Alpha particle emissions of actinides deposited in bone, liver, or lungs (if inhaled) induce cancer. Actinide complexion by transferrin in plasma blocks excretion and facilitates deposition in target tissues. The only known way to reduce cancer risk is acceleration of actinide excretion with chelating agents. The goal of this research is to develop low toxicity ligands, more effective for in vivo actinide chelation than clinically approved CaNa3-DTPA. Similarities in coordination properties of Pu(IV) and Fe(III) suggested that macromolecules composed of bidentate Fe(III)-binding groups of microbial iron-sequestering agents (siderophores) would complex Pu(IV) at pH 7 and spare essential divalent metals. Binding groups include catechol [CAM, modified by adding -- sulfonate, CAM(S); carboxyl, CAM(C); amide, TAM] and hydroxypyridinone isomers [1,2-HOPO, 3,2-HOPO, 3,4-HOPO]. Structural backbones used to date are: aminoalkane (spermine, 3,4,3-L, stable and flexible but hard to synthesize); ethylenediamine, H(2,2); triethyleneamine, TREN; desferrioxamine (DFO, with attachment of a fourth functional group). Ligands (injected or oral) are evaluated initially in mice for promoting excretion of 238Pu(IV), in some cases also 241Am(III) and 237Np(V), and for acute toxicity. Among the many ligands evaluated, nine, injected or administered orally, promoted more Pu excretion than an equimolar amount of CaNa3-DTPA. The new ligands and CaNa3-DTPA were ranked for Pu excretion after ligand injection or gavage, in vivo stability of Pu complex (Pu residue in kidneys), acute toxicity, and in vivo chelation of Am and Np. Ligands with the best combined rankings greater than CaNa3-DTPA are: 3,4,3-LI(1,2-HOPO), DFO-(1,2-HOPO), TREN-(3,2-HOPO), H(2,2)-(3,2-HOPO) (ligands composed of 3,4-HOPO were inferior to CaNa3- DTPA). 3,4,3-LI(1,2-HOPO) is acutely toxic, and DFO-(,2-HOPO) is only moderately effective orally and does not bind Am(III). The ligands composed of 3,2-HOPO are highly effective orally, stably bind Am(III), and are of low to moderate toxicity in preliminary tests. Planned research is focused on those encouraging 3,2-HOPO ligands, as follows: (1) Evaluation of 3,2-HOPO ligands with new backbones to optimize molecular structure; (2) Determination of dosage-effectiveness; (3) Evaluation of potency for removing deposited Pu by repeated injections or gavage and implanted osmotic pumps; (4) Definition of biokinetics using colorimetry of Fe(III) complexes and 3H-labelled 3,2-HOPO; (5) Extension of studies of acute toxicity based on daily injections of 100 micromole kg-1; (6) Verification of potency for in vivo chelation of 237Np(V) and exploration of potency for in vivo chelation of 234,235U(VI) and 210Pb(II), which also form stable oxy-complexes.
