The goal of this project is to develop chelating agents capable of heavy metal decorporation and to reduce radionuclide toxicity by the oral application of these chelators. At present, occupationally exposed individuals are treated with Ca- and Zn-chelates of diethylenetriamine- pentaacetic acid (DTPA). DTPA forms chelates with high stability but is strongly hydrophilic, requires parenteral administration and is rapidly excreted. In the first 2 years of this project, we have designed, synthesized and tested several classes of new chelation compounds. From in vitro testing, several diethylenetriamine-(DT) and triethylenetetramine- (TT) based compounds were identified and tested in vivo. When given orally they are very effective in removing aged 241Am deposits in rats. Am is used as a model of 5f-orbital elements. Specifically we propose to: 1) Continue in vivo testing to determine dose and time effects of DT and TT- based chelons on Am and Pu removal. Excretion rates will be determined and tissue localization patterns of Pu will be obtained by neutron-induced autoradiography. Other classes of polyaminocarboxylic acids will be tested following successful in vitro testing. 2) To determine the efficiency of DT- and TT-based chelons on the decorporation of metals other than actinides. These chelons will bind Pb and Fe and initial studies will be done with Pb, which is a significant environmental and occupational toxin. 3) To develop, synthesize and test chelons with improve target organ specificity. For this, chemical moieties, some analogous to endogenous substrates, will be attached to the polyaminocarboxylic acids. This may offer considerable therapeutic advantage. 4) To determine the organ and tissue distribution of orally administered chelons. Select radiolabeled chelons will be synthesized and their distribution determined using biochemical and autoradiographic methods. 5) To determine the skeletal effects of long term (>6 years) chelation treatment (DTPA) in dogs. We obtained complete skeletons from animals involved in another study and will determine skeletal changes using static and dynamic histomorphometric methods. This will provide some unique and practical information on long term chelation therapy. These studies should lead to the development of new chelation agents that may substantially improve therapeutic approaches for the reduction of toxicity from actinide, lanthanide and perhaps other metals.
