Abstract
The threat of nuclear terrorism by the deliberate detonation of a nuclear weapon or radiological dispersion device (“dirty bomb”) has made emergency response planning a priority. The only FDA-approved treatments for contamination with isotopes of the transuranic elements Am, Pu, and Cm are the Ca and Zn salts of diethylenetriaminepentaacetic acid (DTPA). These injectable products are not well suited for use in a mass contamination scenario as they require skilled professionals for their administration and are rapidly cleared from the circulation. To overcome the mismatch in the pharmacokinetics of the DTPA and the biokinetics of these transuranic elements, which are slowly released from contamination sites, the penta-ethyl ester of DTPA (C2E5) was prepared and formulated in a nonaqueous gel for transdermal administration. When gels comprised of 40% C2E5, 40–45% Miglyol® 840, and 15–20% ethyl cellulose were spiked with [14C]-C2E5 and applied to rat skin; over 60% of the applied dose was absorbed within a 24-h period. Radioactivity was observed in urinary and fecal excretions for over 3 days after removal of the gel. Using an 241Am wound contamination model, transdermal C2E5 gels were able to enhance total body elimination and reduce the liver and skeletal burden of 241Am in a dose-dependent manner. The efficacy achieved by a single 1,000 mg/kg dose to contaminated rats was statistically comparable to intravenous Ca-DTPA at 14 mg/kg. The effectiveness of this treatment, favorable sustained release profile of pro-chelators, and ease of administration support its use following radiological emergencies and for its inclusion in the Strategic National Stockpile.
Similar content being viewed by others
References
Benjamin GC, McGeary M, McCutchen SR, Editors; Committee on Medical Preparedness for a Terrorist Nuclear Event; Institute of Medicine. Assessing Medical Preparedness to Respond to a Terrorist Nuclear Event: Workshop Report. Washington, DC: The National Academies Press; 2009.
International Commission on Radiological Protection. 1990 recommendations of the International Commission on Radiological Protection : user's edition. 1st Ed. Published for the International Commission on Radiological Protection by Pergamon Press, Oxford; New York; 1992.
Wood R, Sharp C, Gourmelon P, Le Guen B, Stradling GN, et al. Decorporation treatment—medical overview. Radiat Prot Dosim. 2000;87(1):51–6.
Harrison JD, Muirhead CR. Quantitative comparisons of cancer induction in humans by internally deposited radionuclides and external radiation. Int J Radiat Biol. 2003;79(1):1–13.
Moysich KB, Menezes RJ, Michalek AM. Chernobyl-related ionizing radiation exposure and cancer risk: an epidemiological review. Lancet Oncol. 2002;3(5):269–79.
Hameln Pharma GmbH. Package insert: pentetate calcium trisodium injection and pentetate zinc trisodium injection. Hameln Pharma GmbH; 2009.
Guilmette RA, Moretti ES, Lindenbaum A. Toward an optimal DTPA therapy for decorporation of actinides: time–dose relationships for plutonium in the dog. Radiat Res. 1979;78(3):415–28.
Taylor DM, Stradling GN, Hengé-Napoli M-H. The scientific background to decorporation. Radiat Prot Dosim. 2000;87(1):11–8.
Stradling GN, Taylor DM, Hengé-Napoli M-H, Wood R, Silk TJ. Treatment for actinide-bearing industrial dusts and aerosols. Radiat Prot Dosim. 2000;87(1):41–50.
Stradling GN, Hengé-Napoli M-H, Paquet F, Poncy J-L, Fritsch P, et al. Approaches for experimental evaluation of chelating agents. Radiat Prot Dosim. 2000;87(1):19–28.
Stevens E, Rosoff B, Weiner M, Spencer H. Metabolism of the chelating agent diethylenetriamine pentaacetic acid (C14DTPA) in man. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, NY), Royal Society of Medicine. 1962; pp 235-238.
Crawley FE, Haines JW. The dosimetry of carbon-14 labeled compounds: the metabolism of diethylenetriamine pentaacetic acid (DTPA) in the rat. Int J Nucl Med Biol. 1979;6(1):9–15.
Phan G, Herbet A, Cholet S, Benech H, Deverre JR, et al. Pharmacokinetics of DTPA entrapped in conventional and long-circulating liposomes of different size for plutonium decorporation. J Control Release. 2005;110(1):177–88.
National Council on Radiation Protection and Measurements. Scientific Committee 57-17 on Radionuclide Dosimetry Model for Wounds. NCRP Report No. 156, pp. 35-117. 2007.
Ansoborlo E, Amekraz B, Moulin C, Moulin V, Taran F, et al. Review of actinide decorporation with chelating agents. Cr Chim. 2007;10(10–11):1010–9.
Guilmette RA, Muggenburg BA. Reducing the radiation dose from inhaled americium-241 using continuously administered DTPA therapy. Int J Radiat Biol Relat Stud Phys Chem Med. 1988;53(2):261–71.
Phan G, Le Gall B, Grillon G, Rouit E, Fouillit M, et al. Enhanced decorporation of plutonium by DTPA encapsulated in small PEG-coated liposomes. Biochimie. 2006;88(11):1843–9.
Cassatt DR, Kaminski JM, Hatchett RJ, DiCarlo AL, Benjamin JM, et al. Medical countermeasures against nuclear threats: radionuclide decorporation agents. Radiat Res. 2008;170(4):540–8.
Brown L, Langer R. Transdermal delivery of drugs. Annu Rev Med. 1988;39(1):221–9.
