OCCUPATIONAL RISK REDUCTION BY RADIOTOXIN CHELATION

这项研究的目标是开发新的口服螯合制剂。 能够去除重金属的试剂。螯合疗法用于治疗 从体内清除放射性和其他有毒金属。新的, 部分亲脂性多氨基甲酸(PACA)基络合剂具有 已经被开发出来，看起来对去孔化非常有效 在实验动物中口服时的放线物。这些化合物 由二乙烯三胺(DT)和三乙烯四胺(TT)组成 具有烷基侧链的化合物以提高其亲油性 并且具有不同的末端基团以提高组织靶向性。这些 经过药物改良的螯合剂能够结合和去除 氡化物，包括Am和Pu，也许还有其他金属， 包括铅和铁。该项目的具体目标是：1) 甲氨蝶呤的肠道吸收和排泄动力学研究 具有不同亲油性的螯合化合物。亲油性 通过改变长度和长度可以改变螯合剂的性质 导致药理变化的烷基链的结构 和药代动力学特性。这将使用无线电标记来完成 原位和体内的化合物和络合金属络合物。2)继续 口服TT基络合剂的有效性研究 具有不同亲油性的化合物对脱色效果的影响 放线菌。这些不同化合物对Am和Pu的去除能力 将在活体内确定。3)继续进行基于TT的螯合试验 具有不同端基的化合物对榄系元素脱孔的影响。通过 改变烷基链上的端基，药物动力学和 组织靶向被改变。一些终端部件包括 醇、糖、酯、羧基和支链。4) 合成了酚氧增强烷基化PACA，并在 色散和铁的脱孔作用。可能会生产出更强的螯合剂 通过添加比碱性更强的酚氧 羧基含氧化合物。生成的分子应该对 Pu(IV)和Fe(III)的结合和去除。5)确定 放线系元素在组织和细胞中的脱孔和再结合 级别。使用中子诱导放射自显影技术来确定 Pu-239从组织和细胞中脱去孢子。从这一点来看， Pu的螯合脱孔和重新结合或移位的程度 可以确定。6)确定基于TT的化合物对 铁的去除。这些化合物的改进的药理特性 螯合剂可能会让这些化合物进入细胞内更深层次的铁储存。 7)确定基于TT的化合物对铅的去除效果。 基于TT的螯合剂的细胞和组织渗透率增加 加强铅的去除。这些研究提供了新的和独特的 螯合化合物和治疗策略具有相当大的 承诺清除体内的各种有毒金属。

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.