高效协同免疫治疗抗肿瘤的酞菁光敏剂的构效关系与作用机制

Recently, PD-1/PD-L1 antibody-based immune checkpoint block therapy (ICB) has made a breakthrough in the treatment of advanced metastatic tumors, but it is only effective for a few types of cancer and is often accompanied with immune-related side effects. The combination of photodynamic therapy (PDT) and immune checkpoint block therapy is expected to overcome the above problems and shows an attractive application prospect. However, the research on combination of PDT-ICB has just started, and their synergistic mechanism is not clear, and the structure characteristics of photosensitizers with high synergistic effects are also not yet known. This project is intended to select and design a series of phthalocyanine photosensitizers with different structural characteristics, and then study their photosensitizing ability, cellular uptake, subcellular localization, the ability to induce immune response, and their synergistic anti-tumor effect with PD-L1 antibody, especially the inhibition of the distal and metastasis tumors. This study will reveal the synergistic mechanisms, structure-activity relationships, and demonstrate the structural characteristics of phthalocyanine photosensitizers with highly effective synergistic anti-tumor effect combined with ICB. And the study will also provide a useful reference for rationally designing combined photosensitizers for PDT-ICB. The ideas and contents of this project are novel. It has significant application prospect and academic significance for promoting the development of photodynamic therapy/immunotherapy and developing high-efficiency new anticancer drugs and technologies.

近年来基于PD-1/PD-L1抗体的免疫检查点阻断疗法（ICB）在治疗晚期转移性肿瘤上取得突破性进展，但其仅对少数类型的癌症有效且常伴有免疫过敏的副反应。将光动力疗法（PDT）和免疫检查点阻断疗法联用可有望克服上述问题，显示了诱人应用前景。但是PDT-ICB联用研究刚刚起步，两者协同机制尚不明确，具有高效协同效应的光敏剂结构特点也尚未知。本项目拟选取和设计合成一系列结构特点不同的酞菁光敏剂，测试其光敏化能力、细胞摄取与亚细胞定位，研究它们与PD-L1抗体协同抗肿瘤效应和协同免疫机制，总结构效关系，重点分析酞菁的结构特点与其协同抗肿瘤转移效应的相关性，揭示较佳协同机制，阐明具有高效协同ICB抗肿瘤转移效应的酞菁光敏剂应具有的结构特征，从而为合理设计联用光敏剂提供指导。本项目的研究思路和研究内容新颖，对于促进光疗/免疫疗法的融合发展，开发新型高效抗癌药物和技术，具有重要的应用前景和学术意义。

近年来基于PD-1/PD-L1抗体的免疫检查点阻断疗法（ICB）在治疗晚期转移性肿瘤上取得突破性进展，但其仅对少数类型的癌症有效且常伴有免疫过敏的副反应。将光动力疗法（PDT）和免疫检查点阻断疗法联用可有望克服上述问题，显示了诱人应用前景。但是PDT-ICB联用研究刚刚起步，两者协同机制尚不明确，基于协同ICB的光敏剂构效关系也尚未被揭示。本项目设计合成了一系列结构特点不同的新型酞菁光敏剂，研究其光敏化能力、细胞摄取、体外抗癌活性、诱导机体产生免疫应答的能力，建立动物模型探讨它们与PD-L1抗体协同抗肿瘤效应，总结构效关系，阐明具有高效协同ICB抗远端肿瘤和抑制肿瘤转移活性的酞菁光敏剂应具有的结构特征。研究发现，（1）端氨基取代的酞菁的光敏剂化能力一般低于其对应的端铵基取代酞菁；（2）酞菁的细胞摄取越高，其体外抗癌活性越高一般也越高；（3）酞菁诱导CRT暴露的能力越强，其与PD-L1抗体的协同抗肿瘤效应一般也越强；（4）阳离子型酞菁一般比中性酞菁和阴离子型酞菁，能更好的诱导CD8+杀伤性T细胞在肿瘤组织中的浸润，能更好的联合PD-L1抗体起协同抗肿瘤效应。本项目的研究思路和研究内容新颖，对于促进光动力疗法和免疫疗法的融合发展，开发新型高效抗癌药物和技术，具有重要的应用前景和学术意义。