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

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

Cite this article

Liu Hongyan, Guo Hongyu, Zhou Jian. Computer Simulations on the Anticancer Drug Delivery System of Docetaxel and PLGA-PEG Copolymer[J]. Acta Chimica Sinica, 2012, 70(23): 2445-2450.

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References

[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.)

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