基于光杀伤-肿瘤免疫治疗新策略的光敏剂/siRNA/CpG共递送纳米体系的构建及协同抗肿瘤研究

With increasing incidence and mortality, cancer is the leading cause of death in China and is a major public health problem. Cancer chemotherapy regimens, together with surgery and radiotherapy, are currently the main means of tumor mass debulking. However, limitations to current approaches remain and the management of malignant tumors is a therapeutic challenge. An ideal cancer therapy should not only eradicate the treated primary tumors but also induce a systemic antitumor immunity, capable of controlling metastatic tumors and long-term tumor resistance. One promising strategy is to combine photodynamic therapy with immunotherapy. In the present project, multifunctional nanocomplexes are designed for the co-delivery of pohotosensitizer, immune adjuvants combined with check point blockers, which may possess an untapped potential to achieve the synergistic/combined effect of photodynamic and immuno therapies; the multifunctional nanocomplexes are tumor extracellular pH-responsive, comprising with siRNA encapsulated porphyrin-embedded polymersomes and CpG-conjugated gold nanoparticles, which reveal an redox-responsive drug release and tumor targeting for photodynamic and immune cancer therapy; we will study the synergistic effect of the functional components in the multifunctional nanocomplexes, explain possible mechanisms of action, and evaluate the antumor effect and antitumor immune responses. Strong antitumor effectiveness, combined with enhanced immune responses, would seem to justify further development of the multifunctional nanocomplexes-based photodynamic-immuno cancer therapy as the new generation cancer therapeutic modality.

恶性肿瘤已成为我国人群疾病死亡的首要原因，寻找高效的多手段综合治疗方法成为恶性肿瘤治疗的关键。“光动力疗法+免疫疗法”的联合抗肿瘤治疗策略为恶性肿瘤的综合治疗提供了一种新思路，即“直接杀伤肿瘤细胞的同时，激活机体自身的抗肿瘤免疫机能清除肿瘤细胞”。针对上述治疗策略，本课题提出在纳米尺度内构建集肿瘤靶向、肿瘤胞外pH微环境响应、氧化还原响应性可控释放的光动力治疗与肿瘤免疫治疗于一体的多功能药物递送体系；实现异靶点药物（包括光敏剂、免疫佐剂和免疫检查点阻断剂）同一纳米载药体系的共递送，使肿瘤杀伤效应与抗肿瘤免疫效应有效结合，达到叠加/协同抗肿瘤的目的，并探索其可能的作用机制和影响规律，为实现肿瘤多模式综合治疗提供切实可行的途径。

基于抗肿瘤免疫联合治疗策略，从光/化疗法的肿瘤免疫原性杀伤作用和免疫激活效应着手，在纳米尺度内构建得到了一系列集肿瘤靶向、环境刺激响应性和可控释放的光/化与免疫治疗于一体多功能纳米递送体系；利用纳米药物的肿瘤杀伤效应消除肿瘤并生成“原位肿瘤疫苗”，启动/增强机体抗肿瘤免疫应答，同时联用免疫治疗药物以实现不同治疗方法之间的叠加与协同，该综合抗肿瘤策略对提高目前肿瘤常规治疗疗效和发展新的肿瘤治疗方案具有积极意义，为实现肿瘤多模式综合治疗提供切实可行的途径，主要研究进展如下： .一、构建基质金属蛋白酶响应型的光敏剂吲哚菁绿和吲哚胺-2,3-双加氧酶抑制剂自组装纳米药物，其介导的光杀伤作用（光热及光动力）在杀伤肿瘤细胞后释放的肿瘤相关抗原能够有效促进抗原提呈细胞的活化，启动机体免疫应答，联合吲哚胺-2,3-双加氧酶抑制剂和PD-L1免疫检查点阻断剂可以进一步增强抗肿瘤免疫效应，有效发挥协同抗肿瘤免疫作用。.二、构建基质金属蛋白酶响应型的聚乙二醇/DPPA多肽-阿霉素共负载自组装纳米药物，用于化疗和PD-L1免疫检查点阻断的联合抗肿瘤研究。在酶响应作用下，释放的阿霉素纳米药物可杀伤肿瘤细胞并诱导肿瘤细胞的免疫原性死亡，引发抗肿瘤免疫应答；同时，经酶响应性连接肽断裂而释放的PD-L1抗体拮抗剂DPPA多肽，可阻断PD-1/PD-L1免疫检查点抑制通路，进而实现化疗联合免疫检查点阻断的协同抗肿瘤作用。该纳米药物介导的化疗-免疫检查点阻断的联合抗肿瘤疗法可诱导长期记忆性抗肿瘤免疫反应，有效抑制肿瘤的复发和转移。.三、构建得到同时具有光热效应及免疫调节效应的氧化石墨烯纳米复合物，表面修饰叶酸后进一步增强该纳米复合物的肿瘤靶向聚集能力，在激光照射下直接杀死肿瘤细胞并激活抗肿瘤免疫应答，抑制远端肿瘤生长。研究结果表明光热杀伤，吲哚胺-2,3-双加氧酶抑制和PD-L1阻断的联合疗法可有效抑制肿瘤生长，通过调控多种抗肿瘤免疫途径可协同增强抗肿瘤免疫效应。