靶向MMPs和肿瘤干细胞CD44受体温敏脂质体的功效与机理研究

项目名称： 靶向MMPs和肿瘤干细胞CD44受体温敏脂质体的功效与机理研究

项目编号： No.81473152

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： 尹莉芳

作者单位： 中国药科大学

项目金额： 70万元

中文摘要： 肿瘤干细胞（CSC）是肿瘤发生和复发的根源（耐药）；CD44在CSC高表达，是杀灭CSC的重要靶点。而肿瘤微环境中的基质金属蛋白酶（MMPs）是降解细胞外基质最为重要的酶类，可以降解细胞外基质，进而促进肿瘤生长、浸润和转移等。本课题利用温敏免疫脂质体同时包载MMPs抑制剂马立马司他（MATT）和透明质酸-紫杉醇前药（HA-PTX），通过热疗作用将两种药物递送于肿瘤部位,靶向于MMPs和肿瘤细胞与CSC 的CD44靶点，获得多靶点联合治疗肿瘤的效果。内容：（1）靶向温敏脂质体构建；（2）抗肿瘤作用评价；（3）协同机制研究。意义：探索新的抗肿瘤策略和新的理论机制。前期研究结果已为本课题打下了良好基础。

中文关键词： 脂质体；肿瘤微环境；肿瘤干细胞；前体药物；靶向给药系统

英文摘要： Cancer stem cells (CSC) with drug-resistance, are the roots of tumor growth and progression, maintenance, metastasis and recurrence.CD44 is highly expressed in CSCs and other cacncer cells, rendering it functions as an importaint target for killing the cells. On the other hand,the matrix metalloproteinases (MMPs) within the tumor microenvironment can degrade the different components of the extracellular matrix, and then promote the tumor progression and metastasis. Thus, combined chemotherapy based on MMPs and CD44 can kill the CSCs and cancer cells efficiently. Herein, we use temperature-sensitive liposomes to co-deliver MMPs inhibitor (marimastat, MATT) and hyaluronic acid-paclitaxel (HA-PTX) prodrug to target site. The two drugs loaded in the liposomes, can be released simultaneously in tumor site after a local heating. The released MATT can function as breaking the microenvironment and then blocking the nutrient supply to the CSC, suppress the CSC proliferation and metastasis; whereas the HA-PTX prodrug target the CD44 marker of CSCs and cancer cells. The work includes: (1)preparation of temperature-sensitive liposomes;(2)evaluation of antitumor function; (3) illustration of incorpation mechanism for synergistic effect. Our work will provede a new strategy and theory mechanism for the cancer cure. The presence of previous results has provided important foundation for the project.

英文关键词： Liposomes;Tumor mircoenvironment;Cancer stem cells;Prodrug;Targeting drug delivery