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

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

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.

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, copoly- mer composition and drug content on self-assembled morphologies were investigated. Simulation results show that the mor- phologies 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 co- polymer 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 PEt~ 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 con- nect 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.