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Title: Biomimetic Actinide Chelators: An Update on the Preclinical Development of the Orally Active Hydroxypyridonate Decorporation Agents 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO)

Abstract

The threat of a dirty bomb or other major radiological contamination presents a danger of large-scale radiation exposure of the population. Because major components of such contamination are likely to be actinides, actinide decorporation treatments that will reduce radiation exposure must be a priority. Current therapies for the treatment of radionuclide contamination are limited and extensive efforts must be dedicated to the development of therapeutic, orally bioavailable, actinide chelators for emergency medical use. Using a biomimetic approach based on the similar biochemical properties of plutonium(IV) and iron(III), siderophore-inspired multidentate hydroxypyridonate ligands have been designed and are unrivaled in terms of actinide-affinity, selectivity, and efficiency. A perspective on the preclinical development of two hydroxypyridonate actinide decorporation agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), is presented. The chemical syntheses of both candidate compounds have been optimized for scale-up. Baseline preparation and analytical methods suitable for manufacturing large amounts have been established. Both ligands show much higher actinide-removal efficacy than the currently approved agent, diethylenetriaminepentaacetic acid (DTPA), with different selectivity for the tested isotopes of plutonium, americium, uranium and neptunium. No toxicity is observed in cells derived from three different human tissue sources treated in vitro up to ligand concentrations of 1 mM, and both ligandsmore » were well tolerated in rats when orally administered daily at high doses (>100 micromol kg d) over 28 d under good laboratory practice guidelines. Both compounds are on an accelerated development pathway towards clinical use.« less

Authors:
; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
Chemical Sciences Division; Life Sciences Division
OSTI Identifier:
1048305
Report Number(s):
LBNL-4954E
Journal ID: ISSN 0017-9078; HLTPAO; TRN: US1204162
DOE Contract Number:  
DE-AC02-05CH11231
Resource Type:
Journal Article
Journal Name:
Health Physics
Additional Journal Information:
Journal Volume: 99; Journal Issue: 3; Journal ID: ISSN 0017-9078
Country of Publication:
United States
Language:
English
Subject:
07 ISOTOPES AND RADIATION SOURCES; 60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL AND ANALYTICAL CHEMISTRY; 61 RADIATION PROTECTION AND DOSIMETRY; ACTINIDES; AMERICIUM; ANIMAL TISSUES; CONTAMINATION; DTPA; EFFICIENCY; IN VITRO; MANUFACTURING; NEPTUNIUM; PLUTONIUM; RADIATIONS; RADIOISOTOPES; RADIOLOGICAL DISPERSAL DEVICES; RECOMMENDATIONS; TOXICITY; URANIUM

Citation Formats

Durbin, Patricia W., Kullgren, Birgitta, Ebbe, Shirley N., Xu, Jide, Chang, Polly Y., Bunin, Deborah I., Blakely, Eleanor A., Bjornstad, Kathleen A., Rosen, Chris J., Shuh, David K., and Raymond, Kenneth N.. Biomimetic Actinide Chelators: An Update on the Preclinical Development of the Orally Active Hydroxypyridonate Decorporation Agents 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO). United States: N. p., 2011. Web.
Durbin, Patricia W., Kullgren, Birgitta, Ebbe, Shirley N., Xu, Jide, Chang, Polly Y., Bunin, Deborah I., Blakely, Eleanor A., Bjornstad, Kathleen A., Rosen, Chris J., Shuh, David K., & Raymond, Kenneth N.. Biomimetic Actinide Chelators: An Update on the Preclinical Development of the Orally Active Hydroxypyridonate Decorporation Agents 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO). United States.
Durbin, Patricia W., Kullgren, Birgitta, Ebbe, Shirley N., Xu, Jide, Chang, Polly Y., Bunin, Deborah I., Blakely, Eleanor A., Bjornstad, Kathleen A., Rosen, Chris J., Shuh, David K., and Raymond, Kenneth N.. Wed . "Biomimetic Actinide Chelators: An Update on the Preclinical Development of the Orally Active Hydroxypyridonate Decorporation Agents 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO)". United States. https://www.osti.gov/servlets/purl/1048305.
@article{osti_1048305,
title = {Biomimetic Actinide Chelators: An Update on the Preclinical Development of the Orally Active Hydroxypyridonate Decorporation Agents 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO)},
author = {Durbin, Patricia W. and Kullgren, Birgitta and Ebbe, Shirley N. and Xu, Jide and Chang, Polly Y. and Bunin, Deborah I. and Blakely, Eleanor A. and Bjornstad, Kathleen A. and Rosen, Chris J. and Shuh, David K. and Raymond, Kenneth N.},
abstractNote = {The threat of a dirty bomb or other major radiological contamination presents a danger of large-scale radiation exposure of the population. Because major components of such contamination are likely to be actinides, actinide decorporation treatments that will reduce radiation exposure must be a priority. Current therapies for the treatment of radionuclide contamination are limited and extensive efforts must be dedicated to the development of therapeutic, orally bioavailable, actinide chelators for emergency medical use. Using a biomimetic approach based on the similar biochemical properties of plutonium(IV) and iron(III), siderophore-inspired multidentate hydroxypyridonate ligands have been designed and are unrivaled in terms of actinide-affinity, selectivity, and efficiency. A perspective on the preclinical development of two hydroxypyridonate actinide decorporation agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), is presented. The chemical syntheses of both candidate compounds have been optimized for scale-up. Baseline preparation and analytical methods suitable for manufacturing large amounts have been established. Both ligands show much higher actinide-removal efficacy than the currently approved agent, diethylenetriaminepentaacetic acid (DTPA), with different selectivity for the tested isotopes of plutonium, americium, uranium and neptunium. No toxicity is observed in cells derived from three different human tissue sources treated in vitro up to ligand concentrations of 1 mM, and both ligands were well tolerated in rats when orally administered daily at high doses (>100 micromol kg d) over 28 d under good laboratory practice guidelines. Both compounds are on an accelerated development pathway towards clinical use.},
doi = {},
journal = {Health Physics},
issn = {0017-9078},
number = 3,
volume = 99,
place = {United States},
year = {2011},
month = {7}
}