38] Rodriguez-Hidalgo, M. D. R.; Soto-Figueroa, C.; Vicente, L. Soft Matter 2011, 7, 8224.
[39] Masoud, H.; Alexeev, A. ACS Nano 2012, 6, 212.
[40] Groot, R. D.; Warren, P. B. J. Chem. Phys. 1997, 107(11), 4423.
[41] Groot, R. D.; Madden, T. J. J. Chem. Phys. 1998, 108(20), 8713.
[42] Groot, R. D.; Rabone, K. L. Biophys. J. 2001, 81(2), 725.
[43] Maiti, A.; McGrother, S. J. Chem. Phys. 2004, 120(3), 1594.
[44] Sun, D.-L.; Zhou, J. Acta Phys.-Chim. Sin. 2012, 28(4), 909. (孙德林, 周健, 物理化学学报, 2012, 28(4), 909.)
[45] Zhuang, Q.-X.; Xue, Z.-J.; Liu, X.-Y.; Yuan, Y.-L.; Han, Z.-W. Polym. Compos. 2011, 32(10), 1671.
[46] Zhao, Y.; You, L.-Y.; Lu, Z.-Y.; Sun, C.-C. Polymer 2009, 50(22), 5333.
[47] Xie, X.-A.; Ding, N.-P.; Liu, H.-B.; Zheng, L.-S.; Xiong, M.-Z. Acta Chim. Sinica 2011, 69(2), 169. (解新安, 丁年平, 刘焕彬, 郑璐丝, 熊明洲, 化学学报, 2011, 69(2), 169.)
[48] Fan, B.-Y.; Fan, Y.-L.; Hu, S.-J.; Sun, L.; Li, M.; Li, Q.; Ji, Y.-B. Chin. Pharm. J. 2011, 46, 1220. (范兵羽, 范玉玲, 胡淑娟, 孙黎, 李淼, 李强, 季宇彬, 中国药学杂志, 2011, 46, 1220.)
Options
文章导航

/

〈 〉