The alpha-particle emissions of the actinides (Pu, Am, Np) induce cancer in bone, liver, and lung (if inhaled), and U is a kidney poison. The only known way to reduce the health risks of internally deposited actinides is to accelerate their excretion with chelating agents.
This research aims to develop low toxicity ligands, more effective than CaNa3-DTPA for in vivo chelation of actinides. Similar coordination properties of Fe(III) and Pu(IV) suggested that synthetic ligands containing the bidentate Fe(III)-binding groups of microbial iron-sequestering agents (siderophores) would stably complex Pu at Ph 7 and spare essential divalent metals. Multidentate ligands were synthesized containing the hydroxypyridinone isomers (1,2-HOPO, Me-3,3-HOPO), several based on backbones providing the favorable 5-unit intergroup spacing of the siderophores. They were evaluated for toxicity and in vivo chelation of actinides in mice by injection and orally; they are the most effective siderophore analogues for chelating actinides in vivo, and all promote significantly more actinide excretion than CaNa3-DTPA. These are the first ligands shown to chelate Np(V) and U(VI) in vivo. Linear tetradentate 5-Li(Me-3,2-HOPO) based on diaminopentane and 5-LIO-(Me-3,2-HOPO) based on diaminoethyl ether are highly effective for U(VI); hexadentate TREN-(Me-3,2-HOPO) based on triaminoethyleneamine is highly effective for Am(III); octadentate H(2,2)-(Me-3,2-HOPO) based on tetrakis-(2-aminoethylene)amine and spermine based 3,4,3-LI(1,2-HOPO) are highly effective for Pu(IV) and Np(V). Research plans focus on the HOPO ligands: 1. Identifying the most favorable HOPO ligand for Pu and Np, by synthesis of H(2,2)-(1,2-HOPO) and 3,4,3-(Me-3,2-HOPO) and resynthesis of 3,4,2-LI(1,2-HOPO) and evaluating them in mice for removal of deposited Pu and Np and for toxicity. 2. Identifying the most favorable ligand for U(VI), by synthesis of four linear tetradentate ligands containing catecholamide (CAM) or 1,2-HOPO groups and evaluating them in mice for reduction of kidney and bone U and for toxicity. 3. Conducting biokinetic studies of HOPO ligands in mice, using colorimetry of ferric complexes, to measure GI absorption and define excretory pathways and rates. 4. Conducting in vivo studies of ligand action at the tissue level, using bone ash and whole bone powder, liver membranes, lysosomes and cytosol, and kidney membranes and cytosol prepared from actinide-injected mice. Those actinide-containing tissue constituents will be incubated with CAM and HOPO ligands over a range of concentrations to evaluate the amounts and rates of removal of tissue-bound actinides and determine relative ligand potencies, and to investigate the influence of biological barriers that limit ligand access to actinides deposited in tissues in vivo.
