Prostate cancer is one of the most common global malignancies, but despite advances in detection and treatment, worldwide mortality rates have increased nearly 70% since 1990. One reason for this alarming trend is the inability to effectively treat PCa induced bone metastasis, which cause the majority of morbidity and mortality among patients, with curative intent. New radionuclide therapy strategies are needed if their clinical utility is to move beyond palliative care. Our project develops a novel targeted alpha particle therapy for PCa based on expression of prostate specific membrane antigen (PSMA), which is a membrane-bound protein expressed at high levels in most PCa bone metastases, but has minimal expression by non-malignant tissues. We have developed a dimeric aptamer complex (anti-PSMADAC) that is selectively internalized at elevated levels only by PSMA+ cells, which is a significant improvement over molecules such as the A10 aptamer. This delivery system is less expensive to produce than a monoclonal antibody (mAb) and facilitates straightforward conjugation chemistry that allows for the covalent and site-specific conjugation of anti-cancer drugs or its incorporation into liposomal formulations. Additionally, we will employ a novel radiochemistry strategy that utilizes the bifunctional chelator PCTA over DOTA. Our preliminary data indicate that 225Ac- PCTA-conjugates can be generated more readily under milder radiochemistry conditions and with improved specific activity. We believe this straight forward chemistry and the robust nature of the aptamer will allow us to conjugate multiple 225Ac-PCTA complexes creating a radiotherapeutic with higher specific activity than can be achieved with mAbs. Theoretically, this approach would increase the number of alpha particles that can be delivered to the cancer cell, and improve the probability of at least one nuclear traversal by an alpha particle, which would result in a catastrophic double-stranded DNA break and cell death. Accordingly, we hypothesize that our [225Ac(PCTA)]N:anti-PSMADAC complex will be an exceptionally useful platform to selectively treat metastatic prostate cancer using targeted alpha particle therapy. In Aim 1 we will optimize chemical conjugation for optimal specificity for PSMA+ PCa cells and radiation delivery. In Aim 2, we evaluate specificity for PSMA+ PCa tumors in vivo using biodistribution studies in a murine model of PCa bone metastases. Dosimetry to all major organs will also be determined from multi-compartmental modeling of the biodistribution data, while survival studies will evaluate the therapeutic efficacy of this approach. The short path length and high linear energy transfer of the alpha particles, when properly targeted and internalized into PSMA+ cancer cells at metastatic sites should overcome the limitations of current alpha particle and beta minus therapies used in the clinic, enhance patient dosimetry and improve patient outcomes.