OCCUPATIONAL RISK REDUCTION BY RADIOTOXIN CHELATION

通过放射性毒素螯合降低职业风险

• 批准号: 3191427
• 负责人: SCOTT C. MILLER
• 金额: $ 13.86万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-03-15 至 1991-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3191427
• 关键词: acetates; actinides; alkylphosphate; calcium; carboxylate; chelating agents; dosage; gastrointestinal absorption /transport; laboratory mouse; laboratory rat; liver pharmacology; occupational hazard; phosphonate; polyamines; radiobiology; rare earth element; skeletal pharmacology; zinc

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.

该项目的目的是生产新的螯合剂 轻松从肠道传递到血液中并显示出改善 针对器官特异性（肝脏和骨骼组织） 从职业中删除actacinide和Lanthanide元素 被污染的人类。 目前核化学工业的工人 用这些元素污染了CA-或 二乙烯甲氨基三乙酸（DTPA）的Zn-氯酸盐，A 批准的研究新药。 Zn-DTPA形成高的螯合物 与actinides和Lanthanides的稳定性，但强烈 需要肠胃外给药的亲水性在A处排泄 快速速率，具有较低的目标器官特异性，不方便 长时间管理。 带基本的新螯 结构类似于DTPA，但具有较高的靶器官 特异性以及从肠中有效吸收的特异性， 适合口服或直肠管理，将改善 拆卸的总体效率，并对 工人的安全。 将要开发的CHELON将包括a）聚氨基辅助羧基 由长链脂肪酸或脂肪产生的酸（PACA）单卜 酸衍生物； b）paca mono-或由 烷基膦酸酯； c）paca用碳水化合物部分代替； d）用天然的代谢类似物的paca单卜生成分 脂质。 这些化合物将从 基于二乙烯甲胺（DT） - 基于三乙基苯甲胺（TT）的PACA 使用标准化的有机合成方法。 初步的 迄今为止的研究表明，这些化合物显示出相当大的 有望在螯合治疗中使用。 化合物是 合成它们将在几个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 和暴露于肌动剂的小鼠和大鼠的毒性。