一种基于计算机辅助设计的新型68Ga标记的环状肽分子探针，用于非侵入性地显像肿瘤中PD-L1表达。
A novel 68Ga-labeled cyclic peptide molecular probe based on the computer-aided design for noninvasive imaging of PD-L1 expression in tumors.
发表日期：2023 Aug 23
作者：
Shushan Ge, Bin Zhang, Jihui Li, Jinyu Shi, Tongtong Jia, Yan Wang, Zhengguo Chen, Shibiao Sang, Shengming Deng
来源：
BIOORGANIC CHEMISTRY
摘要：
程序化死亡配体1（PD-L1）是指导癌症患者筛查和免疫治疗分层的重要生物标记物。然而，由于肿瘤高度异质性，目前能够检测PD-L1表达（免疫组化）的金标准无法全面评估体内的PD-L1整体表达水平。幸运的是，PD-L1靶向放射示踪剂的使用使得可以定量、实时和无创评估肿瘤中PD-L1的表达水平和动态变化。值得注意的是，分析前体与目标蛋白之间的结合模式以寻找不影响目标分子活性的连接物结合位点，可以大大增强分子探针的成功开发。本研究引入了一种具有突破性的环状肽分子探针，名为68Ga-DOTA-PG1，它是从BMS-71环状肽中衍生而来，专门设计用于评估肿瘤中PD-L1的表达。68Ga-DOTA-PG1的放射标记产率超过97%，同时保持放射化学纯度在99%以上。体外实验证实了68Ga-DOTA-PG1对肿瘤细胞中PD-L1的有效靶向作用，A375-hPD-L1细胞（PD-L1+）的细胞摄取显著高于A375细胞（PD-L1-）。体内分布和PET成像研究一致显示68Ga-DOTA-PG1在A375-hPD-L1肿瘤中特异性积聚，在2小时时达到最大摄取量为11.06±1.70% ID/g，显著高于A375细胞中的肿瘤摄取量（1.70±0.17% ID/g）。这些结果强烈表明68Ga-DOTA-PG1作为PET放射示踪剂在PD-L1阳性肿瘤成像方面具有巨大潜力。Copyright © 2023 Elsevier Inc. All rights reserved.
Programmed death-ligand 1 (PD-L1) serves as a crucial biomarker for guiding the screening of cancer patients and the stratification of immunotherapy. However, due to the high heterogeneity of tumors, the current gold standard for detecting PD-L1 expression (immunohistochemistry) fails to comprehensively evaluate the overall PD-L1 expression levels in the body. Fortunately, the use of PD-L1 targeted radiotracers enables quantitative, real-time, and noninvasive assessment of PD-L1 expression levels and dynamics in tumors. Notably, analyzing the binding mode between the precursor and the target protein to find linker binding sites that do not affect the activity of the target molecule can greatly enhance the successful development of molecular probes. This study introduced a groundbreaking cyclic peptide molecular probe called 68Ga-DOTA-PG1. It was derived from the BMS-71 cyclic peptide and was specifically designed to evaluate the expression of PD-L1 in tumors. The radiolabeling yield of 68Ga-DOTA-PG1 surpassed 97% while maintaining a radiochemical purity of over 99%. In vitro experiments demonstrated the effective targeting of PD-L1 in tumor cells by 68Ga-DOTA-PG1, with significantly higher cellular uptake observed in A375-hPD-L1 cells (PD-L1 + ) compared to A375 cells (PD-L1-). Biodistribution and PET imaging studies consistently showed specific accumulation of 68Ga-DOTA-PG1 in A375-hPD-L1 tumors, with a maximum uptake of 11.06 ± 1.70% ID/g at 2 h, significantly higher than the tumor uptake in A375 cells (1.70 ± 0.17% ID/g). These results strongly indicated that 68Ga-DOTA-PG1 held great promise as a PET radiotracer for imaging PD-L1-positive tumors.Copyright © 2023 Elsevier Inc. All rights reserved.