具抑制P糖蛋白作用的自组装环糊精修饰载体的构建及其促药物口服吸收研究

项目名称： 具抑制P糖蛋白作用的自组装环糊精修饰载体的构建及其促药物口服吸收研究

项目编号： No.81473173

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 邱利焱

作者单位： 浙江大学

项目金额： 90万元

中文摘要： 针对肠上皮细胞P糖蛋白（P-gp）分布导致其底物类药物口服生物利用度低的问题，拟设计并可控合成系列具有抑制P-gp作用的环糊精修饰的两亲性聚合物；以P-gp高表达的MDCK-MDR1细胞为模型，采用多种分子生物学实验手段，阐明聚合物抑制P-gp的作用机制及构效关系；在此基础上，选择若干P-gp底物为模型药物，构建载药纳米自组装体；研究其生物膜转运机制，揭示载体化学结构、载体性质与药物跨膜转运的内在关系和规律，特别是环糊精修饰的作用，确定载体结构中的关键影响因素；并进一步通过药动及药效学评价，筛选优化载体结构，最终获得能够高效装载药物并促进药物跨膜转运的新型环糊精修饰药物载体及纳米给药系统，为提高药物口服生物利用度提供新思路以及充分的实验依据。

中文关键词： 药物载体；P糖蛋白；环糊精；自组装；口服生物利用度

英文摘要： It is well known that P-glycoprotein (P-gp) located in intestinal epithelium cells often leads to poor oral bioavailability of those drugs as P-gp substrates. With the aim?to overcome this problem, this project will design and synthesize in a controlled manner a series of amphiphilic β-cyclodextrin (β-CD) modified polymers with the capability to inhibit P-gp action. By testing on MDCK-MDR1 cells with high expression of P-gp, the impact of polymer on P-gp activity and its action mechanism will be fully investigated by various molecular biologic methods. Based on these experiments, we will choose some P-gp substrates with poor bioavailability as model drugs and construct drug-loaded self-assembles using some promising polymeric carriers. Then with MDCK-MDR1 monolayer membrane model, the trans-membrane tests will be explored to find out if the polymer can improve drug membrane transport and how it works. Followed by pharmacokinetics and pharmacodynamics studies, some optimized polymers as drug carriers will be finally obtained. The relationship among polymer chemical structure, polymer physicochemical properties and the assistance to drug absorption is expected to be clarified. And the effect of CD modification is emphasized. This project will not also prepare some polymeric carriers but also contribute some new ideas and experimental evidence to how to improve oral bioavailability via nano-scaled self-assembled polymers.

英文关键词： drug carrier;P-gp;cyclodextrin;self-assemble;oral bioavailability