Biomimetic Lanthanide & Actinide Decorporation Agents: Preclinical Development

描述（由申请人提供）：由于可能存在的放射性核素及其化学/生物特性种类繁多，因此对大量人口受到脏弹或其他事件的放射性同位素污染的治疗将需要混合除污剂。脱孔是减少某些放射性同位素掺入的唯一途径。裂变产物镧系元素和锕系元素是这些元素中最难分解的。虽然二乙烯三胺五乙酸（DTPA）自20世纪50年代由美国原子能委员会开发和使用以来一直是锕系元素/镧系元素降解的标准治疗方法，但其疗效有限。基于钚（IV）、铁（il）和铁载体（细菌的天然铁螯合剂）相似的生化运输特性，采用仿生设计开发了一类新的螯合剂。这些螯合剂选择性更强，对钚（IV）和许多其他锕系金属离子具有更高的亲和力。已经发表了使用小鼠模型的广泛毒性和功效研究，并在狗和狒狒中进行了有限的测试。结果表明，几种新制剂比DTPA更有效，并且与DTPA不同的是，它们可以口服有效。本项目拟将两种先导化合物3,4,3- li -i,2-HOPO（一种八齿配体）和5- lio - me -3,2- hqpo（一种四齿配体）规模化合成，建立符合GMP的制备方法，在小鼠模型中对两种螯合剂的组合进行有限的疗效和毒性研究，完成对人类细胞系的毒性研究。并根据良好实验室规范（GLP）指南建立候选配体的临床前安全性。这项研究的目的是同时提出两种新的去孔剂，并成功地将它们的开发加速到IND前阶段，在IND全面应用之前，只有灵长类动物的研究仍然存在。这将通过劳伦斯伯克利国家实验室（LBNL）与SRI国际（SRI International）的有效合作来实现，前者在igand设计、合成和实验室测试方面具有专业知识，后者在GLP测试和将制药产品推向市场方面具有专业知识。

DESCRIPTION (provided by applicant): Therapy for radioisotope contamination of a large population by a dirty bomb or other event will require a cocktail of decorporation agents because of the wide variety of possible radionuclides and their chemical/biological properties. Decorporation is the only way to reduce exposure of certain incorporated radioisotopes. Fission product lanthanides and the actinides are among the most intractable of these elements to decorporate. While diethylenetriaminepentaacetic acid (DTPA) has been the standard therapy for actinide/lanthanide decorporation since its development and use by the U.S. Atomic Energy Commission in the 1950's, it is limited in efficacy. A new family of sequestering agents has been developed using a biomimetic design based on the similar biochemical transport properties of plutonium(IV) and iron(IIl) and siderophores, the natural iron chelators of bacteria. These chelators are more selective and have higher affinity for plutonium(IV) and a number of other actinide metal ions. Extensive toxicity and efficacy studies using a mouse model have been published and limited tests have been done in dogs and baboons. The results established that several of the new agents are much more effective than DTPA and, unlike DTPA, can be orally active. This project proposes to take two lead compounds 3,4,3-LI-i ,2-HOPO (an octadentate ligand) and 5-LIO-Me-3,2-HQPO (a tetradentate ligand) toward clinical use by scaling up the synthesis, establishing preparation methods suitable for good manufacturing practice (GMP), carrying out limited efficacy and toxicity studies for combinations of the two chelators in a mouse model, completing toxicity studies in human cell lines, and establishing preclinical safety of the candidate ligands under good laboratory practice (GLP) guidelines. The objective of this research is to bring forth two new decorporation agents in tandem and successfully accelerate their development to a pre-IND stage where only primate studies remain prior to a full IND application. This will be accomplished by an effective partnering of Lawrence Berkeley National Laboratory (LBNL) that has expertise in Iigand design, synthesis, and laboratory testing, with SRI International which possesses expertise in GLP testing and bringing pharmaceutical products to market.