OCCUPATIONAL RISK REDUCTION BY RADIOTOXIN CHELATION

该项目的目标是生产新的螯合剂， 容易从肠道进入血液，表现出改善 靶器官特异性(肝脏和骨骼组织) 从职业性的角度去除榄系元素和镧系元素 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接受钙-或 二乙烯三胺-五乙酸(DTPA)锌螯合物 批准的研究新药。锌-DTPA形成高价的络合物 它与吖系元素和镧系元素稳定，但它强烈 亲水性的，需要非肠道给药，在一次 速度快，靶器官特异性低，不方便 长时间地管理。新的Chelons具有基本的 结构类似于DTPA，但靶器官更高 特异性与肠道的有效吸收相结合， 适合于口服或直肠给药，将改善 整体的去除效率，并对 工人的安全。 将要开发的螯合物将由a)多氨基羧酸组成。 由长链脂肪酸或脂肪取代的酸(PACA) 酸衍生物；b)PACA单取代或双取代 烷基膦；c)碳水化合物取代的PACA； 和d)PACA单一被天然的代谢类似物取代 脂类。这些化合物的合成将从 基于二乙烯三胺(DT)和三乙烯三胺(TT)的PACA 使用有机合成的标准化方法。初步 到目前为止的研究表明，这些化合物显示出相当大的 有望在螯合疗法中使用。在化合物被 合成后，它们将在几个体外测试系统中进行测试。 根据这些结果，将对化合物的有效性进行测试 以及对暴露于吖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.