TY - JOUR T1 - Improved <sup>223</sup>Ra Therapy with Combination Epithelial Sodium Channel Blockade JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1751 LP - 1758 DO - 10.2967/jnumed.121.261977 VL - 62 IS - 12 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 M. Michalski AU - Richard L. Wahl AU - Denise Chesner AU - Michele Doucet AU - Nicholas C. Zachos AU - Brian W. Simons AU - Daniel L.J. Thorek Y1 - 2021/12/01 UR - http://jnm.snmjournals.org/content/62/12/1751.abstract N2 - [223Ra]RaCl2 is the first approved α-particle–emitting therapy and is indicated for treatment of bone metastatic castration-resistant prostate cancer. Approximately half the dose is absorbed into the gastrointestinal tract within minutes of administration, limiting disease-site uptake and contributing to toxicity. Here, we investigated the role of enteric ion channels and their modulation for improved therapeutic efficacy and reduced side effects. Methods: Using primary human duodenal organoids (enteroids) as in vitro models of the functional gastrointestinal epithelium, we found that amiloride (epithelial sodium ion channel blocker) and NS-1619 (K+ channel activator) presented significant effects in 223Ra membranal transport. 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 and nearly doubled the uptake at sites of bone remodeling. Bone tumor growth inhibition with the combination as measured by bioluminescent imaging and radiography was significantly greater than that with single agents alone, and the combination resulted in no weight loss. Conclusion: This combination of approved agents may readily be implemented as a clinical approach to improve the outcomes of bone-metastatic cancer patients with the benefit of ameliorated tolerability. ER -