基于新药环巴胺的微环境响应自纳米化白蛋白-CD44双靶向PD-L1单抗纳 米体系在三阴性乳腺癌中的作用及机制研究

The breakthrough of tumor microenvironment barrier is the key and precondition for the efficacy of antitumor drugs. In the early stage, the applicant completed a large number of anti-tumor drug cyclopamine nanodrug studies, and gradually explored the multiple potential of cyclopamine: 1) powerful anti-tumor effect; 2) to promote the physical infiltration of drug in tumor microenvironment; 3) enhance the efficacy of immunotherapy. This topic attempts to break through the tumor microenvironment barrier, build self-nano-albumin and CD44 dual-targeting-cyclopamine-PD-L1 monoclonal antibody sequential drug release system. Select the self-nano-albumin nanoparticles as carrier and SPARC targeting ligands, physical loading cyclopamine, hyaluronic acid as CD44 targeting ligands, introduction of pH response chemical bond to connect aPD - L1. Realize the CD44 tumor active targeting; pH sensitive response release of aPD - L1; anti-tumor effect, promoting drug physical infiltration in tumor microenvironment, increased immune cell infiltration via cyclopamine. This topic through the exquisite nano design, not only explored the multiple potential of cyclopamine, also attempt physical infiltration and chemical response release for the tumor microenvironment multi-stage response, preliminary discussion related mechanism, realize the dual-target, chemotherapy and immunotherapy combination therapy for anti-triple negative breast cancer treatment.

突破肿瘤微环境屏障是抗肿瘤药物发挥治疗疗效的关键和前提。申请人前期完成大量抗肿瘤新药环巴胺纳米药物转化研究，发掘出环巴胺具多重潜能：强大抗肿瘤作用；促进药物在肿瘤微环境物理浸润；增强免疫治疗疗效。本课题尝试突破肿瘤微环境屏障，构建肿瘤微环境多级响应自纳米化白蛋白和CD44双靶向的环巴胺-PD-L1单抗序贯释药体系，透明质酸作CD44靶向配体，以自纳米白蛋白为载体，物理负载环巴胺，引入pH响应化学键连接aPD-L1。实现自纳米化白蛋白和透明质酸双靶向，pH响应化学键敏感释放aPD-L1，环巴胺抗肿瘤同时促进肿瘤微环境物理渗透，增加免疫细胞浸润以增强aPD-L1反应性。本课题通过精巧纳米设计，高效发挥环巴胺抗肿瘤作用、促进药物物理浸润和增强免疫疗效的所有潜能；尝试进行物理浸润和化学释放的肿瘤微环境多级响应；并且初步探讨其相关机制。实现肿瘤双靶向、化疗和免疫治疗综合协同抗三阴性乳腺癌新策略。

突破肿瘤微环境屏障是抗肿瘤药物发挥治疗疗效的关键和前提。申请人前期完成大量抗肿瘤新药环巴胺纳米药物转化研究，发掘出环巴胺具多重潜能：强大抗肿瘤作用；促进药物在肿瘤微环境物理浸润；增强免疫治疗疗效。本课题尝试突破肿瘤微环境屏障，构建肿瘤微环境多级响应自纳米化白蛋白和CD44双靶向的环巴胺-PD-L1单抗序贯释药体系，透明质酸作CD44靶向配体，以自纳米白蛋白为载体，物理负载环巴胺，引入pH响应化学键连接aPD-L1。实现自纳米化白蛋白和透明质酸双靶向，pH响应化学键敏感释放aPD-L1，环巴胺抗肿瘤同时促进肿瘤微环境物理渗透，增加免疫细胞浸润以增强aPD-L1反应性。本课题通过精巧纳米设计，高效发挥环巴胺抗肿瘤作用、促进药物物理浸润和增强免疫疗效的所有潜能；尝试进行物理浸润和化学释放的肿瘤微环境多级响应；并且初步探讨其相关机制。实现肿瘤双靶向、化疗和免疫治疗综合协同抗三阴性乳腺癌新策略。