The goal of this research is to develop new, orally administered chelating agents capable of heavy metal removal. Chelation therapy is used for the removal of radioactive and other toxic metals from the body. New, partially lipophilic polyaminocarboxylic acid (PACA)-based chelators have been developed that appear to be remarkably effective on the decorporation of actinides when given orally in experimental animals. These compounds consist of diethylenetriamine (DT) and triethyienetetramine (TT) based compounds with alkyl side chains to increase their lipophilic character and with different terminal groups to improve tissue targeting. These pharmacologically improved chelators are capable of binding and removing actinides, including americium and plutonium, and perhaps other metals, including lead and iron.
The specific aims of this project are to: 1) To determine the intestinal absorption and excretion kinetics of TT-based chelation compounds with differing lipophilic properties. The lipophilic character of the chelator can be altering by changing the length and structure of the alkyl chain which results in changes in pharmacological and pharmacokinetic properties. This will be done using radiolabeled compounds and chelate-metal complexes in situ and in vivo. 2) To continue to establish the efficacies of orally administered TT-based chelation compounds with differing lipophilic properties on the removal of actinides. The ability of these different compounds to remove Am and Pu will be determined in vivo. 3) To continue testing of TT-based chelation compounds with different terminal moieties on actinide decorporation. By changing the terminal groups on the alkyl chains, the pharmacokinetics and tissue targeting is altered. Some of the terminal moieties include alcohols, sugars, esters, carboxyl groups, and branched alkyl chains. 4) To synthesize and test phenolic oxygen-enhanced alkylated PACAs on the decorporation of actinides and iron. A stronger chelator may be produced by the addition of phenolic oxygens which are much more basic than carboxyl oxygens. The resultant molecule should be very effective for the binding and removal of Pu(IV) and Fe(III). 5) To determine the decorporation and reincorporation of actinides at the tissue and cellular levels. Neutron induced autoradiography is used to determine the decorporation of Pu-239 from tissues and cells. From this the sites of chelate decorporation and extent of reincorporation or translocation of Pu can be determined. 6) To establish the efficacy of TT-based compounds on the removal of iron. The improved pharmacological properties of these chelators may allow the compounds to access deeper cellular stores of Fe. 7) To establish the efficacy of TT-based compounds on the removal of lead. Increased cellular and tissue penetration of the TT-based chelators my enhance the removal of lead. These studies are providing new and unique chelation compounds and therapeutic strategies that have considerable promise for the removal of a variety of toxic metals from the body.
