Investigating Actinium-225 Radiochemistry: A Step Towards Next-Generation Radiotherapy

The U.S. Department of Energy (DoE) highlighted potential applications of Actinium-225 (225Ac) in treating prostate cancer in 2018, opening a new era of alpha emitter-based targeted therapy. Alpha particle emitter, 225Ac has high linear energy transfer that leads to lethal double stranded DNA breaks that can effectively kill tumor cells. Additionally, 225Ac has a short path length (< 100 µm) in tissues, which confines the off-target toxicity. Therefore, developing targeted radiotherapy with 225Ac and exploring its applications in hard-to-treat cancers is timely and innovative, and brings strong impact to patients suffering from untreatable tumors that cannot be completely removed by surgical resection and are resistant to frontline chemo- and immuno-therapies.
We propose to investigate the feasibility of targeted 225Ac radiotherapy in immune-evasive metastatic ovarian cancer via a highly collaborative multidisciplinary study that will design and systematically characterize novel 225Ac-labeled antibody-based probes and evaluate their anti-tumor efficacy in vitro and in vivo. This project aligns with University’s four strategic goals: 1) the proposed work will set important guidelines for future research on targeted alpha radiotherapy at the University of Utah as well as the scientific community; 2) students involved in this study will gain unique experience and skillset by conducting interdisciplinary research and publishing high-profile papers; 3) this work engages multidisciplinary research community including radiology, biotechnology, chemistry, and cancer therapy to build an inclusive team to eventually benefit clinical management of refractory cancers; 4) this work will contribute to the University’s long-term visibility. To achieve these goals, we have established a new cross-campus collaboration between the School of Medicine (Dr Sixiang Shi), College of Engineering (Dr Tara Mastren) and College of Pharmacy (Dr Shreya Goel).

Current Status

2025-02-04
Targeted alpha therapy has emerged as a promising treatment approach in cancer. Developing targeted radiotherapy with Actinium-225 (225Ac, Half-life ~ 10 days) and exploring its applications in hard-to-treat cancers is timely and innovative, and brings strong impact to patients suffering from untreatable tumors that cannot be completely removed by surgical resection and are resistant to frontline chemo- and immuno-therapies. Ovarian cancer is the leading cause of death from gynecological malignancies, which is often presented at an advanced stage, has poor prognosis, low survival rate, high reoccurrence rate and limited therapeutic options. Herein, we have developed a folate receptor (FRα)-targeted 225Ac-antibody conjugate with high selectivity for ovarian cancers. We used Mirvetuximab, an FDA-approved FRα-targeting antibody, for targeted delivery of 225Ac, since FRα expression is excessively elevated in ovarian cancer. In this study, we have established exceptional pharmacokinetic profile and high tumor selectivity of FRα-targeted Mirvetuximab for delivery of 225Ac in SKOV3 xenograft tumor model. 225Ac-Macropa-Mirvetuximab demonstrated marked tumor regression and prolonged survival, providing one of the first successful examples of antibody-based alpha therapy against ovarian cancer.