超声介导转铁蛋白修饰共载表阿霉素和薯蓣皂苷脂质体微泡复合物双靶向给药系统的构建及其逆转多药耐药研究

项目名称： 超声介导转铁蛋白修饰共载表阿霉素和薯蓣皂苷脂质体微泡复合物双靶向给药系统的构建及其逆转多药耐药研究

项目编号： No.81502992

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 杨晓波

作者单位： 大连医科大学

项目金额： 17.9万元

中文摘要： 多药耐药（MDR）是导致临床化疗失败的主要原因之一，目前认为P-糖蛋白（P-gp）过表达造成抗癌药物外排增加、药效降低，是耐药形成的主要原因。针对P-gp介导的MDR，单纯联合使用抗癌药物与P-gp抑制剂的传统逆转策略，由于逆转耐药效率低、毒副作用大而限制其临床应用。本研究将转铁蛋白-转铁蛋白受体介导的主动靶向释药技术与超声微泡定向释药技术相结合，通过脂质体与微泡的共价连接，首次构建超声介导转铁蛋白修饰的共载表阿霉素（EPI）和薯蓣皂苷脂质体微泡复合物双靶向给药系统，并阐明其逆转人乳腺癌MCF-7/ADR细胞多药耐药的分子作用机制，明确载药系统各组成部分在逆转MCF-7/ADR细胞多药耐药中的作用，旨在从药剂学入手，提高人乳腺癌耐药细胞对EPI的摄取，减少P-gp的外排，增加EPI在肿瘤细胞中的蓄积，力求寻找一种高效、低毒逆转肿瘤细胞多药耐药的新策略，为临床提高EPI肿瘤化疗效果提供依据。

中文关键词： 靶向给药系统；多药耐药；表阿霉素；薯蓣皂苷；脂质体微泡复合物

英文摘要： Multidrug resistance (MDR) is one of the major obstacles to the successful cancer chemotherapy. It is known that MDR is frequently associated with upregulation of the P-glycoprotein (P-gp), an efflux pump that reduces intracellular drug concentration. To overcome MDR, the general strategy has been to co-administer anti-cancer drugs with chemical inhibitors of P-gp. Unfortunately, this approach has not yet reached clinical success due to the complex array of drug toxicity, altered pharmacokinetics and adverse drug interactions. In this study, transferrin-transferrin receptor induced active targeting technology in combination with ultrasound triggered local targeting technology is used for the first time to prepare ultrasound triggered transferrin conjugated epirubicin and dioscin co-loaded dual tumor targeting liposome-microbubble-complexes drug delivery system (Tf-EPI/Dioscin-LMC) by coupling drug containing liposomes to the surface of microbubbles. The purpose of this study is to investigate the effectiveness and possible mechanisms of the reversal of MDR phenotype in human breast cancer MCF-7/ADR cells by using ultrasound triggered Tf-EPI/Dioscin-LMC, and to clarify the ameliorating effects of ultrasound, transferrin, P-gp inhibitor dioscin and microbubbles in overcoming drug resistance as parts of Tf-EPI/Dioscin-LMC drug delivery system. The design of this formulation is aimed at improving cellular uptake of EPI, decreasing cellular efflux of EPI mediated by P-gp，increasing intracellular EPI accumulation, reducing cardiotoxicity of EPI by selective targeting of tumor cells, as well as overcoming P-glycoprotein-mediated MDR phenotype. The aim of this work is to develop and generate a targeted, effective and non-toxic novel strategy to eradicate the presence of MDR in cancer by pharmaceutical approach. This study provides important information to circumvent MDR and to enhance the therapeutic index of the chemotherapy.

英文关键词： targeting drug delivery system;multidrug resistance;epirubicin;dioscin;liposome-microbubble-complex