TY - JOUR T1 - Improved Radium-223 Therapy with Combination Epithelial Sodium Channel Blockade JF - Journal of Nuclear Medicine JO - J Nucl Med DO - 10.2967/jnumed.121.261977 SP - jnumed.121.261977 AU - Diane S Abou AU - Amanda Fears AU - Lucy Summer AU - Mark Longtine AU - Nadia Benabdallah AU - Ryan C. Riddle AU - David Ulmert AU - Jeff Michalski AU - Richard L. Wahl AU - Denise Chesner AU - Michele Doucet AU - Nicholas Zachos AU - Brian Simons AU - Daniel LJ Thorek Y1 - 2021/04/01 UR - http://jnm.snmjournals.org/content/early/2021/04/09/jnumed.121.261977.abstract N2 - Background: Radium-223 dichloride ([223Ra]RaCl2) is the first approved alpha particle-emitting therapy and is indicated for treatment of bone metastatic castrate resistant prostate cancer. Approximately half of the dose is absorbed into the gastrointestinal (GI) tract within minutes of administration, limiting disease-site uptake and contributing to toxicity. Here, we investigate the role of enteric ion channels and their modulation for improved therapeutic efficacy and reduced side effects. Methods: Utilizing primary human duodenal organoids (enteroids) as in vitro models of the functional GI epithelium, we found that Amiloride (ENaC blocker) and NS-1619 (K+ channel activator) presented significant effects in 223Ra membranal transport. The radioactive drug distribution was evaluated for lead combinations in vivo, and in osteosarcoma and prostate cancer models. Results: Amiloride shifted 223Ra uptake in vivo from the gut, to nearly double the uptake at sites of bone remodeling. Bone tumor growth inhibition with the combination as measured by bioluminescent and X-ray imaging was significantly greater than single agents alone, and the combination resulted in no weight loss. Conclusion: This combination of approved agents may be readily implemented as a clinical approach to improve outcomes of bone metastatic cancer patients with the benefit of ameliorated tolerability. ER -