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)
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.
- Research Organization:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Organization:
- Chemical Sciences Division; Life Sciences Division
- DOE Contract Number:
- DE-AC02-05CH11231
- OSTI ID:
- 1048305
- Report Number(s):
- LBNL-4954E; HLTPAO; TRN: US1204162
- Journal Information:
- Health Physics, Vol. 99, Issue 3; ISSN 0017-9078
- Country of Publication:
- United States
- Language:
- English
Similar Records
From early prophylaxis to delayed treatment: Establishing the plutonium decorporation activity window of hydroxypyridinonate chelating agents
3,4,3-LI(1,2-HOPO): In Vitro Formation of Highly Stable Lanthanide Complexes Translates into Efficacious In Vivo Europium Decorporation
Related Subjects
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