EGF/PAMAM自组装纳米载体介导siRNA沉默MDR1基因逆转肿瘤多药耐药的研究

项目名称： EGF/PAMAM自组装纳米载体介导siRNA沉默MDR1基因逆转肿瘤多药耐药的研究

项目编号： No.31271070

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 郝艳丽

作者单位： 清华大学

项目金额： 80万元

中文摘要： 肿瘤多药耐药（MDR）问题是当前肿瘤治疗药物研究领域中的重大问题。利用RNA干扰等基因治疗方法逆转肿瘤MDR被认为是最有前景的手段，但如何解决RNA给药问题，以实现其体内靶向递送及功能高效表达是目前RNA药物发展中需迫切解决的关键技术及难点。本课题针对肿瘤MDR问题，拟设计一种细胞-基因递次靶向siRNA给药系统。首先以MDR1基因为靶点，设计合成针对MDR1基因不同位点的siRNA，在此基础上为实现siRNA的体内靶向递送，进一步以EGFR为靶点，采用表皮生长因子（EGF）修饰活化的树枝状高分子聚酰胺-胺（PAMAM），设计并构建新型的肿瘤靶向纳米载体，通过此靶向纳米载体介导siRNA沉默目的基因MDR1，达到细胞-基因递次靶向，从而有效逆转EGFR+肿瘤细胞MDR。在此基础上，尝试采用这种靶向纳米载体同时介导针对不同位点的siRNA，探索多靶点基因联合治疗肿瘤MDR的可能及机制。

中文关键词： 肿瘤多药耐药；基因递送；小干扰RNA；树枝状高分子聚酰胺-胺；表皮生长因子受体

英文摘要： Tumor multidrug resistance (MDR) is a serious obstacle to cancer chemotherapy. Currently, drug resistance to chemotherapy is believed to cause failure in over 90% of patients with metastatic cancers. RNA interference (RNAi) represents a promising gene silencing technology for functional genomics and a potential therapeutic strategy for a variety of genetic diseases. However, in the absence of safe and effective carriers for in vivo delivery of small interfering RNAs (siRNAs), application of this technology for therapeutic purposes has lagged behind. The objective of this research is to develop a promising MDR 1-targeted siRNA nano delivery system for effectively reversing EGFR+ tumor MDR. Toward this goal, MDR 1 siRNA based on different target is firstly to be designed and synthesized, and their combined anti-MDR efficiency is also to be studied. Further, a novel self-assembled EGF-dendriplexes by binding negatively charged EGF to activated PAMAM dendrimer-siRNA complex will be designed and prepared. We expect to utilize this EGF/activated PAMAM/siRNA system to silence MDR 1 gene, thus reversing EGRF+ tumor MDR. Moreover, we also expect to study the possibility and mechanism of muti-target gene therapy for reversal of tumor MDR.

英文关键词： tumor multidrug resistance；gene delivery；siRNA；PAMAM；EGFR