This application is in response to RFA-A1-06-030, Radionuclide Decorporation Agents for Radiation/Nuclear Emergencies: Project BioShield (ROl). We propose to further develop a series of amphipathic, orally administered, polyaminocarboxylic (PACA) chelators. These are based on triethylenetetraminehexaacetic acid (TT) and are related to diethylenetriamine-pentaacetic acid (DTPA). The orally administered amphipathic TT chelators are very effective for the elimination of systemic deposits of americium and plutoniurn) and some transition metals. They also have broad chemical binding affinities for a range of potentially toxic metals. We propose 3 studies. 1) To perform pharmacokinetic (PK) studies to determine the absorption, distribution, metabolism and excretion of the TT chelators as a function of their amphipathic properties. C-14 labeled compounds will be synthesized and tested using established PK methods. These data will help optimize chelator design and dose range profiles. 2) To determine the binding stabilities for a range of metals and determine the ability of the amphipathic TT chelators to extract these metals in vitro. Liver and erythrocyte assays will determine the binding and extraction of metals to include uranium, cobalt, strontium and cerium. These data will help optimize chelator design for various metals for the in vivo studies. 3) To determine the ability of the orally administered TT chelators, to promote excretion of internally incorporated metals. The same metals as used in study 2 will be used (U, Co, Sr, Ce) and these represent different chemical classes (e.g. actinide, transition metal, alkaline earth metal and lanthanide) and their radioactive isotopes are potential components of a radiological dispersion device. Effective doses of injected DTPA will be used as a comparison control. Further development may include specific radionuclide efficacy studies, perhaps to include exposures by different routes (e.g. inhalation, wounds). Regulatory compliant toxicity and safety studies should to be conducted. Because the pharmacology and toxicology of PACA chelators, such as DTPA and EDTA, are quite well understood, the development pathway of the related TT-based chelators may proceed rapidly. ? ? ? ?
| Miller, Scott C; Wang, Xuli; Bowman, Beth M (2010) Pharmacological properties of orally available, amphipathic polyaminocarboxylic acid chelators for actinide decorporation. Health Phys 99:408-12 |
