新型多功能紫杉醇pluronic/PEG-PHIS混合胶束的构建及其逆转多药耐药的机制研究

Lung cancer is a common malignancy with the higher mortality rate. There are poor efficacy and toxicity for lung cancer treatment due to the lower selectivity of traditional chemotherapy drugs and multidrug resistance phenomenon.We build a variety of tumor-targeting drug delivery system including polyethylene glycol as the carrier, and unsaturated fatty acids or folate for the targeted groups with good anti-tumor activity in vitro and in vivo. Preliminary study suggested that a stable, efficient endocytosis, the intracellular burst release, the reversal of multidrug resistance is the key to drug delivery systems construction. In our current projects, a new type of mixed paclitaxel nano-micelles with PEG-(poly-histidine)/ P123 block copolymer modified with high affinity anti-EGFR single chain antibody will be synthesized with stabilized, pH-response, active targeting, reversal multi-drug resistant. The effect of above micelles on lung cancer will be evaluated in vitro and in vivo to explore the underlying mechanism of reversal multi-drug resistant.This study will provide the experimental basis and theoretical guidance for the design of the small molecule chemotherapy targeted drug delivery system to solve the current difficulties faced by the lung cancer chemotherapy, and improve the survival and living quality of lung cancer patients, and provides a new idea for the chemical treatment of lung cancer.

肺癌是常见的恶性肿瘤，死亡率极高，传统化疗药物因选择性低、易产生多药耐药现象，导致疗效不佳、毒副作用明显。我们前期以聚乙二醇为载体，以不饱和脂肪酸、叶酸等为靶向基团构建了多种肿瘤靶向递药系统，体内外试验均证实具有良好抗肿瘤活性，提示稳定、高效入胞、胞内突释、逆转多药耐药是构建递药系统的关键。本课题拟选用普罗流尼P123为载体材料，经抗EGFR单链抗体修饰后与具有酸敏特性的聚乙二醇/聚组氨酸嵌段共聚物(PEG-PHIS)混合，包裹紫杉醇自组装得到稳定、pH响应、主动靶向、逆转多药耐药的新型多功能紫杉醇混合胶束。体内外试验评价该胶束对肺癌的治疗作用，探讨胶束逆转多药耐药的相关分子机制和途径。本研究为小分子化疗药物靶向递药系统的设计提供了实验依据和理论指导，有望解决目前肺癌化疗面临的困境，提高肺癌患者的存活率和生存质量，为肺癌的化学治疗提供了新思路和新途径。