线粒体靶向的多功能近红外小分子的设计合成与肿瘤光学、免疫联合治疗研究

Phototherapy is usually confined to the superficial, local primary tumor treatment，the efficacy of metastatic deep tumors is very little, greatly limiting its application in the treatment of cancer prospects. In recent years, the combination of Phototherapy and immunotherapy strategies against deep metastatic tumors has drawn great attention. Applicant's preliminary study found that a class of mitochondrial targeted near-infrared multifunctional small molecule-based photosensitizers, can significantly improve the efficacy of tumor phototherapy. On the basis of those work, this project intends to chemical covalently link the mitochondria-targeted photosensitizer to the clinical approved adjuvant R-837 through a singlet oxygen cleavable aminoacrylate bond. While light inducing the production of mitochondria-associated antigens in tumor cells, R-837 is released and further promotes the uptake and presentation of antigens by antigen-presenting cells (APCs), thereby enhancing the specific anti-tumor immune response and enhancing the therapeutic effects of metastatic deep tumors. The project will adopt physical and chemical properties, tumor targeting properties, light-induced immune response, tumor combination therapeutic efficacy and mechanism study. For the first time mitochondria-targeted phototherapy and immunotherapy are closely combined to provide experimental and theoretical basis for expanding the application of phototherapy in the treatment of distal and deep metastatic tumors.

光学治疗通常局限于浅表、局部的原发肿瘤的治疗，对转移性深部肿瘤的疗效甚微，极大地限制了其在肿瘤治疗中的应用前景。近年来，光学、免疫联合治疗对抗深部转移肿瘤的策略受到极大关注。申请人前期研究发现一类以线粒体为靶点的近红外多功能小分子光敏剂，可以显著提高肿瘤光学治疗疗效。在此基础上，本项目设想将该类线粒体靶向的光敏剂，通过单态氧可切断的氨基丙烯酸酯键，与临床免疫佐剂R-837进行化学共价连接，在光诱导肿瘤细胞线粒体相关抗原产生的同时，释放R-837促进抗原递呈细胞（APCs）对抗原的摄取和递呈，从而增强特异性抗肿瘤免疫反应，提高对转移至深部肿瘤的治疗。本项目拟通过理化性质鉴定、肿瘤靶向特性、光诱导免疫应答、肿瘤联合治疗疗效及机制研究，首次将线粒体靶向的光学治疗与免疫治疗紧密结合，为拓展光学治疗应用于远端和深部转移肿瘤治疗提供实验和理论依据。

光学治疗通常局限于浅表、局部的原发肿瘤的治疗，对转移性深部肿瘤的疗效甚微，极大地限制了其在肿瘤治疗中的应用前景。申请人前期研究发现一类以线粒体为靶点的近红外多功能小分子光敏剂，可以显著提高肿瘤光学治疗疗效。在此基础上，本项目通过化学共价连接策略将线粒体靶向的光敏剂与临床免疫佐剂R-837进行化学共价连接或以人血清白蛋白（HSA）为中间载体策略同时携载上述两种效应化合物，在光诱导肿瘤细胞线粒体相关抗原产生的同时，释放R-837促进抗原递呈细胞（APCs）对抗原的摄取和递呈，从而增强特异性抗肿瘤免疫反应，提高对转移至深部肿瘤的治疗。本项目通过化学合成、理化性质鉴定、肿瘤靶向特性、光诱导免疫应答、肿瘤联合治疗疗效及机制研究，首次将线粒体靶向的光学治疗与免疫治疗紧密结合，为拓展光学治疗应用于远端和深部转移肿瘤治疗提供实验和理论依据。