²²⁵Ac-RAX104:一种针对锕-225优化的新型PSMA靶向放射性配体,展现出增强的肿瘤滞留和更优的疗效

Prostate cancer is the second most common malignancy in men and remains a significant cause of cancer-related mortality worldwide. Although the clinical success of ¹⁷⁷Lu-PSMA-617 (Pluvicto) has established PSMA-targeted radioligand therapy (RLT) as an effective treatment for metastatic castration-resistant prostate cancer (mCRPC), emerging clinical evidence indicates that ²²⁵Ac-based RLT can deliver even greater therapeutic efficacy owing to the high linear energy transfer of alpha-particles and the radionuclide's 9.92-day physical half-life. To fully exploit these properties, ²²⁵Ac-RAX104 was rationally designed to enhance PSMA affinity and tumor retention, thereby kinetically matching the physical and radiobiological characteristics of ²²⁵Ac to maximize antitumor potency. RAX104 was successfully synthesized and radiolabeled with ²²⁵Ac at a molar activity of up to 3 µCi/nmol, achieving radiochemical purity greater than 95% and maintaining stability for more than 110 hours. Surface plasmon resonance analysis revealed that the RAX104 precursor exhibited approximately 22-fold higher affinity for PSMA than PSMA-617, primarily driven by slower dissociation kinetics. In PSMA-overexpressing PC3 cells, ²²⁵Ac-RAX104 showed markedly enhanced cellular uptake and internalization compared with ²²⁵Ac-PSMA-617. In PSMA-low 22Rv1 xenografts, ²²⁵Ac-RAX104 achieved more than 3-fold higher tumor-absorbed activity (AUC₀₋∞) and a significantly prolonged biological half-life in tumors relative to ²²⁵Ac-PSMA-617, while both radioligands showed comparable blood pharmacokinetics. Consistent with these pharmacokinetic advantages, ²²⁵Ac-RAX104 demonstrated superior antitumor efficacy: a single 14.8 kBq dose produced greater tumor growth inhibition and longer survival than 74 kBq (fivefold higher activity) of ²²⁵Ac-PSMA-617 in the 22Rv1 model. Toxicity evaluation in normal ICR mice revealed only transient and reversible reductions in white blood cell, neutrophil, and reticulocyte counts, without clinical chemistry abnormalities, indicating a favorable safety profile. An investigator-initiated trial (IIT) of ²²⁵Ac-RAX104 has been proposed in mCRPC patients to generate human dosimetry data to inform the design of subsequent clinical studies. Collectively, these results demonstrate that ²²⁵Ac-RAX104 achieves optimal kinetic alignment with ²²⁵Ac's physical decay and biological action, delivering enhanced tumor exposure and potent therapeutic efficacy at one-fifth the dose of ²²⁵Ac-PSMA-617. These findings support ²²⁵Ac-RAX104 as a promising next-generation PSMA alpha-radioligand therapy with the potential to improve outcomes in mCRPC and warrant further clinical development.