In vitro and in vivo evaluation of 211At-labeled fibroblast activation protein inhibitor for glioma treatment

Huan Ma; Feize Li; Guohua Shen; Lili Pan; Weihao Liu; Ranxi Liang; Tu Lan; Yuanyou Yang; Jijun Yang; Jiali Liao; Ning Liu

doi:10.1016/j.bmc.2021.116600

In vitro and in vivo evaluation of ²¹¹At-labeled fibroblast activation protein inhibitor for glioma treatment

Bioorg Med Chem. 2022 Feb 1:55:116600. doi: 10.1016/j.bmc.2021.116600. Epub 2022 Jan 5.

Authors

Huan Ma¹, Feize Li², Guohua Shen³, Lili Pan³, Weihao Liu¹, Ranxi Liang¹, Tu Lan¹, Yuanyou Yang¹, Jijun Yang¹, Jiali Liao¹, Ning Liu⁴

Affiliations

¹ Key Laboratory of Radiation Physics and Technology of the Ministry of Education; Institute of Nuclear Science and Technology, Sichuan University, Chengdu 610064, PR China.
² Key Laboratory of Radiation Physics and Technology of the Ministry of Education; Institute of Nuclear Science and Technology, Sichuan University, Chengdu 610064, PR China. Electronic address: lifeize@scu.edu.cn.
³ Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, PR China.
⁴ Key Laboratory of Radiation Physics and Technology of the Ministry of Education; Institute of Nuclear Science and Technology, Sichuan University, Chengdu 610064, PR China. Electronic address: nliu720@scu.edu.cn.

PMID: 34999526
DOI: 10.1016/j.bmc.2021.116600

Abstract

Glioma is the most common primary intracranial tumor without effective treatment. Positron emission tomography tracers labeled with ⁶⁸Ga targeting fibroblast activation protein (FAP) have shown favorable characteristics in the diagnosis of glioma. However, to the best of our knowledge, FAP-targeted endoradiotherapy has never been explored in glioma. Hence, in this study, we investigated the therapeutic effect of ²¹¹At-labeled fibroblast activation protein inhibitor (FAPI) for glioma in vitro and in vivo. By astatodestannylation reaction, we prepared ²¹¹At-FAPI-04 with a radiochemical yield of 45 ± 6.7% and radiochemical purity of 98%. With good stability in vitro, ²¹¹At-FAPI-04 showed fast and specific binding to FAP-positive U87MG cells, and could significantly reduce the cell viability, arrested cell cycle at G2/M phase and suppressed cell proliferative efficacy. Biodistribution studies revealed that 6-fold higher accumulation in tumor sites was achieved by intratumoral injection in comparison with intravenous injection. In U87MG xenografts, ²¹¹At-FAPI-04 obviously suppressed the tumor growth and prolonged the median survival in a dose-dependent manner without obvious toxicity to normal organs. In addition, reduced proliferation and increased apoptosis were also observed after ²¹¹At-FAPI-04 treatment. All these results suggest that targeted alpha-particle therapy (TAT) mediated by ²¹¹At-FAPI-04 can provide an effective and promising strategy for the treatment of glioma.

Keywords: (211)At; Fibroblast activation protein; Glioma; Inhibitors; Targeted alpha-particle therapy.