Abstract：
In clinical practice, tumor-targeting diagnosis and immunotherapy against programmed death ligand 1 (PD-L1) have a significant impact. In this research, a PD-L1-antagonistic affibody dimer (ZPD-L1) was successfully prepared through Escherichia coli expression system, and conjugated with the photosensitizer of ICG via N-hydroxysuccinimide (NHS) ester to develop a novel tumor-targeting agent (ICG-ZPD-L1) for both tumor imaging diagnosis and photothermal-immunotherapy simultaneously. In vitro, ZPD-L1 could specifically bind to PD-L1-positive LLC and MC38 tumor cells, and ICG-ZPD-L1-mediated photothermal therapy (PTT) also showed excellent phototoxicity to these tumor cells. In vivo, ICG-ZPD-L1 selectively enriched into the PD-L1-positive MC38 tumor tissues, and the high-contrast optical imaging of tumors was obtained. ICG-ZPD-L1-mediated PTT exhibited a potent anti-tumor effect in vivo due to its remarkable photothermal properties. Furthermore, ICG-ZPD-L1-mediated PTT significantly induced the immunogenic cell death (ICD) of primary tumors, promoted maturation of dendritic cells (DCs), up-regulated anti-tumor immune response, enhanced immunotherapy, and superiorly inhibited the growth of metastatic tumors. In addition, ICG-ZPD-L1 showed favorable biosafety throughout the brief duration of treatment. In summary, these results suggest that ICG-ZPD-L1 is a multifunctional tumor-targeting drug integrating tumor imaging diagnosis and photothermal-immunotherapy, and has great guiding significance for the diagnosis and treatment of clinical PD-L1-positive tumor patients.
摘要：
在临床实践中,针对程序性死亡配体1(PD-L1)的肿瘤靶向诊断和免疫治疗具有显著影响.在这项研究中,通过大肠杆菌表达系统成功制备了一种PD-L1拮抗亲和体二聚体(ZPD-L1),并通过N-羟基琥珀酰亚胺（NHS）酯与ICG的光敏剂缀合，以开发同时用于肿瘤成像诊断和光热免疫疗法的新型肿瘤靶向剂（ICG-ZPD-L1）。体外，ZPD-L1可以特异性结合PD-L1阳性LLC和MC38肿瘤细胞，ICG-ZPD-L1介导的光热疗法（PTT）也对这些肿瘤细胞显示出优异的光毒性。在体内,ICG-ZPD-L1选择性富集到PD-L1阳性MC38肿瘤组织中，并获得了肿瘤的高对比度光学成像。ICG-ZPD-L1介导的PTT由于其显著的光热特性而在体内表现出有效的抗肿瘤作用。此外，ICG-ZPD-L1介导的PTT显著诱导原发性肿瘤的免疫原性细胞死亡(ICD),促进树突状细胞（DC）的成熟，上调的抗肿瘤免疫反应，增强的免疫疗法，并显著抑制转移性肿瘤的生长。此外,ICG-ZPD-L1在整个短暂的治疗期间显示出良好的生物安全性。总之,这些结果表明，ICG-ZPD-L1是一种多功能的肿瘤靶向药物，整合了肿瘤成像诊断和光热免疫疗法，对临床PD-L1阳性肿瘤患者的诊治具有重要的指导意义。
