基于免疫检查点阻断和声化疗于一体的多功能卟啉脂质体治疗脑胶质瘤的研究

脑胶质瘤因其病灶部位的特殊性和复杂性，临床治疗难度大且现行治疗方案功效甚微，亟需探索高效、靶向、安全的治疗新策略。项目拟在前期超声开放血脑屏障(BBB)、声动力杀伤脑胶质瘤工作基础上，构建携载抗癌药Oxaliplatin (OXP)和免疫检查点抑制剂BMS-202的超声响应型卟啉脂质体(POB)，实现影像指导下的多模式协同治疗新探索。首先制备POB并考察超声颅内定点递送效率和机制；其次，通过聚焦超声提升POB在脑胶质瘤靶区的特异性聚集和可控性释药，探究声化疗在抑制原位脑胶质瘤的同时亦诱导免疫原性细胞死亡机制，分析自噬在肿瘤抗原提呈、摄取及免疫细胞活化中调节作用；此外，利用BMS-202抑制免疫负调控因子PD-1/PD-L1，提升抗脑胶质瘤免疫应答效率。该研究设计即能跨越BBB造成原位瘤的直接损伤，又能激活机体免疫系统对残余的瘤细胞进行识别、捕捉和破坏，可为临床提供一种高精准治疗新思路。

Glioma is the most common and lethal malignant brain tumor, with a very poor prognosis despite of the current gold-standard treatment--maximal resection followed by radiotherapy and chemotherapy, which has failed to show survival benefits because the tumor recurs in virtually all patients. Therefore, novel treatment strategies especially those with multiple combinatorial mechanisms and potentially synergistic approaches are urgently needed. Previously, we have got some findings on the blood-brain barrier (BBB) opening using focused ultrasound, and the cell killing of brain tumors by sonodynamic therapy. Based on previous works, this project is to establish an intelligent ultrasound-responsive porphyrin-liposome, encapsulating the anticancer drug oxaliplatin (OXP) and the small molecule inhibitor (BMS-202) of immune checkpoint, aiming to explore the potential synergy of sonochemotherapy and immunotherapy for orthotopic gliomas under the guidance of multimodal imaging of porphyrin. In the present study, we firstly prepare an immunogenic nanoliposomes (POB), to investigate the transcranial local delivery efficiency of POB with the assist of focused ultrasound. Then, from the intro and in vivo experiments, we attempt to analyze the features of nanoporphyrin-liposomes, the controllable on-demand drug release by sonochemical reactions, and the target accumulation and penetration of nanomedicine in orthotopic gliomas. We suppose the combination of sonodynamic therapy and chemotherapeutics will cause obvious cell cytotoxicity as well as immunogenic cell death (ICD), and the concomitant autophagy will facilitate the tumor antigen presentation and anticancer immunity during ICD process. The intricate and complex relationships within the troika of autophagy, ICD and anti-tumor immunity should be further explained. In addition, the application of BMS-202, a small molecule for PD-L1 blockage, would alleviate the immunosuppression status of glioma and enhance the immunoreactivity, achieving high efficiency of complementary immunomodulation. Therefore, the proposed strategy not only can cause direct damage to the brain tumors in situ, but also can concurrently activate the immune system of the body to eradicate the metastatic and diffused tumor cells to prevent the relapses. Success of this proposal will lay a scientific foundation for high-precision and accurate theranostics of glioma, and provide new possible option for this devasting disease.