NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China.
Laboratory for Experimental Teratology of the Ministry of Education and Biomedical Isotope Research Center School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
ACS Appl Mater Interfaces. 2023 Sep 27;15(38):44654-44664. doi: 10.1021/acsami.3c07479. Epub 2023 Sep 13.
Legumain, a lysosomal cysteine protease overexpressed in a variety of tumors, has been considered a promising biomarker for various cancers. Precise detection of legumain activity in the lysosome represents an important strategy for early diagnosis and prognosis of tumors. Small-molecule probes with the property of target-enabled self-assembly hold great potential for molecular imaging. In this study, we reported two dual-targeting radiotracers ([F] and [F]) with a property of legumain-mediated self-assembly for positron emission tomography (PET) imaging. Both the radiotracers were synthesized with high labeling yield (>50%) and the radiochemical purity was over 99% via one-step straightforward F-labeling. Both tracers were efficiently activated by the reducing agent and legumain to self-assemble into aggregates and showed enhanced retention in legumain-overexpressed MDA-MB-468 cells and tumors, indicating that the introduction of lysosome-targeting morpholine increased the tumor uptake and extended the retention of radiotracers in legumain-overexpressed tumors. In addition, [F] with a hydrophilic (histidine-glutamate) tag displayed significantly reduced liver uptake with no conspicuous reduction in tumor uptake, affording high signal-to-noise ratios (tumor/liver and tumor/muscle). All of these results suggest that dual-targeting tracer [F] could provide a promising tool for monitoring legumain activity in tumors.
组织蛋白酶 L，一种在多种肿瘤中过表达的溶酶体半胱氨酸蛋白酶，被认为是各种癌症有前途的生物标志物。在溶酶体中精确检测组织蛋白酶 L 的活性是肿瘤早期诊断和预后的重要策略。具有靶标激活自组装特性的小分子探针在分子成像中具有很大的潜力。在这项研究中，我们报道了两种具有组织蛋白酶 L 介导的自组装特性的双重靶向放射性示踪剂 ([F] 和 [F]) 用于正电子发射断层扫描 (PET) 成像。两种放射性示踪剂均通过一步直接 [F] 标记以高标记产率 (>50%) 和放射性化学纯度 (>99%) 合成。两种示踪剂均被还原剂和组织蛋白酶 L 有效激活，自组装成聚集体，并在组织蛋白酶 L 过表达的 MDA-MB-468 细胞和肿瘤中表现出增强的保留，表明引入溶酶体靶向吗啉增加了肿瘤摄取并延长了放射性示踪剂在组织蛋白酶 L 过表达肿瘤中的保留。此外，带有亲水 (组氨酸-谷氨酸) 标签的 [F] 显示出肝摄取明显减少，而肿瘤摄取没有明显减少，提供了高信噪比 (肿瘤/肝和肿瘤/肌肉)。所有这些结果表明，双重靶向示踪剂 [F] 可以为监测肿瘤中的组织蛋白酶 L 活性提供一种有前途的工具。
