Biomimetic Lanthanide & Actinide Decorporation Agents: Preclinical Development

描述（由申请人提供）：由于可能的放射性核素及其化学/生物学特性的多样性，治疗脏弹或其他事件造成的大量人群放射性同位素污染需要使用去污剂混合物。促排是减少某些掺入的放射性同位素暴露的唯一方法。裂变产物镧系元素和锕系元素是这些元素中最难分解的。虽然二亚乙基三胺五乙酸（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用于锕系元素/镧系元素脱硝的标准疗法，但其功效有限。一个新的家庭的螯合剂已开发使用仿生设计的基础上类似的生化运输性质的钚（IV）和铁（III）和铁载体，天然铁螯合剂的细菌。这些螯合剂对钚（IV）和许多其他锕系金属离子具有更高的选择性和亲和力。已经发表了使用小鼠模型进行的广泛的毒性和功效研究，并且在狗和狒狒中进行了有限的测试。结果表明，几种新药物比DTPA有效得多，并且与DTPA不同，可以口服。本项目提出以两种先导化合物3，4，3-Li-i，2-HOPO（八齿配体）和5-LIO-Me-3，2-HQPO（一种四齿配体）用于临床应用，方法是按比例扩大合成，建立适合于良好生产规范（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功效和毒性研究，完成人类细胞系中的毒性研究，并根据良好实验室实践（GLP）指南建立候选配体的临床前安全性。这项研究的目的是提出两种新的去甲肾上腺素药物，并成功地加速其开发到IND前阶段，在全面IND申请之前，只剩下灵长类动物研究。这将通过劳伦斯伯克利国家实验室（LBNL）与SRI国际的有效合作来实现，劳伦斯伯克利国家实验室（LBNL）拥有配体设计，合成和实验室测试的专业知识，SRI国际拥有GLP测试和将药品推向市场的专业知识。

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.