Abstract
The increasing threats of nuclear terrorism have made the development of medical countermeasures a priority for international security. Injectable formulations of diethylenetriaminepentaacetic acid (DTPA) have been approved by the FDA; however, an oral formulation is more amenable in a mass casualty situation. Here, the diethyl ester of DTPA, named C2E2, is investigated for potential as an oral treatment for internal radionuclide contamination. C2E2 was synthesized and characterized using NMR, MS, and elemental analysis. The physiochemical properties of solubility, lipophilicity, and stability were investigated in order to predict its oral bioavailability. Finally, an animal efficacy study was conducted in Sprague Dawley rats pre-contaminated by intramuscular injection with 241Am(NO3)3 to establish effectiveness of the therapy via the oral route. Synthesis of C2E2 yielded a crystalline powder with high solubility and improved lipophilicity over DTPA. The ester was stable in both simulated gastric and intestinal fluids over the anticipated time course of absorption. Capsules containing C2E2 were demonstrated to be stable for 12 months under accelerated stability conditions. After a single dose, C2E2 enhanced the elimination of 241Am in a dose-dependent manner. Significant improvement was seen in both total 241Am decorporation and reduction of 241Am liver and skeletal burden. C2E2 was concluded to be effective when orally administered to 241Am-contaminated rats. It may therefore have potential for medical countermeasure in treating humans contaminated with 241Am or other transuranic elements. An oral capsule or powder for reconstitution may be suitable formulations for future development based on the physiochemical properties and anticipated dose required for efficacy.
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Acknowledgments
This work was funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and U.S. Department of Health and Human Services under contracts HHSN266200500045C and HHSN272201000030C.
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Drs. Jay and Mumper are co-founders of Capture Pharmaceuticals, which owns intellectual property related to C2E2. In addition to Drs. Jay and Mumper, Drs. Huckle and Sadgrove are named on a patent licensed to Capture Pharmaceuticals. However, no financial support from Capture Pharmaceuticals was provided in these studies.
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Huckle, J.E., Sadgrove, M.P., Leed, M.G.D. et al. Synthesis and Physicochemical Characterization of a Diethyl Ester Prodrug of DTPA and Its Investigation as an Oral Decorporation Agent in Rats. AAPS J 18, 972–980 (2016). https://doi.org/10.1208/s12248-016-9916-z
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DOI: https://doi.org/10.1208/s12248-016-9916-z