高载药率的多重靶向抗肿瘤纳米药物载体研究

项目名称： 高载药率的多重靶向抗肿瘤纳米药物载体研究

项目编号： No.81201179

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 影像医学与生物医学工程

项目作者： 范黎

作者单位： 中国人民解放军第四军医大学

项目金额： 23万元

中文摘要： 化疗药物的非特异性毒性及肿瘤细胞的耐药性等问题已成为当今肿瘤治疗亟待解决的问题。微纳米药物载体载药率普遍较低的现状也成为制约肿瘤靶向治疗的瓶颈。本课题拟采用叶酸和壳聚糖为原料，制备能主动靶向叶酸受体过多的肿瘤细胞，并能灵敏响应肿瘤pH值释药的纳米凝胶系统，同时合成高载药率负电荷纳米金，共转运抗肿瘤药物DOX及其增敏剂PDTC，并通过静电吸附将载药纳米金包裹于纳米凝胶内部。通过NMR、HPLC、透射电镜、体外荧光成像、流式细胞术、Western blot和ICP-MS等手段测定载药纳米凝胶理化性质、定量分析纳米金提高载药率的能力、及验证载体pH响应释药性能，增敏剂促进药物入胞的能力及主动靶向提高药物入胞率等相关生物学特性。本课题整体设计以同时实现提高载药率、主动靶向、智能响应释药，克服阿霉素多药耐药性为最终目的，以期制备出具有高载药率的多重靶向纳米抗肿瘤药物载体。

中文关键词： 高载药率；多重靶向；序贯药物递送；自降解二氧化硅纳米粒；壳聚糖

英文摘要： Existing chemotherapeutic drugs are far from perfect with limitations such as lack of tumor selectivity and intrinsic or acquired drug resistance. At present, low drug loading efficiency of micro/nano drug carriers become a bottleneck of tumor targeted therapy as well. In this study, conjugates folate-chitosan (FA-CS) are synthesized by FA and chitosan to form tumor pHe responsive drug release nanogels. At the same time, PDTC is co-delivered with DOX using synthesized negative charged gold nanoparticles. Drug loaded gold nanoparticles is encapsulated into FA-CS nanogels through electrostatic interaction. Characterization is determined by NMR and UV-Vis spectrum. Size distribution is measured using a laser light scattering technique and transmission electron microscope (TEM) (JEM-2000EX) is also used to determine the size distribution and amorphous of nanogels. The amount of entrapped DOX and PDTC are determined by HPLC. The pH sensitive drug release profile is assayed by HPLC. To validate the choice of Hela folate free cell lines as a positive control overexpressing FR-α, the expression of FR-α is investigated by Western blot. To test the cytotoxicity of FA-CS and further evaluate the role of folate in the cellular uptake of drug loaded FA-CS nanogels, cancer cells are used for MTT assay, Fluorescence Microsc

英文关键词： High payload efficacy；multiple targeting；sequential drug release；self-decomposable SiO2 nanoparticles；chitosan