肿瘤细胞核靶向HPMA聚合物给药系统的研究

To overcome the problem that many anticancer drug couldn't enter into the tumor cell nuclear, a pH-responsive and biodegradable crosslinked micelle system based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer is developed, with the incorporation of intracellularly releasable subcellular targeting group (STG) containing both nuclear targeting ligand and anticancer drug. The cross-linked micelles are expected to protect drugs and remain stable in blood circulation to avoid non-specific distribution in vivo. With the aid of active targeting and enhanced EPR effect, the micelles could accumulate in the tumor tissue and enter into the tumor cells. After endocytosed into the lysosome, the structure of the micelles will collapse in responsive to the lysosomal pH 5~6 and also release the STG subsequently. Then the nuclear targeting ligand could direct the STG to finally localize in nuclear to achieve high therapeutic efficacy delivery with low toxicity. In this study, the synthesis and preparation, biodegradable characteristics and drug release profile of nuclear targeting HPMA copolymer cross-linked micelles will be systemically investigated. The cytotoxicity, nuclear targeting capability and its relative mechanisms, in vivo biodistribution and anticancer efficacy will also be studied in order to provide useful strategy for nuclear-targeting of anti-cancer drugs.

针对目前大多数抗癌药物难以到达肿瘤细胞核发挥疗效的问题，本课题拟通过引入细胞核靶向配体和可特异性释放的含有药物的亚细胞结构靶向基团，构建基于pH敏感和可降解特性的肿瘤细胞核靶向HPMA聚合物交联胶束。该交联胶束可保护治疗药物和细胞核靶向配体在血液中稳定，避免在正常组织的非特异性分布，通过配体介导和EPR效应蓄积于肿瘤组织并被肿瘤细胞摄取后，在溶酶体pH5~6的环境下，胶束解体，暴露的亚细胞结构靶向基团迅速释放，继续通过细胞核靶向配体的介导实现细胞核定位。从而达到提高抗癌药物疗效、减低毒副作用的目的。本课题将系统研究HPMA聚合物交联胶束的制备条件及方法，体外释药规律及降解特性；在此基础上，进一步研究其对肿瘤细胞的毒性、细胞核靶向及作用机理，荷瘤动物体内分布、肿瘤靶向性及药效学。为肿瘤细胞核靶向给药系统的深入研究提供理论依据及新的方法和手段。

针对目前大多数抗癌药物难以到达肿瘤细胞核发挥疗效的问题，本课题成功构建了三种肿瘤细胞核靶向HPMA聚合物给药系统，分别为：pH响应的HPMA聚合物交联胶束；肿瘤微环境程序化响应、级联靶向的HPMA聚合物递药系统；基于高分子HPMA聚合物构建的环境响应性肿瘤靶向递药系统。该三种递药系统可保护治疗药物在血液中稳定，避免在正常组织的非特异性分布，通过配体介导和EPR效应蓄积于肿瘤组织并被肿瘤细胞摄取后，在溶酶体pH5~6的环境下，通过结构变化，暴露的亚细胞结构靶向基团迅速释放，继续通过细胞核靶向配体的介导实现细胞核定位。从而达到提高抗癌药物疗效、减低毒副作用的目的。本课题系统研究了三种递药系统的制备条件及方法，体外释药规律及降解特性；在此基础上，进一步研究了其对肿瘤细胞的毒性、细胞核靶向及作用机理，荷瘤动物体内分布、肿瘤靶向性及药效学。以通讯作者在国际主流刊物Adv. Funct.Mater.(IF 13.325)，Biomaterials (IF 8.806)，J. Control. Release (IF 7.877)，Nanoscale (IF 7.760) , ACS Appl Mater Interfaces (IF 8.097)等本领域权威杂志发表SCI文章19篇，课题负责人入选国家“万人计划”科技创新领军人才、四川省学术技术带头人等，在国内外学术会议进行报告交流7次。培养毕业博士研究生3名，硕士研究生8名。为肿瘤细胞核靶向给药系统的深入研究提供理论依据及新的方法和手段。