AMPHIPATHIC ORAL CHELATORS AND RADIONUCLIDE CONTAMINATION

两亲性口腔螯合剂和放射性核素污染

基本信息

批准号：
7568517
负责人：
SCOTT C. MILLER
金额：
$ 59.56万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-01 至 2009-09-30
项目状态：
已结题

项目摘要

This application is in response to RFA-A1-06-030, Radionuclide Decoproration Agents for Radiation/Nuclear Emergencies: Project BioShield (R01). 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 plutonium)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 Jtudies, 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.

该应用是响应RFA-A1-06-030，放射性核素解释剂用于辐射/核的剂量紧急情况：Bioshield项目（R01）。我们建议进一步发展一系列两亲性，口头给药，聚氨基羧基（PACA）螯合剂。这些基于三乙烯乙酰胺乙酰乙酰乙酰乙醇酸（TT）与二乙烯氨基三乙酸（DTPA）有关。口服管理两亲性TT螯合剂非常有效地消除美国的全身矿床和 prutonium）和一些过渡金属。他们还具有广泛的化学结合亲和力潜在的有毒金属。我们提出了3项研究。 1）进行药代动力学（PK）研究以确定 TT螯合剂的吸收，分布，代谢和排泄随其两亲性的作用特性。 C-14标记化合物将使用已建立的PK方法合成和测试。这些数据。将有助于优化螯合剂设计和剂量范围。 2）确定a的结合稳定性金属范围并确定两亲性TT螯合剂在体外提取这些金属的能力。 .. 肝脏和红细胞分析将确定金属的结合和提取，包括铀，钴，锶和处值。这些数据将有助于优化体内各种金属的螯合剂设计研究。 3）确定口服施用TT螯合剂的能力，促进内部排泄合并金属。将使用与研究2中使用的金属相同的金属（U，CO，SR，CE），这些代表不同的化学类别（例如，actacinide，过渡金属，碱土金属和灯笼）及其放射性同位素是放射性分散装置的潜在组成部分。有效注射剂量 DTPA将用作比较控制。进一步的发展可能包括特定的放射性核素功效 JTudies，也许包括通过不同途径的暴露（例如吸入，伤口）。符合法规的规定毒性和安全研究应进行。因为PACA的药理学和毒理学 Chelators，例如DTPA和EDTA，都对相关TT-的发展途径进行了充分的了解基于的螯合剂可能会迅速进行。