多功能生物可降解聚膦腈药物载体的合成及其肿瘤靶向性研究

The design and structural fabrication of micelles for drug polymer compounds with controlled drug release and tumour targeting functions has been paid much attention in the field of cancer therapy. In this project, the amphiphilic polyphosphazene copolymers will be designed and synthesized.The copolymers are composed of polyphosphazene, polyethylene glycol and enzyme responsive peptide as polymer chain backbone, hydrophilic segment, and hydrophobic segment, respectively. Antitumor drugs will be covalently bonded onto the amphiphilic polyphosphazene copolymers to supply drug for carrier polymers. The nanomicelle systems from drug carrier amphipathic block copolymer bill be studied including its structure, physical and chemical properties and in vitro drug release pharmacokinetics, in order to investigate the mechanism of the targeting drug delivery to the pathologic area and controlled drug release, open up new application of biodegradable polyphosphazene drug delivery nanomicelles system, and provide theoretical and practical basis for its further utilization in controlled drug release, gene therapy applications.

具有可控缓释和靶向功能的药物聚合物及基于药物聚合物胶束的设计和构筑一直受到人们的广泛关注。本研究拟以聚膦腈为骨架，聚乙二醇为亲水链段、设计含有功能性基团及酶响应性的短肽为疏水链段合成两亲聚膦腈接枝共聚物，共价键合抗肿瘤药物制备载药聚膦腈。通过聚膦腈纳米载药胶束体系的研究，探讨其结构、物理化学性质和体外释药性能，揭示向病理区域靶向输送药物和控制释药的机理，开拓生物可降解聚膦腈纳米载药胶束体系应用的新方向，为进一步用于药物控制释放、基因治疗等医学方面提供理论上和实践上的依据。

肿瘤细胞产生耐药性已成为肿瘤研究领域急待解决的问题。本项目制备了多个系列以聚膦腈为骨架，聚乙二醇为亲水链段，肽为疏水链段的两亲聚膦腈接枝共聚物，以其为药物载体构建具有疏水内腔和亲水膜结构的自组装体，键接抗肿瘤药物阿霉素，用于耐药性肿瘤治疗。利用相应的实验手段深入研究两亲性接枝共聚聚膦腈及载药聚膦腈在水中自组装形成的化学结构条件，以及给药系统在体外药物释放试验，探讨载药聚膦腈的PH和酶的响应性。通过实验优化载体材料分子设计和自组装体的制备方法，获得了具有明显PH值和酶响应性的载体材料。该新型药物载体材料将为逆转肿瘤耐药提高化疗效果提供新思路。