多功能高分子-姜黄素轭合物混合胶束的微结构调控及抗癌药物组合递送研究

项目名称： 多功能高分子-姜黄素轭合物混合胶束的微结构调控及抗癌药物组合递送研究

项目编号： No.21304068

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 数理科学和化学

项目作者： 赵燕军

作者单位： 天津大学

项目金额： 25万元

中文摘要： 本课题的创新点在于：针对肿瘤化疗的毒副作用和多药耐药问题，利用姜黄素增敏剂的多靶点和多效能特性，设计具有长循环、可降解、主动靶向、可控释放和逆转耐药的纳米胶束组合给药系统。以阿霉素为模型药物，叶酸为靶向分子，分别合成姜黄素、阿霉素和叶酸与高分子(PEG-PLA)的轭合物。利用不同类型轭合物的共同自组装构建系列姜黄素/阿霉素共包载纳米混合胶束，通过轭合物分子内二硫键和腙键实现肿瘤微环境条件下药物的pH/redox应答释放。探讨混合胶束组成、微结构、载体物化和递送性能之间的内在关系；通过细胞摄取、细胞毒性和凋亡实验在细胞水平揭示胶束结构和性能对其生物转运和药效的作用规律；利用蛋白免疫印迹法研究混合胶束特性以及姜黄素/阿霉素剂量比例对阿霉素逆转耐药的影响规律；利用"组合指数"评价姜黄素和阿霉素共递送的协同效应及其剂量比依赖关系。本课题将为环境应答型多功能抗肿瘤纳米给药系统的设计和开发提供新思路。

中文关键词： 胶束；轭合物；靶向；环境应答；姜黄素

英文摘要： Background: The tumor microenvironment is characteristic of the over-expression of certain receptors, vascular abnormalities, low pH in the intracelluar endosome/lysosome and excellular matrix, and the high redox potential in the cytosol and cell nucleus. Chemotherapy has been suffering from the toxic side-effects to the healthy tissues and the multidrug resistance. Curcumin has been reported as a pleiotropic anticancer agent and chemosensitizer because of its ability to interfere with multiple cell signaling pathways including angiogenesis, inflammation, proliferation, metastasis, and apoptosis etc. Hypothesis: It was hypothesized that the co-delivery of curucmin with other anticancer agents (e.g. doxorubicin) in a multifuntional micellar nanocarrier can address the side-effects and multidrug resistance issues of chemotherapy. Purpose: The aim of this study was to generate, evaluate and optimize the multifunctional micelles with the capability of active targeting, dual pH/redox- reponsive drug release, multidrug resistance reversal, and combinational synergism. Materials & Methods: Hydrophilic poly(ethylene glycol) and hydrophobic poly(lactic acid) was linked via the disulfide bond to generate the amphiphilic copolymer. Curcumin was modified with levulinic acid producing two types of curcumin derivatives, whi

英文关键词： Micelle；Conjugate；Targeting；Stimuli-responsive；Curcumin