pH响应双聚合物混合载药胶束的设计、制备与构性关系研究

With the pH difference between tumor cells and normal tissue cells in human body, the pH-responsive polymer micelles for anti-cancer drug delivery have drawn lots of focus in the field of drug controlled release. Although some achievements have been obtained, there are still some deficiencies of performance existing in drug-loading efficiency or in drug controlled release. How to make the drug-loading micelles pH-responsive intelligently and eliminate drug burst release, how to improve the drug-loading efficiency are the two major problems needed to be overcome. In this work, to instruct the structure design and preparation of the pH-sensitive drug-loading micelles formed by MPEG-PEAEMA and MPEG-PCL mixed polymers, the DPD mesoscopic molecular simulation is employed. To improve the drug-loading efficiency, mixed micelles formed by double polymers are used by expanded the interior space, and the liquid-liquid equilibria of polymer-hydrophobic drugs-solvent- water and their multiple phase diagrams are investigated to obtain the optimum formula of the drug-loading mixed micelles formed by the double polymers. On this basis, the study on the relationship of the molecular microstructure of polymers, mesoscopic structure of the drug-loading micelles and macroscopic properties of drug-loading efficiency and drug controlled release might provide some general methods for the design and preparation of new polymer materials used in drug controlled release. The investigation of this work are expected to achieve some improvement or breakthrough in the drug-loading efficiency of the pH-responsive drug-loading polymer micelles, which might provide the technical and theoretical fundamental to improve the treatment effects and reduce the drug side effects for the new drug delivery system.

基于肿瘤细胞与人体正常组织细胞pH值的差异，pH响应聚合物胶束对抗癌药物的输送是当前药物控释领域的研究热点之一。如何实现聚合物载体的pH靶向响应并消除药物突释，如何提高载药效率，是目前该领域急需解决的问题。本项目拟运用DPD介观模拟与实验研究相结合的方法，通过采用双聚合物混合胶束以扩大胶束内部载药空间的方式，设计合成出一种pH响应性能优越、载药效率高的双聚合物混合载药胶束。并通过对聚合物-疏水性药物-溶剂-水多元物系相平衡关系的研究，获取有效提高胶束载药量的方法。在此基础上，研究聚合物分子微观结构、胶束介观结构和宏观载药、控释性能之间的构性关系，并提出依据目标需求，设计和调控载药聚合物材料的分子结构和胶束结构的系统方法。其研究成果可望在聚合物胶束载药量和载药效率方面取得进展或突破，为提高疾病治疗效果、降低药物毒副作用的新型药物传输体系的开发和临床应用提供技术和理论基础。

有效提高药物疗效、降低毒副作用一直是人类抗击疾病特别是癌症不懈努力的目标。聚合物载药胶束在降低药物毒性、增加疏水药物溶解性和提高药物生物利用度方面具有独特优势，是目前药物递送系统的研究热点之一。尽管聚合物载药胶束作为载药体系的研究已取得巨大进展，但在药物包载和控释性能方面还存在不足。本项目运用DPD分子介观模拟技术和实验研究结合的方法，在满足载药胶束药物控释性能的基础上，采用双聚合物混合胶束的方式，设计合成了MPEG-b-PAE-b-PLA、MPEG-PCL、MPEG-PDEAEMA、PCL-PPEGMA、PDEAEMA-PPEGMA、PCL-SS-PPEGMA、PEG-SS-PCL和FA-PEG-PDEAEMA等两亲性聚合物分子，并将其或其混合物胶束应用于包载广谱抗癌药物阿霉素，以寻求获得靶向响应性能优越、载药量和药物包封率高、可生物降解、无毒性的纳米混合聚合物载药胶束，以解决纳米载药胶束释放性能不足、载药量和药物包封率不高的问题。结果发现双聚合混合载药胶束体系MPEG-PCL/ MPEG-PDEAEMA、PCL-PPEGMA/PDEAEMA-PPEGMA比单聚合物载药胶束体系MPEG-b-PAE-b-PLA的载药性能明显提高；MPEG-PDEAEMA/MPEG-PCL混合载药胶束pH响应性能良好，载药量和药物包封率可达27%和63%；PDEAEMA-PPEGMA/PCL-PPEGMA混合载药胶束，载药量可保持在30%左右，CMC值可降至1.58mg/L，胶束稳定性进一步提高，pH 7.4时药物释放量进一步降低，24小时释放量约7%，药物控释性能得到有效改善。而为进一步改善载药胶束药物控释性能而设计的PCL-SS-PPEGMA /PDEAEMA-PPEGMA，PEG-SS-PCL/FA-PEG-PDEAEMA混合载药胶束，具有pH和还原双重响应，细胞毒性试验表明，以上pH/还原双重响应的混合聚合物载药胶束体系，抗肿瘤效果明显优于pH单响应的体系。在此基础上，本项目通过DPD模拟计算结果，结合实验实测数据，对聚合物分子微观结构、胶束介观结构和宏观载药和控释性能之间的构性关系进行研究，从而总结依据目标需求，设计和调控载药聚合物材料分子结构和胶束结构的系统方法，为提高疾病治疗效果、降低药物毒副作用的新型药物传输体系的开发和临床应用提供技术和理论基础。