OCCUPATIONAL RISK REDUCTION BY RADIOTOXIN CHELATION

本研究的目的是开发新的，口服螯合剂 能够去除重金属的试剂。螯合疗法用于 从体内清除放射性和其他有毒金属。新的， 基于部分亲脂性聚氨基羧酸（PACA）的螯合剂具有 似乎对消除 在实验动物中口服锕系元素。这些化合物 由二乙烯三胺（DT）和三乙烯四胺（TT）组成 具有烷基侧链以增加其亲脂性的化合物 并且具有不同的末端基团以改善组织靶向。这些 药理学改进的螯合剂能够结合和去除 锕系元素，包括镅和钚，也许还有其他金属， 包括铅和铁。该项目的具体目标是：1） 测定基于TT的肠吸收和排泄动力学 螯合化合物具有不同的亲脂性。亲脂性 螯合剂的特性可以通过改变长度来改变， 导致药理学改变的烷基链结构 和药代动力学性质。这将使用放射性标记的 化合物和螯合物-金属络合物。2)继续 确定口服TT基螯合剂的疗效 具有不同亲脂性的化合物对去除 锕系元素。这些不同化合物去除Am和Pu的能力 将在体内测定。3)继续检测基于TT的螯合作用 在锕系元素脱嵌上具有不同末端部分的化合物。通过 改变烷基链上的端基，药代动力学和 组织靶向被改变。一些末端部分包括 醇、糖、酯、羧基和支链烷基链。四、 合成并测试了酚类氧增强烷基化PACAs， 锕系元素和铁的分解。可以产生更强的螯合剂 通过加入比它们碱性大得多的酚氧， 羧基氧所得到的分子应该对免疫反应非常有效。 Pu（IV）和Fe（III）的结合和去除。5)确定 锕系元素在组织和细胞中的分解和再结合 程度.中子诱导放射自显影用于确定 从组织和细胞中去除Pu-239。从这里， 螯合物的去除和钚的再结合或移位程度 可以确定。6)确定基于TT的化合物对 去除铁。这些化合物的改善的药理学性质 螯合剂可以允许化合物进入更深的Fe细胞储存。 7)确定基于TT的化合物对铅去除的有效性。 基于TT的螯合剂的细胞和组织渗透增加， 提高铅的去除率。这些研究提供了新的和独特的 螯合化合物和治疗策略， 承诺从体内清除各种有毒金属。

The goal of this research is to develop new, orally administered chelating agents capable of heavy metal removal. Chelation therapy is used for the removal of radioactive and other toxic metals from the body. New, partially lipophilic polyaminocarboxylic acid (PACA)-based chelators have been developed that appear to be remarkably effective on the decorporation of actinides when given orally in experimental animals. These compounds consist of diethylenetriamine (DT) and triethyienetetramine (TT) based compounds with alkyl side chains to increase their lipophilic character and with different terminal groups to improve tissue targeting. These pharmacologically improved chelators are capable of binding and removing actinides, including americium and plutonium, and perhaps other metals, including lead and iron. The specific aims of this project are to: 1) To determine the intestinal absorption and excretion kinetics of TT-based chelation compounds with differing lipophilic properties. The lipophilic character of the chelator can be altering by changing the length and structure of the alkyl chain which results in changes in pharmacological and pharmacokinetic properties. This will be done using radiolabeled compounds and chelate-metal complexes in situ and in vivo. 2) To continue to establish the efficacies of orally administered TT-based chelation compounds with differing lipophilic properties on the removal of actinides. The ability of these different compounds to remove Am and Pu will be determined in vivo. 3) To continue testing of TT-based chelation compounds with different terminal moieties on actinide decorporation. By changing the terminal groups on the alkyl chains, the pharmacokinetics and tissue targeting is altered. Some of the terminal moieties include alcohols, sugars, esters, carboxyl groups, and branched alkyl chains. 4) To synthesize and test phenolic oxygen-enhanced alkylated PACAs on the decorporation of actinides and iron. A stronger chelator may be produced by the addition of phenolic oxygens which are much more basic than carboxyl oxygens. The resultant molecule should be very effective for the binding and removal of Pu(IV) and Fe(III). 5) To determine the decorporation and reincorporation of actinides at the tissue and cellular levels. Neutron induced autoradiography is used to determine the decorporation of Pu-239 from tissues and cells. From this the sites of chelate decorporation and extent of reincorporation or translocation of Pu can be determined. 6) To establish the efficacy of TT-based compounds on the removal of iron. The improved pharmacological properties of these chelators may allow the compounds to access deeper cellular stores of Fe. 7) To establish the efficacy of TT-based compounds on the removal of lead. Increased cellular and tissue penetration of the TT-based chelators my enhance the removal of lead. These studies are providing new and unique chelation compounds and therapeutic strategies that have considerable promise for the removal of a variety of toxic metals from the body.