Novel astatine (²¹¹At)-labelled prostate-specific membrane antigen ligand with a neopentyl-glycol structure: evaluation of stability, efficacy, and safety using a prostate cancer xenograft model.

Abstract

Prostate-specific membrane antigen (PSMA)-targeted alpha therapy is considered a promising alternative treatment for metastatic castration-resistant prostate cancer (mCRPC). Though astatine-211 (²¹¹At) is potentially useful alpha-emitter producible by cyclotrons, its clinical application has been limited by instability and a tendency to deastatination in vivo. To overcome these challenges, we developed [²¹¹At]At-NpG-PSMA, a novel PSMA ligand with a neopentyl-glycol structure that enhances in vivo stability against deastatination. This study aimed to evaluate the stability, anti-tumour effect, and safety of [²¹¹At]At-NpG-PSMA in mice. Xenograft models were prepared by subcutaneous transplantation of PSMA-positive PC-3 PIP cells into BALB/c nu/nu mice. [²¹¹At]At-NpG-PSMA was administered to assess biodistribution, and the anti-tumour effect was evaluated at doses of 0.32, 1.00 and 1.93 MBq in comparison with saline. Histopathological examinations were performed to evaluate damage to normal organs. [²¹¹At]At-NpG-PSMA demonstrated high tumour uptake (42.0 ± 13.1%ID/g at 3 h) with minimal uptake in non-target tissues, including thyroid, stomach and salivary grands (0.28 ± 0.20%ID, 0.71 ± 0.12%ID/g and 0.88 ± 0.10%ID/g at 3 h, respectively). A dose-dependent anti-tumour effect was observed, with tumour volumes increasing by 796.0 ± 437.6% in the control versus 161.0 ± 213.4%, -76.4 ± 19.2% and - 59.5 ± 41.6% in the 0.32, 1.00 and 1.93 MBq groups, respectively, by day 15. Mild renal tubule regeneration was noted in the 1.00 MBq group. [²¹¹At]At-NpG-PSMA demonstrated significant stability in vivo and anti-tumour effects with minimal side effects, indicating its potential as a new therapeutic drug for PSMA-targeted alpha therapy in mCRPC.