基于碳酸氢钠酸触发反应的pH响应聚合物纳米粒的构建及其克服肿瘤多药耐药性研究

项目名称： 基于碳酸氢钠酸触发反应的pH响应聚合物纳米粒的构建及其克服肿瘤多药耐药性研究

项目编号： No.31300789

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 盛燕

作者单位： 烟台大学

项目金额： 26万元

中文摘要： 多药耐药性是导致肿瘤化疗失败的重要原因，其主要形成机制为肿瘤细胞表面P-糖蛋白过表达所致药物外排增加。本项目基于肿瘤细胞酸性特征和碳酸氢钠的酸触发反应以及聚乙二醇1000维生素E琥珀酸酯(TPGS)对P-糖蛋白的抑制作用，设计并构建了具有克服多药耐药性的新型pH响应聚合物纳米粒。以可生物降解聚乳酸羟基乙酸共聚物-TPGS共聚物为载体材料，采用复乳法制备同时包埋抗癌药物多柔比星和 pH 响应分子碳酸氢钠的纳米粒。通过体外细胞摄取和细胞毒性、细胞内药物释放、体内药效学等实验系统研究纳米粒逆转多药耐药性的基本规律和机制。探讨碳酸氢钠浓度依赖性的pH响应释药新模式，明确TPGS修饰对细胞摄取的提高作用，揭示抑制P-糖蛋白外排的细胞摄取和 pH 响应细胞内药物快速释放的协同作用效应。研究将为克服肿瘤耐药、提高化疗效果的药物载体设计提供理论与实践基础，为pH响应药物释放领域的研究提供新思路和新手段。

中文关键词： pH响应；碳酸氢钠；聚合物纳米粒；多药耐药性；药物输送

英文摘要： Multidrug resistance (MDR) is one of the main obstacles to effective cancer chemotherapy. The most common mechanism of MDR has been correlated with the overexpression of P-glycoprotein (P-gp), leading to the efflux of many anticancer drugs with consequent drug insensitivity. According to acidic organelles of cancer cell, acid-triggered chemical reaction of sodium bicarbonate (NaHCO3) and P-gp inhibition by D-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS), novel pH-responsive polymeric nanoparticles (NPs) for overcoming MDR are designed and established in this project. To achieve this, biodegradable poly(lactic-co-glycolic acid)-TPGS copolymer is chosen as the carrier material, and an anticancer drug doxorubicin with pH-responsive molecule NaHCO3 are readily incorporated into NPs together by the double emulsion method. In vitro cytotoxicity and cellular uptake, intracellular drug release and in vivo anticancer activity against drug-sensitive and drug-resistant cancer cells are extensively evaluated to explore the fundamental law and mechanism of these NPs in the reversion of MDR. A novel NaHCO3-concentration-dependent, pH-responsive drug release pattern is developed. The enhanced effect of TPGS modification on the cellular uptake efficiency is determined. A combinatorial effect of P-gp-inhibited cellula

英文关键词： pH-responsive；sodium bicarbonate；polymeric nanoparticles；multidrug resistance；drug delivery