European journal of nuclear medicine and molecular imaging · 2024
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.
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Yaginuma Kei, Takahashi Kazuhiro, Hoshi Seiji, Joho Taiki, Shimoyama Saki, Hasegawa Naoko, Hasegawa Koki, Zhao Songji, Ukon Naoyuki, Makabe Syunta, Meguro Satoru, Onagi Akifumi, Matsuoka Kanako, Ogawa Soichiro, Uemura Motohide, Yamashita Tomoki, Suzuki Hiroyuki, Uehara Tomoya, Kojima Yoshiyuki
Аннотация
PURPOSE: 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.
METHODS: 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.
RESULTS: [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.
CONCLUSION: [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.
METHODS: 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.
RESULTS: [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.
CONCLUSION: [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.