Laboratory of Drug Discovery and Design, School of Pharmaceutical Sciences, Liaocheng University, Liaocheng 252000, PR China.
Department of Pharmacy (Shandong Provincinal Key Traditional Chinese Medical Discipline of Clinical Chinese Pharmacy), Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, PR China.
Int J Biol Macromol. 2024 Jun;269(Pt 2):132058. doi: 10.1016/j.ijbiomac.2024.132058. Epub 2024 May 3.
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 (Z) 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-Z) for both tumor imaging diagnosis and photothermal-immunotherapy simultaneously. In vitro, Z could specifically bind to PD-L1-positive LLC and MC38 tumor cells, and ICG-Z-mediated photothermal therapy (PTT) also showed excellent phototoxicity to these tumor cells. In vivo, ICG-Z selectively enriched into the PD-L1-positive MC38 tumor tissues, and the high-contrast optical imaging of tumors was obtained. ICG-Z-mediated PTT exhibited a potent anti-tumor effect in vivo due to its remarkable photothermal properties. Furthermore, ICG-Z-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-Z showed favorable biosafety throughout the brief duration of treatment. In summary, these results suggest that ICG-Z 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.
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重要意义。本研究通过大肠杆菌表达系统成功制备了 PD-L1 拮抗型亲和体二聚体（Z），并通过 N-羟基琥珀酰亚胺（NHS）酯将其与 ICG 的光敏剂相连接，开发出一种新型的肿瘤靶向剂（ICG-Z），用于同时进行肿瘤成像诊断和光热免疫治疗。体外实验中，Z 能够特异性结合 PD-L1 阳性的 LLC 和 MC38 肿瘤细胞，而 ICG-Z 介导的光热治疗（PTT）对这些肿瘤细胞也表现出优异的光毒性。在体内，ICG-Z 选择性地富集到 PD-L1 阳性的 MC38 肿瘤组织中，并获得了肿瘤的高对比度光学成像。由于 ICG-Z 具有显著的光热特性，其介导的 PTT 在体内表现出强大的抗肿瘤作用。此外，ICG-Z 介导的 PTT 可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，上调抗肿瘤免疫反应，增强免疫治疗，并能更好地抑制转移性肿瘤的生长。此外，ICG-Z 在整个短暂的治疗过程中表现出良好的生物安全性。综上所述，这些结果表明，ICG-Z 是一种集肿瘤成像诊断和光热免疫治疗于一体的多功能肿瘤靶向药物，对临床 PD-L1 阳性肿瘤患者的诊断和治疗具有重要的指导意义。
