肿瘤微环境响应聚氨基酸水凝胶化疗/免疫联合治疗系统的构建与抗肿瘤应用研究

针对现有水凝胶局部药物缓释载体缺乏对于肿瘤微环境（微酸性pH、免疫抑制性分子高表达等）的响应性与调节性能的局限性，本项目拟通过开环聚合、点击反应等方法将三级胺基团、D-1-甲基-色氨酸等功能单元引入聚氨基酸链段，制备能对肿瘤微环境产生响应或调节作用的聚乙二醇-聚氨基酸嵌段共聚物水凝胶。以该水凝胶为载体联合担载化疗药物与免疫治疗药物，研究水凝胶载药系统在肿瘤微环境下的响应与调节机制，以及载体材料的调节作用对于联合药物抗肿瘤免疫响应与抗肿瘤疗效的影响规律。采用甘露糖修饰的纳米颗粒对免疫治疗药物进行预先担载，构建水凝胶/纳米颗粒多级释放系统，实现水凝胶对联合药物释放行为的精确调控与免疫治疗药物的局部靶向传输，阐明其影响联合药物抗肿瘤作用的机制。该研究将为揭示“水凝胶-联合药物-肿瘤组织”三方面之间的相互影响机制提供实验和理论依据，并为发展新一代智能性水凝胶局部药物缓释载体材料奠定坚实的基础。

To overcome the shortcomings of current hydrogel-based local drug delivery carriers that are lack of the responsive and regulatory properties to the tumor microenvironment (TME) (weakly acidic pH, high level of immunosuppressive molecules, etc.), this project proposes to prepare TME responsive and regulable poly(ethylene glycol)-polypeptide block copolymer hydrogels, by introducing tertiary amine and D-1-methyl-tryptophan into the polypeptide blocks via ring-opening polymerization and click reaction. After co-loading chemotherapy and immunotherapy drugs into the hydrogels, the responsiveness and regulation mechanisms of the drug-loaded hydrogels to TME, as well as their effects on the anti-tumor immune response and anti-tumor efficacy will be investigated. Morevoer, the immunotherapy drugs are planned to pre-loaded in mannose-conjugated nanoparticles to construct hydrogel/nanoparticle hierarchical drug delivery systems, resulting in the systems capable of precisely controlling the drug release behavior and targeted delivery of immunotherpy drugs. The mechanisms will be explored. This project will provide important experimental and theoretic data for disclosing the mutual effects of the three aspects of “hydrogel, drugs and tumor tissue”. This study can also lay the base for the development of next generation of intelligent hydrogel-based systems for local, sustained drug delivery.