Project Summary/Abstract In 2017, cancer was the second leading cause of death in the USA [1], illustrating the dire need for innovative, effective therapies. We propose to test the Meitner-Auger electron (MAE)-emitting radionuclide antimony-119 (119Sb) for cancer targeted radionuclide therapy (TRT) by measuring cell killing efficacy, comparing against clinical standard, and quantifying biodistriubtion and lethal dose delivery via in vivo and ex vivo experiments. TRT uses biological targeting vectors (signal molecules, antibodies) tuned to cellular disease markers (receptors, overexpressed proteins) to deliver radionuclides that emit short range, highly damaging radioactivity inside diseased cells. TRT holds curative potential, including metastatic disease, and can mitigate current radiation therapy side effects. Radionuclides with b- (high energy electron) emissions, a particle (helium nucleus) emissions, and low energy MAE emissions have been proposed for TRT application [2]. MAE- emitting radionuclides provide high radiation dose delivery (an advantage over clinical standard b--emitters [3]), decay to stable isotopes providing simple dose tracking (an advantage over a-emitters), and can be produced on small cyclotrons networked across the world (an advantage over a-emitters which are very challenging to produce [4]). Many in silico studies on MAE TRT promote 119Sb as an ideal TRT candidate [5–7] due to the highly localized energy deposition of its 23- 24 low energy MAEs [8], low x-ray emissions providing clean dose profile, and high cyclotron production yields. However, the lack of developed production technology and bifunctional chelator scaffolds have prevented application of 119Sb. I spent the first three years of my predoctoral training developing production of medical quality 119Sb, and we have reported the first stable complexation of radioantimony with a bifunctional chelator – I am now uniquely positioned to explore its biological application. We hypothesize that 119Sb TRT agents will kill cancer cells more effectively than the current clinical TRT standard. We propose to conjugate our bifunctional chelator to a glutamate-urea-lysine moiety which binds prostate specific membrane antigen (PSMA), a well-recognized prostate cancer disease marker, and characterize the 119Sb-trithiol- PSMA radiopharmaceutical with HPLC, serum stability, lipophilicity, and apparent molar activity (AMA) measurements. To prove retention of the PSMA vector’s targeting, binding affinity, internalization kinetics, and efflux kinetics assays will be conducted. ATP cell viability assays will measure cell killing efficacy and a clonogenic assay will monitor hereditary effects. Similar studies of 177Lu-PSMA-617 will compare our TRT agent with the clinical standard. We will also investigate the mechanism of damage with fluorescence microscopy using g-H2AX to quantify double stranded DNA breaks. We will measure the radioisotope imaging analogue 117Sb-trithiol-PSMA in v...