Frontiers in oncology · 2026
Actinium-225-rhPSMA-10.1 as a novel, alpha-particle-emitting therapy for prostate cancer: results of a preclinical evaluation.
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Foxton Caroline, Waldron Bradley, Wurzer Alexander, D'Alessandria Calogero, Morgenstern Alfred, Bruchertseifer Frank, Kirkegaard Nielsen Tea, Veggerby Grønlund Rikke, Wikke Hallund Mathias, Stevens Daniel J
Аннотация
BACKGROUND: Novel, radiohybrid, beta-particle-emitting, PSMA-targeted radiopharmaceutical therapy [177Lu]Lu-rhPSMA-10.1 shows promising preclinical and clinical efficacy in prostate cancer. Here, we evaluated [225Ac]Ac-rhPSMA-10.1 as a potential alpha-particle-emitting, PSMA-targeted radiopharmaceutical therapy for prostate cancer.
METHODS: Lipophilicity of [225Ac]Ac-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.1 (0.1-0.3 MBq) was assessed by shake-flask method. PSMA-binding affinity (IC50) was evaluated in a competitive binding assay using rhPSMA-10.1 complexed with natural Lanthanum ([natLa]; non-radioactive [225Ac]Ac surrogate) or natural Lutetium ([natLu]) in PSMA-expressing LNCaP cells. Cellular internalization (normalized to that of [177Lu]Lu-PSMA-I&T) was assessed after 1-hour incubation of LNCaP cells (5x105 cells in 1 mL/well) with [225Ac]Ac-rhPSMA-10.1 or [177Lu]Lu-rhPSMA-10.1. In vivo assessments were conducted using PSMA-expressing 22Rv1 prostate cancer xenografts (eight mice/group plus untreated controls). Efficacy (tumour growth and survival) versus controls was assessed ≤49 days after a single-dose of [225Ac]Ac-rhPSMA-10.1 (30 KBq) or [177Lu]Lu-rhPSMA-10.1 (30 MBq). Tolerability was evaluated by bodyweight monitoring.
RESULTS: [225Ac]Ac-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.1 showed similar in vitro profiles: low lipophilicity (log Doct/PBS pH 7.4 = -3.4 ± 0.2 and log Doct/PBS pH 7.4 = -3.8 ± 0.1, respectively), high PSMA binding affinity ([natLa]La-rhPSMA-10.1 IC50 = 3.6 ± 0.6 nM, [natLu]Lu-rhPSMA-10.1 IC50 = 1.6 ± 0.1 nM) and high internalization (99% ± 14 and 108% ± 5, respectively). In vivo, [225Ac]Ac-rhPSMA-10.1 significantly reduced tumour growth versus controls from Day 14-31 (p < 0.05), and significantly prolonged median survival (43.5 days) versus controls (27.0 days; p = 0.006). There were no significant differences in tumour growth suppression or survival between the radiopharmaceuticals, and both were well tolerated.
CONCLUSION: [225Ac]Ac-rhPSMA-10.1 displayed similar in vivo properties to [177Lu]Lu-rhPSMA-10.1 and similar efficacy in prostate cancer xenografts at lower administered radioactivity.
METHODS: Lipophilicity of [225Ac]Ac-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.1 (0.1-0.3 MBq) was assessed by shake-flask method. PSMA-binding affinity (IC50) was evaluated in a competitive binding assay using rhPSMA-10.1 complexed with natural Lanthanum ([natLa]; non-radioactive [225Ac]Ac surrogate) or natural Lutetium ([natLu]) in PSMA-expressing LNCaP cells. Cellular internalization (normalized to that of [177Lu]Lu-PSMA-I&T) was assessed after 1-hour incubation of LNCaP cells (5x105 cells in 1 mL/well) with [225Ac]Ac-rhPSMA-10.1 or [177Lu]Lu-rhPSMA-10.1. In vivo assessments were conducted using PSMA-expressing 22Rv1 prostate cancer xenografts (eight mice/group plus untreated controls). Efficacy (tumour growth and survival) versus controls was assessed ≤49 days after a single-dose of [225Ac]Ac-rhPSMA-10.1 (30 KBq) or [177Lu]Lu-rhPSMA-10.1 (30 MBq). Tolerability was evaluated by bodyweight monitoring.
RESULTS: [225Ac]Ac-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.1 showed similar in vitro profiles: low lipophilicity (log Doct/PBS pH 7.4 = -3.4 ± 0.2 and log Doct/PBS pH 7.4 = -3.8 ± 0.1, respectively), high PSMA binding affinity ([natLa]La-rhPSMA-10.1 IC50 = 3.6 ± 0.6 nM, [natLu]Lu-rhPSMA-10.1 IC50 = 1.6 ± 0.1 nM) and high internalization (99% ± 14 and 108% ± 5, respectively). In vivo, [225Ac]Ac-rhPSMA-10.1 significantly reduced tumour growth versus controls from Day 14-31 (p < 0.05), and significantly prolonged median survival (43.5 days) versus controls (27.0 days; p = 0.006). There were no significant differences in tumour growth suppression or survival between the radiopharmaceuticals, and both were well tolerated.
CONCLUSION: [225Ac]Ac-rhPSMA-10.1 displayed similar in vivo properties to [177Lu]Lu-rhPSMA-10.1 and similar efficacy in prostate cancer xenografts at lower administered radioactivity.