Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou 215006, China; Institutes of Biology and Medical Sciences, Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou 215006, China; Nuclear Medicine Laboratory of Mianyang Central Hospital, Mianyang 621099, China.
Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
Bioorg Chem. 2024 Nov;152:107745. doi: 10.1016/j.bioorg.2024.107745. Epub 2024 Aug 28.
The diagnosis and treatment of triple negative breast cancer (TNBC) are huge challenges due to the lack of identifiable molecular targets. The high expression of Nectin4 in a variety of tumors, including TNBC, is associated with the occurrence, invasion, progression and poor prognosis of tumors. Therefore, Nectin4 is an emerging biomarker for the diagnosis and treatment of TNBC. A PET imaging method to non-invasively quantify Nectin4 expression levels may aid in TNBC diagnosis and classification. In this study, a novel bicyclic peptide molecular probe [Ga]Ga-DN68 was used to evaluate the expression of Nectin4 in tumors. The radiolabeling rate of [Ga]Ga-DN68 was over 97 %, while maintaining more than 99 % radiochemical purity. In vitro experiments showed that [Ga]Ga-DN68 could effectively target Nectin4 in tumor cells, and the cellular uptake of MC38-Nectin4 cells (Nectin4+) was significantly higher than that of MC38 cells (Nectin4-). Biodistribution and PET imaging studies consistently showed that [Ga]Ga-DN68 was specifically accumulated in MC38-Nectin4 and MDA-MB-468 tumors, which was significantly higher than that of MC38. When co-injected with cold DN68, the specific accumulation could block the tumor uptake of MDA-MB-468. Notably, the signal-to-noise ratio at the tumor site gradually increased over time, reaching a peak at 1 h. These results strongly suggest that [Ga]Ga-DN68 has broad application prospects as a PET tracer in TNBC imaging.
三阴性乳腺癌（TNBC）缺乏可识别的分子靶点，其诊断和治疗极具挑战性。Nectin4 在多种肿瘤中的高表达与肿瘤的发生、侵袭、进展和不良预后有关。因此，Nectin4 是 TNBC 诊断和治疗的新兴生物标志物。一种用于非侵入性定量检测 Nectin4 表达水平的 PET 成像方法可能有助于 TNBC 的诊断和分类。在这项研究中，使用一种新型双环肽分子探针 [Ga]Ga-DN68 来评估肿瘤中 Nectin4 的表达。[Ga]Ga-DN68 的标记率超过 97%，同时保持超过 99%的放射化学纯度。体外实验表明，[Ga]Ga-DN68 可以有效地靶向肿瘤细胞中的 Nectin4，并且 MC38-Nectin4 细胞（Nectin4+）的细胞摄取率明显高于 MC38 细胞（Nectin4-）。生物分布和 PET 成像研究一致表明，[Ga]Ga-DN68 特异性地积聚在 MC38-Nectin4 和 MDA-MB-468 肿瘤中，明显高于 MC38。当与冷 DN68 共同注射时，肿瘤摄取 MDA-MB-468 的特异性积聚可被阻断。值得注意的是，肿瘤部位的信噪比随时间逐渐增加，在 1 小时达到峰值。这些结果强烈表明，[Ga]Ga-DN68 作为 TNBC 成像的 PET 示踪剂具有广阔的应用前景。
