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)
- 1 September 2010
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Health Physics
- Vol. 99 (3), 401-407
- https://doi.org/10.1097/hp.0b013e3181c21273
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 ligands were well tolerated in rats when orally administered daily at high doses (>100 μmol kg−1 d−1) over 28 d under good laboratory practice guidelines. Both compounds are on an accelerated development pathway towards clinical use.Keywords
This publication has 16 references indexed in Scilit:
- LAURISTON S. TAYLOR LECTURE: THE QUEST FOR THERAPEUTIC ACTINIDE CHELATORSHealth Physics, 2008
- Rational Design of Sequestering Agents for Plutonium and Other ActinidesChemical Reviews, 2003
- Synchrotron infrared spectromicroscopy as a novel bioanalytical microprobe for individual living cells: cytotoxicity considerationsJournal of Biomedical Optics, 2002
- Synthesis of 3,4,3 LI 1,2 HOPO labelled with14CJournal of Labelled Compounds and Radiopharmaceuticals, 2001
- 237NpHealth Physics, 1998
- Specific Sequestering Agents for the Actinides. 28. Synthesis and Initial Evaluation of Multidentate 4-Carbamoyl-3-hydroxy-1-methyl-2(1H)-pyridinone Ligands for in Vivo Plutonium(IV) ChelationJournal of Medicinal Chemistry, 1995
- Gadolinium complex of tris[(3-hydroxy-1-methyl- 2-oxo-1,2-didehydropyridine-4-carboxamido)ethyl]-amine: A New Class of gadolinium magnetic resonance relaxation agentsJournal of the American Chemical Society, 1995
- Specific sequestering agents for the actinides. 16. Synthesis and initial biological testing of polydentate oxohydroxypyridinecarboxylate ligandsJournal of Medicinal Chemistry, 1988
- Ferric ion sequestering agents. 13. Synthesis, structures, and thermodynamics of complexation of cobalt(III) and iron(III) tris complexes of several chelating hydroxypyridinonesInorganic Chemistry, 1985
- Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assaysJournal of Immunological Methods, 1983