The goal of this project is to produce new chelating agents that pass easily from the intestine into the blood and show improved target organ specificity (liver and skeletal tissue) for the removal of actinide and lanthanide elements from occupationally contaminated humans. At present workers in the nuclear and chemical industry contaminated with these elements are being treated with the Ca- or Zn-chelate of diethylenetriamine-pentaacetic acid (DTPA), an approved investigational new drug. Zn-DTPA forms a chelate of high stability with actinides and lanthanides, but it is strongly hydrophilic, requires parenteral administration, is excreted at a fast rate, has a low target organ specificity and is inconvenient to administer over long periods of time. New chelons with a basic structure similar to DTPA but having higher target organ specificity coupled with efficient absorption from the intestine, suitable for oral or rectal administration, will improve the overall efficiency of removal and contribute significantly to the safety of workers. The chelons to be developed will consist of a) polyaminocarboxylic acids (PACA) monosubstituted by a long chain fatty acid or fatty acid derivative; b) PACA mono- or disubstituted by alkylphosphonates; c) PACA substituted with carbohydrate moieties; and d) PACA monosubstituted with metabolic analogues of natural lipids. These compounds will be synthesized beginning with diethylenetriamine (DT)- and triethylenetriamine (TT)-based PACA using standardized methods of organic synthesis. Preliminary studies to date suggest that these compounds show considerable promise for use in chelation therapy. After the compounds are synthesized they will be tested in several in vitro assay systems. Based upon these results the compounds will be tested for efficacy and toxicity in mice and rats exposed to actinides.
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