Skip to main content

Advertisement

SpringerLink
Log in

Radionuclide Decorporation: Matching the Biokinetics of Actinides by Transdermal Delivery of Pro-chelators

  • Research Article
  • Published:
The AAPS Journal Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. 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.

  2. 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.

  3. 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.

    Article  CAS  Google Scholar 

  4. 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.

    PubMed  CAS  Google Scholar 

  5. Moysich KB, Menezes RJ, Michalek AM. Chernobyl-related ionizing radiation exposure and cancer risk: an epidemiological review. Lancet Oncol. 2002;3(5):269–79.

    Article  PubMed  Google Scholar 

  6. Hameln Pharma GmbH. Package insert: pentetate calcium trisodium injection and pentetate zinc trisodium injection. Hameln Pharma GmbH; 2009.

  7. 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.

    Article  PubMed  CAS  Google Scholar 

  8. Taylor DM, Stradling GN, Hengé-Napoli M-H. The scientific background to decorporation. Radiat Prot Dosim. 2000;87(1):11–8.

    Article  CAS  Google Scholar 

  9. 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.

    Article  CAS  Google Scholar 

  10. 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.

    Article  CAS  Google Scholar 

  11. 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.

  12. 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.

    Article  PubMed  CAS  Google Scholar 

  13. 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.

    Article  PubMed  CAS  Google Scholar 

  14. 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.

  15. 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.

    Article  CAS  Google Scholar 

  16. 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.

    Article  PubMed  CAS  Google Scholar 

  17. 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.

    Article  PubMed  CAS  Google Scholar 

  18. 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.

    Article  PubMed  CAS  Google Scholar 

  19. Brown L, Langer R. Transdermal delivery of drugs. Annu Rev Med. 1988;39(1):221–9.

    Article  PubMed  CAS  Google Scholar 

  20. Chien YW. Novel drug delivery systems. 2nd ed. New York: M. Dekker; 1992.

    Google Scholar 

  21. Jay M, Mumper RJ. Methods and pharmaceutical compositions for decorporation of radioactive compounds. United States Patent 8,030,358; 2011.

  22. 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.

    Article  PubMed  CAS  Google Scholar 

  23. 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.

    Article  PubMed  Google Scholar 

  24. 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.

    Article  PubMed  CAS  Google Scholar 

  25. Walters KA. Dermatological and transdermal formulations: Informal HealthCare; 2002.

  26. US Food and Drug Administration. Guidance for Industry, Internal Radioactive Contamination—Development of decorporation Agents. 2006.

  27. 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.

    Article  PubMed  CAS  Google Scholar 

  28. 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.

    Article  PubMed  CAS  Google Scholar 

  29. 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.

    Article  PubMed  CAS  Google Scholar 

  30. 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.

    Book  Google Scholar 

  31. 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.

    Article  PubMed  CAS  Google Scholar 

  32. 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.

    Article  PubMed  Google Scholar 

  33. Taylor D. Some aspects of the comparative metabolism of plutonium and americium in rats. Health Phys. 1962;8(6):673–7.

    Article  PubMed  CAS  Google Scholar 

  34. Turner G, Taylor D. The transport of plutonium, americium, and curium in the blood of rats. Phys Med Biol. 1968;13:535–46.

    Article  PubMed  CAS  Google Scholar 

  35. Ménétrier F, Taylor DM, Comte A. The biokinetics and radiotoxicology of curium: a comparison with americium. Appl Radiat Isot. 2008;66(5):632–47.

    Article  PubMed  Google Scholar 

  36. 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.

    Article  PubMed  CAS  Google Scholar 

  37. 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.

    Article  PubMed  CAS  Google Scholar 

  38. 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.

    Article  PubMed  CAS  Google Scholar 

  39. 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.

  40. Roberts R, McCune S. Animal studies in the development of medical countermeasures. Clin Pharmacol Ther. 2008;83(6):918–20.

    Article  PubMed  CAS  Google Scholar 

  41. 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.

    Article  CAS  Google Scholar 

  42. Farriol M, Rosselló J, Schwartz S. Body surface area in Sprague–Dawley rats. J Anim Physiol Anim Nutr. 1997;77(1–5):61–5.

    Article  Google Scholar 

  43. 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.

    Article  PubMed  CAS  Google Scholar 

  44. Durbin P, Schmidt C. Predicting the kinetics of chelating agents in man from animal data. Heal Phys. 1989;57:165–74.

    Article  CAS  Google Scholar 

  45. 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.

    Article  CAS  Google Scholar 

Download references

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

  1. Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, CB 7362, 120 Mason Farm Rd, Chapel Hill, North Carolina, 27599-7362, USA

    Yong Zhang, Matthew P. Sadgrove, Russell J. Mumper & Michael Jay

Authors
  1. Yong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthew P. Sadgrove
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Russell J. Mumper
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Jay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Jay.

Rights and permissions

Reprints 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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12248-013-9527-x

Key words

Search

Navigation