抗原介导仿生合成免疫刺激功能性诊疗探针及其抗肿瘤机制研究

肿瘤微环境中免疫细胞功能低下、乏氧、高GSH水平等因素极大限制了抗肿瘤疗效及预后。因此设计和制备具有免疫刺激功能性探针并能同步调控肿瘤微环境进行增效治疗显得尤为重要。申请人前期研究发现：模式抗原OVA可原位仿生合成具有免疫佐剂特性的二氧化锰纳米粒（MnO2@OVA），抗原负载率高，能显著激活CD8+T细胞并分泌IFN-γ，但其作用机制尚不明确。为此，本项目将着重研究MnO2的免疫刺激作用机制，并利用MnO2具备调控（耗竭或利用）肿瘤微环境中过表达因子的特性，拟进一步仿生集成光敏剂，获得具有示踪功能的免疫/PDT双增强MnO2@OVACe6诊疗探针。本项目利用抗原直接仿生合成免疫刺激性智能复合物，具有高抗原载量和肿瘤特异性，利用小鼠肿瘤模型评价探针负载后DC的体内淋巴结迁移能力，探究其免疫记忆应答效应，深入研究其免疫激活和抗肿瘤作用机制，为研制高效安全的新型多功能肿瘤疫苗提供实验依据。

In tumor microenvironment, immune cell dysfunction, hypoxia, high GSH levels and other factors greatly limits the anti-tumor efficacy and prognosis. Therefore, it is very important to design and fabricate functional probes with both immune stimulating ability and simultaneously regulating the tumor microenvironment for synergistic treatment. Applicant's preliminary study found that the model antigen OVA has good performance in in-situ biomimetic synthesis of manganese dioxide nanoparticles (MnO2 @ OVA) with immune adjuvant properties and with high antigen loading. Particularly, MnO2 @ OVA can significantly activate CD8+ T cells and secrete IFN-γ. However, it's not yet clear how it works. To this end, the project will focus on the study of its immune stimulation mechanism, and further the use of MnO2 to regulate (deplete or utilize) overexpression factors in tumor microenvironment. With this feature, the project further exerts biomimetic integration of photosensitizer Ce6 into MnO2 @ OVA, providing an immune / PDT dual enhanced MnO2 @ OVACe6 probe with MR/US imaging functions. This project uses antigen to directly synthesize immune stimulating intelligent complex, with high antigen loading and tumor specificity. We will use mouse tumor model to evaluate the lymph node migration ability of DCs in vivo after probe loading, and explore the effect of immune memory response, in-depth study of its immune activation and anti-tumor mechanism. This study will provide experimental evidence for the development of a new type of multi-functional tumor vaccines that are efficient and safe.