Enhanced Antitumor Efficacy of ²²⁵Ac-NM600 Compared to ¹⁷⁷Lu-NM600 in Prostate Cancer Models.

Abstract

Many men with prostate cancer (PCa) develop metastatic castration-resistant PCa (mCRPC) after current treatment, which has a death rate of more than 50%. Although many approaches target mCRPC and show promising results, mCRPC is still incurable. Therefore, we aimed to investigate the efficacy and dosimetry of α (²²⁵Ac) versus β (¹⁷⁷Lu) radiopharmaceutical therapy using NM600 in murine PCa models. NM600 was radiolabeled with ¹⁷⁷Lu and ²²⁵Ac for radiopharmaceutical therapy studies in immunocompetent mice. Single-photon emission computed tomography (SPECT)/CT imaging was conducted on syngeneic Myc-CaP and TRAMP-C1 PCa mouse models administered 7.4 MBq of ¹⁷⁷Lu-NM600 in the tail vein. We calculated the dosimetry of ¹⁷⁷Lu-NM600 therapy using SPECT/CT imaging and biodistribution data. Complete blood count, comprehensive metabolic panel, and histology analysis were carried out to assess toxicity in Myc-CaP and TRAMP-C1-beering mice (n = 9), which were given 5.55 (low injected activity [IA]) or 18.5 MBq (high IA) of ¹⁷⁷Lu-NM600, and 7.4 (low IA) or 18.5 KBq (high IA) of ²²⁵Ac-NM600. Finally, the overall survival and tumor growth rate were monitored periodically for all groups. Both ²²⁵Ac/¹⁷⁷Lu-NM600 demonstrated tumor-specific uptake and retention. ²²⁵Ac-NM600 exhibited superior antitumor effects and significantly improved overall survival compared to ¹⁷⁷Lu-NM600 at similar doses. The enhanced efficacy of ²²⁵Ac-NM600 was attributed to its higher relative biological effectiveness. Toxicity studies revealed transient, dose-dependent hematological changes for both agents, with no significant long-term adverse effects. ²²⁵Ac-NM600 demonstrated enhanced antitumor efficacy compared to ¹⁷⁷Lu-NM600 in murine PCa models, with a favorable toxicity profile. These outcomes reveal a strong rationale for further developing α-emitting radiopharmaceutical therapy agents for PCa treatment.