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.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2021 Apr 09 [Epub ahead of print]
Diane S Abou, Amanda Fears, Lucy Summer, Mark Longtine, Nadia Benabdallah, Ryan C Riddle, David Ulmert, Jeff Michalski, Richard L Wahl, Denise Chesner, Michele Doucet, Nicholas Zachos, Brian Simons, Daniel Lj Thorek
Washington University in St. Louis School of Medicine, United States., Johns Hopkins University., University of California Los Angeles., Baylor College of Medicine.