基于光合细菌负载纳米光敏剂的免疫光动力治疗及机制研究

Photodynamic therapy (PDT) has become a hot spot in the field of tumor treatment due to its non-invasive property and excellent ability of spatial and temporal control. However, it has suffered from limitations in clinical therapy against tumor metastasis and recurrence due to the local treatment modality of PDT. How to induce antitumor immune response is very important for the future application of PDT. Our previous studies found that oxygen supply in tumor with nanoparticles can enhance the effect of PDT and elicit immunogenic cell death (ICD). In the current project, we propose photosynthetic bacteria that produce oxygen through photosynthesis as nanoparticles vectors, which will targeted-deliver photosensitizer-encapsulated nanoparticles to tumor, and stimulate antitumor immune response to inhibit tumor metastasis and recurrence. In our project, we will employ the fluorescence and photoacoustic imaging ability of nanoparticles to monitor the tumor targeting efficiency and oxygen supply in tumor by local photosynthesis. Moreover, we will determine the effect of oxygen-intervening PDT and clarify the mechanism of ICD-based anti-cancer immune response induced by oxygen-intervening PDT. We will also study the effect of metabolism and PDT on bacterial elimination, and evaluate the safety of bacteria-mediated PDT treatment. The successful implementation of this project will not only provide a highly effective and controllable means to overcome tumor hypoxia, but also provide a promising immunogenic PDT strategy for anti-cancer treatment.

光动力疗法(PDT)具有非侵入和时空可控的优势成为目前治疗肿瘤的研究热点，但由于PDT是局部治疗和肿瘤容易转移复发的特点，如何在机体引发抗肿瘤免疫应答对未来PDT应用尤为重要。我们前期研究结果发现，借助纳米材料增氧改善肿瘤微环境能增效PDT，诱导肿瘤发生免疫原性细胞死亡(ICD)。在前期研究基础上，本项目拟采用光合作用产氧的光合细菌携载具有肿瘤靶向性和响应性的纳米光敏剂颗粒，研究通过局部光合作用增氧改善肿瘤微环境，增效PDT诱发ICD，激活抗肿瘤免疫应答抑制肿瘤转移复发。采用荧光/光声成像技术监控纳米颗粒的肿瘤富集效率和光合作用增氧情况，探索氧干预肿瘤PDT介导ICD的规律，阐明增氧增效PDT激活抗肿瘤免疫应答的机制。并研究机体自身代谢及PDT效应对细菌清除的作用，评估细菌介导PDT治疗的安全性。本项目研究成果将不仅提供高效可控改善肿瘤缺氧微环境的手段，还将为肿瘤免疫光动力治疗提供新策略。

肿瘤转移已成为当前临床癌症治疗的主要挑战，占所有癌症死亡的90%以上。一种理想的肿瘤治疗策略不仅能够切除原发肿瘤，而且还能预防肿瘤复发和远端转移。光动力疗法（PDT）是近年来发展起来的一种理想的、有效的肿瘤治疗方法，具有非侵入和时空可控的优势，利用光敏剂和氧气在光照射下产生单线态氧来杀死癌细胞。然而，由于实体瘤组织中血管系统的异常增殖，无法形成正常的血液循环，使得实体瘤往往形成一种特殊的缺氧微环境。局部缺氧的肿瘤微环境不仅极大地限制了PDT 的疗效，而且还与肿瘤的侵袭性和转移性有关。因此，研发安全有效的肿瘤定向增氧策略，以增氧增效PDT 显得尤为重要。本研究选取了蓝细菌作为供养体，通过肿瘤定向增氧改善肿瘤微环境，增效PDT诱发免疫原性细胞死亡（ICD），激活抗肿瘤免疫应答抑制肿瘤转移复发。采用多模成像技术监控肿瘤增氧情况，探索氧干预肿瘤PDT 介导ICD 的规律，阐明增氧增效PDT 激活抗肿瘤免疫应答的机制。结果显示，通过氧增强PDT效应不仅能有效地破坏原发肿瘤，还能诱发肿瘤细胞发生ICD增加损伤相关分子模式分子信号的释放和表面暴露，进而诱导树突状细胞成熟和效应细胞活化，从而促发有效地抗肿瘤免疫反应抑制肿瘤生长转移。本研究成果不仅提供了有效定点改善肿瘤缺氧微环境的手段，还将为肿瘤免疫PDT 治疗提供新策略。