Synthesis and Preclinical Evaluation of a Novel FAPI-04 Dimer for Cancer Theranostics

多塔 成纤维细胞活化蛋白 体内 化学 连接器 放射性核素治疗 癌症研究 二聚体 放射化学 核化学 癌症 核医学 螯合作用 医学 生物 生物技术 有机化学 内科学 操作系统 计算机科学
作者
Xuan Zhong,Jingru Guo,Xiuping Han,Wenyu Wu,Rui Yang,Jun Zhang,Guoqiang Shao
出处
期刊:Molecular Pharmaceutics [American Chemical Society]
卷期号:20 (5): 2402-2414 被引量:16
标识
DOI:10.1021/acs.molpharmaceut.2c00965
摘要

Overexpression of fibroblast activation protein (FAP) in cancer-associated fibroblasts in a wide variety of tumors enables a highly selective targeting strategy using FAP inhibitors (FAPIs). Quinoline-based FAPIs labeled with radionuclides have been widely developed for tumor-targeted nuclear medicine imaging. However, the short retention time of FAPIs at the tumor site limits their application in radionuclide therapy. In this study, a novel FAPI-04 dimer was synthesized and labeled with radionuclides to prolong the retention time in tumors for imaging and therapy. To prepare the FAPI-04 dimer complex, DOTA-Suc-Lys-(FAPI-04)2, we used Fmoc-Lys(Boc)–OH as the linker to conjugate two FAPI-04 structures by an amide reaction. The resulting product was further modified by DOTA groups to allow for conjugation with radioactive metals. Both [68Ga]Ga-(FAPI-04)2 and [177Lu]Lu-(FAPI-04)2 showed a radiochemical purity of >99% and remained stable in vitro. In vivo, micro-PET images of SKOV3, A431, and H1299 xenografts revealed that the tumor uptake of [68Ga]Ga-(FAPI-04)2 was about twice that of [68Ga]Ga-FAPI-04 and that the accumulation of [68Ga]Ga-(FAPI-04)2 at the tumor site did not significantly decrease even 3h after injection. The tumor–abdomen ratio of [68Ga]Ga-(FAPI-04)2 images was significantly higher than that of [18F]F-FDG images. For radionuclide therapy, [177Lu]Lu-(FAPI-04)2 effectively retarded tumor growth and displayed good tolerance. In conclusion, the DOTA-Suc-Lys-(FAPI-04)2 design enhanced its uptake in FAP-expressing tumors, improved its retention time at the tumor site, and produced high-contrast imaging in xenografts after radionuclide labeling. Furthermore, it showed a noticeable antitumor effect. DOTA-Suc-Lys-(FAPI-04)2 provides a new approach for applying FAPI derivatives in tumor theranostics.
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