State Key Laboratory of Vaccines for Infectious Diseases, Center for Molecular Imaging and Translational Medicine, Xiang An Biomedicine Laboratory School of Public Health, Xiamen University, 4221-116 Xiang'An South Rd, Xiamen 361102, China.
Theranostics and Translational Research Center, Institute of Clinical Medicine & Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing 100730, China.
Mol Pharm. 2024 Oct 7;21(10):4960-4969. doi: 10.1021/acs.molpharmaceut.4c00209. Epub 2024 Sep 16.
The limited progress in treatment options and the alarming survival rates in advanced melanoma emphasize the significant research importance of early melanoma diagnosis. RFVT3, a crucial protein at the core of energy metabolism reprogramming in melanoma, might play a pivotal role in early detection. In this study, [Ga]Ga-NOTA-RF, based on riboflavin (RF), was rationally developed and validated, serving as an innovative tool for positron emission tomography (PET) imaging of RFVT3 expression in melanoma. The assays of RFVT3 specificity of [Ga]Ga-NOTA-RF were performed on B16F10 melanoma cells. Then, PET imaging of melanoma was investigated in B16F10 allograft mouse models with varying volumes. Biodistribution studies are used to clarify the behavior of [Ga]Ga-NOTA-RF . [Ga]Ga-NOTA-RF was obtained with high radiochemical purity (>95%). A significant uptake (37.79 ± 6.86%, = 4) of [Ga]Ga-NOTA-RF was observed over time in B16F10 melanoma cells, which was significantly inhibited by RFVT3 inhibitors RF or methylene blue (MB), demonstrating the specific binding of [Ga]Ga-NOTA-RF. At 60 min postinjection, the tumor-to-muscle (T/M) ratio of [Ga]Ga-NOTA-RF was 4.03 ± 0.34, higher than that of the RF-blocked group (2.63 ± 0.19) and MB-blocked group (2.14 ± 0.20). The T/M ratios for three distinct tumor volumes-small (5 mm), medium (10 mm), and large (15 mm) were observed to be 5.25 ± 0.28, 4.03 ± 0.34, and 3.19 ± 0.55, respectively. The expression of RFVT3 was validated by immunohistochemical staining in various tumor models, with small B16F10 tumors exhibiting the highest expression. [Ga]Ga-NOTA-RF demonstrates promising properties for the early diagnosis of melanoma and the examination of minute metastatic lesions, indicating its potential to assist in guiding clinical treatment decisions.
RFVT3 是黑色素瘤能量代谢重编程核心的关键蛋白，可能在早期检测中发挥关键作用。在这项研究中，基于核黄素 (RF) 的 [Ga]Ga-NOTA-RF 被合理开发和验证，可作为正电子发射断层扫描 (PET) 成像黑色素瘤 RFVT3 表达的创新工具。在 B16F10 黑色素瘤细胞上进行了 [Ga]Ga-NOTA-RF 对 RFVT3 特异性的测定。然后，在具有不同体积的 B16F10 同种异体移植小鼠模型中研究了黑色素瘤的 PET 成像。生物分布研究用于阐明 [Ga]Ga-NOTA-RF 的行为。[Ga]Ga-NOTA-RF 获得了>95%的高放射化学纯度。在 B16F10 黑色素瘤细胞中，随着时间的推移，观察到 [Ga]Ga-NOTA-RF 的摄取显著增加（37.79 ± 6.86%， = 4），这被 RFVT3 抑制剂 RF 或亚甲蓝 (MB) 显著抑制，证明了 [Ga]Ga-NOTA-RF 的特异性结合。在注射后 60 分钟，[Ga]Ga-NOTA-RF 的肿瘤与肌肉 (T/M) 比值为 4.03 ± 0.34，高于 RF 阻断组（2.63 ± 0.19）和 MB 阻断组（2.14 ± 0.20）。对于三个不同肿瘤体积-小（5mm）、中（10mm）和大（15mm），观察到的 T/M 比值分别为 5.25 ± 0.28、4.03 ± 0.34 和 3.19 ± 0.55。通过免疫组织化学染色在各种肿瘤模型中验证了 RFVT3 的表达，其中小 B16F10 肿瘤表现出最高的表达。[Ga]Ga-NOTA-RF 具有黑色素瘤早期诊断和检查微小转移灶的潜力，表明其有望辅助指导临床治疗决策。
