Department of Laboratory Medicine, School of Medicine, Yangtze University, Jingzhou 434023, P. R. China.
College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, P. R. China.
ACS Sens. 2022 Jul 22;7(7):1837-1846. doi: 10.1021/acssensors.2c00126. Epub 2022 Jun 17.
Melanoma is a malignant cancer with a high risk of metastasis and continued increase in death rates over the past decades, and its prognosis is highly related to the disease's stage, while early detection and treatment of melanoma are significant to the improvement of its therapy outcome. Different from the traditional methods for disease diagnosis, enzyme-activated fluorescent probes were developed rapidly due to their high sensitivity and temporal-spatial ratio and have been widely applied in tumor detection, surgical navigation, and cancer-related research. Fibroblast activation protein-α (FAPα), a serine-type cell surface protease that plays important roles in cell invasion and extracellular matrix degradation, is widely involved in tumor progression such as malignant melanoma, so developing a FAPα activity-based molecular tool would be of great potential for the early diagnosis and therapy of melanoma. However, few fluorescent probes targeting FAPα have been applied in melanoma-related studies, and thus, the construction of FAPα activity-based fluorescent probes for melanoma detection is in urgent need. By incorporating the selective recognition unit with a red-emission fluorophore, cresyl violet, we herein report an ultrasensitive (limit of detection = 5.3 ng/mL) fluorogenic probe for FAPα activity sensing, named ; the acquired probe showed a significantly higher binding affinity (15.7-fold) and overall catalytic efficiency (2.6-fold) when compared with those of the best reported FAPα probes. The good performance of made it possible to discriminate malignant melanoma cells and tumor-bearing mice from normal cells and mice with high contrast. More importantly, showed significant antitumor activity toward melanoma in cultured cells and tumor-bearing nude mice (over 95% inhibited tumor growth) with good safety, which made it an ideal theranostic agent for melanoma.
黑色素瘤是一种恶性癌症，具有很高的转移风险，且在过去几十年中死亡率持续上升，其预后与疾病分期密切相关，而早期发现和治疗黑色素瘤对改善其治疗效果至关重要。与传统的疾病诊断方法不同，酶激活荧光探针由于具有高灵敏度和时空比，得到了快速发展，并已广泛应用于肿瘤检测、手术导航和癌症相关研究。成纤维细胞激活蛋白-α（FAPα）是一种丝氨酸型细胞表面蛋白酶，在细胞侵袭和细胞外基质降解中发挥重要作用，广泛参与恶性黑色素瘤等肿瘤的进展，因此开发基于 FAPα 活性的分子工具对于黑色素瘤的早期诊断和治疗具有很大的潜力。然而，针对 FAPα 的荧光探针在黑色素瘤相关研究中应用较少，因此，迫切需要构建用于黑色素瘤检测的基于 FAPα 活性的荧光探针。通过将选择性识别单元与红色发射荧光团结合，我们在此报告了一种用于 FAPα 活性传感的超灵敏（检测限=5.3ng/mL）荧光探针，命名为 ；与已报道的最好的 FAPα 探针相比，获得的探针具有更高的结合亲和力（15.7 倍）和整体催化效率（2.6 倍）。良好的性能使 能够高对比度地区分恶性黑色素瘤细胞和荷瘤小鼠与正常细胞和小鼠。更重要的是， 在培养的细胞和荷瘤裸鼠中对黑色素瘤表现出显著的抗肿瘤活性（超过 95%抑制肿瘤生长），且具有良好的安全性，使其成为黑色素瘤理想的治疗药物。
