基于介孔硅胶纳米粒的逆转多药耐药性siRNA/药物共传递体系的构建及其递送机制的研究

项目名称： 基于介孔硅胶纳米粒的逆转多药耐药性siRNA/药物共传递体系的构建及其递送机制的研究

项目编号： No.81473155

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： 吴传斌

作者单位： 中山大学

项目金额： 80万元

中文摘要： 多药耐药是肿瘤化学治疗的最大障碍，也是单纯药物治疗失败的主要原因之一。利用基因与化疗药物的协同作用，可特异性地沉默靶基因，抑制耐药蛋白表达，从而达到更好治疗效果。如何将基因和药物同时递送到肿瘤细胞是其发挥协同效应的关键。传统给药系统往往无法满足体内共传递的要求，因而构建高效共传递系统是目前基因与药物协同治疗迫切需要解决的难题。介孔硅胶纳米粒高度有序的孔道结构能够在理论上确保多种客体分子的装载。前期研究证实，该载体能够递送不同药物分子进入细胞。本项目拟针对肿瘤多药耐药生物学机制，构建基于扩孔介孔硅胶纳米粒的基因（p糖蛋白siRNA）和药物(多西紫杉醇)的共传递体系，保护siRNA的活性，辅助siRNA及药物进入肿瘤细胞发挥基因沉默效应及抗癌作用。并通过荧光标记-亚细胞器定位分析及免疫印迹法，从细胞及分子水平探讨介孔硅胶纳米粒共传递系统的递送机制，为基因与药物共传递系统的研究提供实验依据。

中文关键词： 介孔硅胶纳米粒；共传递；肿瘤；多药耐药；基因载体

英文摘要： The multidrug resistance in cancer cells is the major obstacle for effective cancer chemotherapy. A novel approach for cancer drug resistance is to establish an efficient gene and drug co-delivery system, which provides the opportunity of knocking down genes involved in drug resistance and helping to restore the intracellular drug levels that required for induction of apoptosis and cytotoxicity. However, co-delivery gene and drug to cancer cells for enhanced chemotherapy efficacy has been rarely reported due to the lack of efficient co-delivery techniques. The mesoporous silica nanoparticles (MSNs), which have been widely studied for the medical and biological applications, are showed great potential for guest molecules co-delivery system because of the highly regular mesoporous structure and large pore volume. Different types of MSNs have been successfully prepared and characterized by our research group, and these MSNs were employed as a cancer cell-specific carrier to deliver various model drugs. The purpose of this subject is to develop a siRNA and drug co-delivery system based on pore enlarged MSNs, which would deliver Pgp siRNA as suppressor of pump cellular resistance and docetaxel as model drug simultaneously into cancer cells for synergistic reversal of multidrug resistance. This system may knock down the Pgp gene expression and restore the intracellular drug concentration. In this study, in vivo synergistic inhibition will be tested in a multidrug resistant xenograft model, and the intracellular trafficking will be investigated to demonstrate the cellular internalization and the intracellular release of DTX and siRNA. Moreover, immunoblotting, qPCR analysis, and multiple biopsies will be used to explore the mechanism of the reversal of multidrug resistance. It was expected that this study would solve the clinical problems of chemotherapy failure due to multidrug resistance by utilizing the novel MSNs as efficient co-delivery carriers for drug and gene in vivo applications.

英文关键词： mesoporous silica nanoparticles;co-delivery;cancer;multidrug resistance;gene vector