胞内触发释药的仿生型siRNA自组装胶束纳米复合物的构建、抗肿瘤转移作用及细胞内药物动力学研究

项目名称： 胞内触发释药的仿生型siRNA自组装胶束纳米复合物的构建、抗肿瘤转移作用及细胞内药物动力学研究

项目编号： No.81202467

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 朱红艳

作者单位： 南通大学

项目金额： 23万元

中文摘要： 病毒是一种天然的核酸药物载体，其细胞外稳定存在，细胞内解组装且动态转染的特点为非病毒基因载体的设计提供了很好的启示。模仿病毒的结构，本项目构建了一种以壳聚糖为基本骨架，精胺和疏水长链辛基为核心、肿瘤靶向肽RGD和融合肽HA2共同修饰的仿生型胶束纳米载体。该载体具备主动靶向、内涵体逃逸、触发释药、长循环、安全稳定等多种性能。并且以靶向VEGF基因的siRNA为模型药物制备仿生型siRNA胶束纳米复合物，期望能解决siRNA在生物体内容易被降解，转染效率低的问题，增强靶向VEGF基因的siRNA抗肿瘤生长和转移的效应。同时本项目还利用量子点独特的光学特点以及荧光共振能量转移的作用，动态监测该复合物在细胞内摄取、分布、释放siRNA的动力学过程。预计本项目的实现将为研发安全高效的siRNA药物传输系统提供一种新的思路，并为细胞内药物动力学研究创立一种快速、准确的新方法。

中文关键词： 胶束；肿瘤靶向；siRNA；壳聚糖；量子点

英文摘要： Viruses are natural masterpieces of nucleic acid drugs with the stable structure outside the cell, disassembly and dynamic process as they enter living cells, which present a good enlightenment for the design of artificial carriers for synthetic nucleic acids such as siRNA. Based on bionic principles, a polymeric micellar system was constructed from degradable chitosan grafted with spermine (SP), Octyl and PEG by the disulfide bond in this project. The virus mimetic shell was conferred by attaching two ligands, i.e., the integrin αvβ3-specific ligand (cRGD) for active cancer targeting and the influenza virus haemagglutinin HA2 for membrane-disruption of endosomes. These structures contain elements that mimic the delivery functions of viral particles and surface domains that shield against undesired biological interactions and enable specific host cell receptor binding through the presentation of targeting ligands cRGD. After internalization by receptor-mediated endocytosis into the acidifying endosomes of cells, synthetic siRNA can escape from these vesicles through the activation of membrane-disruption domains of HA2 as viruses do and reach the cytoplasm, the location of RNA interference. The siRNA against VEGF gene was entrapped into this virus mimetic polymeric micellar system to improve the efficacy of siRNA

英文关键词： micelles；tuomor targetting；siRNA；chitosan；quantum dots