基于纳米胶束的肿瘤治疗和成像一体化的多功能药物传递系统的构建与评价

项目名称： 基于纳米胶束的肿瘤治疗和成像一体化的多功能药物传递系统的构建与评价

项目编号： No.81502996

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： 霍虹

作者单位： 中国医科大学

项目金额： 17.9万元

中文摘要： 肿瘤治疗与诊断一体化是临床中提高肿瘤治愈率急需解决的问题。课题组研究发现miR-302S可以调节乳腺癌耐药蛋白表达，基于聚合物合成的工作基础，为解决肿瘤成像诊断、多药耐药及miRNA体内递送的问题，本研究拟构建共传递miRNA和化疗药物的多功能递送系统。借助Aptamer使系统靶向肿瘤部位，通过pH敏感的腙键控制药物释放，借助生物可降解荧光聚合物使胶束可作为荧光探针。通过制备该传递系统，提高基因药物稳定性，降低化疗药毒性，提高化疗药的抗肿瘤效果并对肿瘤实时诊断成像。通过流式细胞仪、共聚焦显微镜、活体成像仪和western blot等表征手段在体内外验证该传递系统的靶向性、荧光成像诊断、减少化疗药物外排和抑制肿瘤生长的能力，阐明其逆转多药耐药的机制。该多功能传递系统的构建，不仅为建立一种通用性较强的核酸类药物和化疗药物共传递系统奠定了基础，也为基于临床诊断治疗学进行载体设计提供了一个新思路。

中文关键词： 聚合物胶束；肿瘤诊断治疗学；多药耐药；微小RNA；生物成像探针

英文摘要： Multidrug resistance and bioimaging are important problems to be sloved in cancer treatment. Our research team found that miR-302S can directly regulate BCRP expression and reverse chemotherapeutic drug resistance in breast cancer. Given the growing needs for theranostic micelle systems, on the basis of polymer synthesis, we construct a multi-functional drug delivery system for co-delivery of miRNA and chemotherapeutic drugs. With the help of aptamer, pH-responsive hydrazone bond and biodegradable photo-luminescent polymers, this delivery system exhibits tumor-targeting, pH-responsive controlled drug release and imaging abilities. This drug delivery system with high miRNA and chemotherapeutic drugs loading is prepared to improve the stability of miRNA, reduce the toxicity of chemotherapeutic drugs, reduce chemotherapy drug efflux and furthermore enhance the antitumor effect of chemotherapeutic agents. Cytotoxicity assay, flow cytometry, confocal microscopy, in vivo imaging instrument, real-time PCR and western blot are employed to verify the abilities of this delivery to be functioning as an imaging probe, improve intracellular chemotherapeutic drug concentration and then suppress tumor growth. They are also used to clarify the mechanisms of reversing multidrug resistance in vitro and in vivo. The development of this novel multifunctional drug delivery system not only lays a foundation for the universal drug co-delivery system for nucleic acid and chemotherapy drug, but also provides a new approach for targeted cancer theranostics.

英文关键词： polymeric micelles;cancer theranostics;multidrug resistance;miRNA;bioimaging probe