The actinide elements (nearly all alpha emitters) are carcinogenic if deposited and retained in bone, lung or liver. They are poorly excreted and largely recirculated and redeposited; the only way known to reduce the radiation risk is to accelerate their excretion with chelating agents. Potent, selective iron-sequestering agents elaborated by microorganisms contain weakly acidic functional groups--catechol in enterobactin and hydroxamate in the ferrioxamines. The similar chemical and circulatory transport properties of Pu(IV) and Fe(III) suggested that macromolecules containing those electron-donor groups would chelate Pu(IV) at pH 7 and not bind essential divalent metals. Macromolecules have been prepared containing catechoylamide (CAM), hydroxamate (DFO), and/or hydroxypyridinone (HOPOCAM) groups connected by alkyl chains. The potency of those ligands for promoting Pu(IV) excretion in mice has been demonstrated by assaying Pu in excreta and tissues at 24 hr, when 238Pu(IV) citrate was injected i.v., and 30 Mumole/kg of ligand was given i.p. 1 hr later. The most effective ligands are straight-chain structures containing three or four functional groups acidified with a sulfonate (CAMS) or carboxylate (CAMC) substitutent on the benzene rings; and hydrophilicity can be controlled, their excretory route shifted to feces, and their biological retention prolonged by adding alkyl groups to the terminal N's. All ligands are tested for acute toxicity. Less hydrophilic ligands are tested for delayed Pu excretion (7 days). Prototype ligands are (or will be) tested for dosage-effectiveness and the efficacy of extended multiple ligand injections. Planned research includes: screening new ligands for Pu removal and acute toxicity; completing the above tests and obtaining descriptions of the biokinetics for the prototypes, 3,4,3-LICAM(C), desferriCAM(C) and 3,4-HOPOCAM; conduct of special studies (e.g., stop-flow preparation) to investigate renal tubular secretion of the hydrophilic, sulfonated CAM ligands; development of a test of oral ligand activity; and development of an in vitro test of ligand toxicity using cultured C3HT101/2 (mouse embryo) cells to supplement in vivo toxicity screening.
