OCCUPATIONAL RISK REDUCTION BY RADIOTOXIN CHELATION

该项目的目标是生产新的螯合剂， 很容易从肠道进入血液， 靶器官特异性（肝脏和骨骼组织） 从职业中除去锕系和镧系元素 被污染的人类 目前，核工业和化学工业的工人 被这些元素污染的人正在用钙或 二乙烯三胺五乙酸锌螯合物（DTPA）， 已批准的研究性新药。 Zn-DTPA形成高浓度的螯合物， 稳定与锕系元素和镧系元素，但它是强烈的 亲水性，需要胃肠外给药，以 速度快，靶器官特异性低，不方便 长期服用。 新的海龟有一个基本的 结构与DTPA相似，但靶器官更高 特异性加上肠道的有效吸收， 适用于口服或直肠给药，将改善 整体去除效率，并有助于显着 工人的安全。 待开发的螯合剂将由a）聚氨基羧酸 被长链脂肪酸或脂肪酸单取代的脂肪酸（PACA） 酸衍生物; B）PACA，其被 c）被碳水化合物部分取代的PACA; 和d）被天然的PACA的代谢类似物单取代的PACA， 脂质。 这些化合物的合成将从 基于二亚乙基三胺（DT）和三亚乙基三胺（TT）的PACA 使用标准化的有机合成方法。 初步 迄今为止的研究表明，这些化合物显示出相当大的 有望用于螯合疗法。 在化合物被 合成后，它们将在几种体外测定系统中进行测试。 基于这些结果，将测试化合物的功效 以及接触锕系元素的小鼠和大鼠的毒性。

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.