Chien YW. Novel drug delivery systems. 2nd ed. New York: M. Dekker; 1992.
Jay M, Mumper RJ. Methods and pharmaceutical compositions for decorporation of radioactive compounds. United States Patent 8,030,358; 2011.
Sueda K, Sadgrove MP, Fitzsimmons JM, Jay M. Physicochemical characterization of a prodrug of a radionuclide decorporation agent for oral delivery. J Pharm Sci. 2012;101(8):2844–53.
Zhang Y, Sadgrove MP, Sueda K, Yang Y-T, Pacyniak EK, et al. Nonaqueous gel for the transdermal delivery of a DTPA penta-ethyl ester prodrug. AAPS J. 2013;15(2):523–32.
Volf V. Chelation therapy of incorporated plutonium-238 and americium-241: comparison of LICAM(C), DTPA, and DFOA in rats, hamsters, and mice. Int J Radiat Biol Relat Stud Phys Chem Med. 1986;49(3):449–62.
Walters KA. Dermatological and transdermal formulations: Informal HealthCare; 2002.
US Food and Drug Administration. Guidance for Industry, Internal Radioactive Contamination—Development of decorporation Agents. 2006.
Roffey SJ, Obach RS, Gedge JI, Smith DA. What is the objective of the mass balance study? A retrospective analysis of data in animal and human excretion studies employing radiolabeled drugs. Drug Metab Rev. 2007;39(1):17–43.
Lloyd RD, Bruenger FW, Mays CW, Atherton DR, Jones CW, et al. Removal of Pu and Am from beagles and mice by 3,4,3-LICAM(C) or 3,4,3-LICAM(S). Radiat Res. 1984;99(1):106–28.
Bunin DI, Chang PY, Doppalapudi RS, Riccio ES, An D, et al. Dose-dependent efficacy and safety toxicology of hydroxypyridinonate actinide decorporation agents in rodents: towards a safe and effective human dosing regimen. Radiat Res. 2013;179(2):171–82.
Morss LR, Edelstein NM, Fuger J, Katz JJ. The chemistry of the actinide and transactinide elements, vol. 2. 3rd ed. Dordrecht: Springer; 2006. p. 1265–395.
Sherry AD, Cacheris WP, Kuan KT. Stability constants for Gd3+ binding to model DTPA-conjugates and DTPA-proteins: implications for their use as magnetic resonance contrast agents. Magn Reson Med. 1988;8(2):180–90.
Sérandour AL, Grémy O, Fréchou M, Renault D, Poncy JL, et al. In vitro and in vivo assessment of plutonium speciation and decorporation in blood and target retention tissues after a systemic contamination followed by an early treatment with DTPA. Radiat Res. 2008;170(2):208–15.
Taylor D. Some aspects of the comparative metabolism of plutonium and americium in rats. Health Phys. 1962;8(6):673–7.
Turner G, Taylor D. The transport of plutonium, americium, and curium in the blood of rats. Phys Med Biol. 1968;13:535–46.
Ménétrier F, Taylor DM, Comte A. The biokinetics and radiotoxicology of curium: a comparison with americium. Appl Radiat Isot. 2008;66(5):632–47.
Markley JF. Removal of polymeric plutonium from mice by combined therapy with the calcium chelate and penta-ethyl ester of DTPA. Int J Radiat Biol Relat Stud Phys Chem Med. 1963;7:405–7.
Guilmette RA, Parks JE, Lindenbaum A. Synthesis and therapeutic testing of mono- and dialkyl esters of pentetic (diethylenetriaminepentaacetic) acid for decorporation of polymeric plutonium. J Pharm Sci. 1979;68(2):194–6.
Taylor GN, Lloyd RD, Mays CW, Angus W, Miller SC, et al. Plutonium- or americium-induced liver tumors and lesions in beagles. Health Phys. 1991;61(3):337–47.
International Commission on Radiological Protection. International Commission on Radiological Protection. Limits for intakes of radionuclides by workers. ICRP 30, Part 1. Ann. ICRP 2 (3-4). Oxford; New York: Pergamon Press; 1979.
Roberts R, McCune S. Animal studies in the development of medical countermeasures. Clin Pharmacol Ther. 2008;83(6):918–20.
Snoy PJ. Establishing efficacy of human products using animals: the US Food and Drug Administration's “Animal Rule”. Vet Pathol Online. 2010;47(5):774–8.
Farriol M, Rosselló J, Schwartz S. Body surface area in Sprague–Dawley rats. J Anim Physiol Anim Nutr. 1997;77(1–5):61–5.
Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 2004;89(5):2085–98.
Durbin P, Schmidt C. Predicting the kinetics of chelating agents in man from animal data. Heal Phys. 1989;57:165–74.
Sueda K, Sadgrove MP, Jay M, Di Pasqua AJ. Species-dependent effective concentration of DTPA in plasma for chelation of 241Am. Heal Phys. 2013;105:208–14.
Acknowledgments
The authors thank Mrs. Shraddha Shapariya for her help on in vivo decorporation studies and Dr. Yu-Tsai Yang for his help on the graphical abstract. This work was funded in part by the National Institute of Health, US Department of Health and Human Services under contract HHSN266200500045C.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhang, Y., Sadgrove, M.P., Mumper, R.J. et al. Radionuclide Decorporation: Matching the Biokinetics of Actinides by Transdermal Delivery of Pro-chelators. AAPS J 15, 1180–1188 (2013). https://doi.org/10.1208/s12248-013-9527-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1208/s12248-013-9527-x