Biomimetic Lanthanide & Actinide Decorporation Agents: Preclinical Development

仿生镧系元素

• 批准号: 7585996
• 负责人: KENNETH N RAYMOND
• 金额: $ 87.85万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2009-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585996
• 关键词: Acids; Actinoid Series Elements; Affinity; Bacteria; Biochemical; Biological; Biomimetics; Canis familiaris; Chelating Agents; Chemicals; Clinical; Development; Elements; Event; Family; Human Cell Line; International; Ions; Iron; Laboratories; Lanthanoid Series Elements; Lead; Ligands; Marketing; Methods; New Agents; Nuclear Energy; Numbers; Papio; Pharmacologic Substance; Plutonium; Population; Practice Guidelines; Preparation; Primates; Property; Publishing; Radioisotopes; Research; Safety; Siderophores; Staging; Standards of Weights and Measures; Testing; Toxic effect; base; design; dirty bomb; ferryl iron; mouse model; pre-clinical; scale up

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(lll) 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 efficacystudies 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-1,2-HOPO (anoctadentate ligand) and 5-LIO-Me-3,2-HOPO (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 goodlaboratory }practice (GLP) guidelines. The objective of this research is to bring forth two new decorporation agents in tandem andsuccessfully 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 ligand design, synthesis, and laboratory testing, with SRI International which possesses expertise in GLP testing and bringing pharmaceutical products to market.

通过肮脏的炸弹或其他事件对大众污染的放射性同位素污染的治疗将需要 装饰剂的鸡尾酒是由于种类繁多的放射性核素及其 化学/生物学特性。装饰是减少某些合并的曝光的唯一方法 放射性同位素。裂变产物灯笼和阳离子是其中最棘手的 装饰元素。虽然二乙烯酸苯甲酸乙酸（DTPA）一直是标准疗法 自美国原子能委员会的开发和使用以来 在1950年代，它的功效受到限制。使用了一个新的隔离剂家族 基于p的类似生化转运特性（IV）和铁（LLL）和 铁载体，细菌的天然铁螯合剂。这些螯合剂更具选择性，并且具有更高的 对p的亲和力（IV）和许多其他actinide金属离子。广泛的毒性和有效研究 使用小鼠模型已经发布，并且在狗和狒狒中进行了有限的测试。这 结果表明，几种新代理比DTPA更有效，与DTPA不同， 可以口服活跃。该项目建议服用两种铅化合物3,4,3-LI-1,2-HOPO（anoctadentate 配体）和5 lio-me-3,2-hopo（四齿配体）朝临床使用，通过扩大合成， 建立适合良好制造实践（GMP）的准备方法，进行有限 小鼠模型中两个螯合剂组合的功效和毒性研究，完成毒性 在人类细胞系中的研究，并在良好的顾问配体的临床前安全性建立临床前安全 }练习（GLP）指南。 这项研究的目的是在串联和成功的情况下提出两个新的装饰剂 将其发展加速到一个预印本阶段，在该阶段，只有灵长类动物研究才能在完整的IND之前保留 应用。这将通过劳伦斯·伯克利国家实验室的有效合作来实现 （LBNL）在配体设计，合成和实验室测试方面具有专业知识，SRI International 在GLP测试中拥有专业知识，并将药品推向市场。

项目成果

Using the antenna effect as a spectroscopic tool: photophysics and solution thermodynamics of the model luminescent hydroxypyridonate complex [Eu(III)(3,4,3-LI(1,2-HOPO))]-.

• DOI: 10.1021/ic9013703
• 发表时间: 2009-12-07
• 期刊: INORGANIC CHEMISTRY
• 影响因子: 4.6
• 作者: Abergel, Rebecca J.;D'Aleo, Anthony;Leung, Clara Ng Pak;Shuh, David K.;Raymond, Kenneth N.
• 通讯作者: Raymond, Kenneth N.

Biomimetic actinide chelators: an update on the preclinical development of the orally active hydroxypyridonate decorporation agents 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO).

• DOI: 10.1097/hp.0b013e3181c21273
• 发表时间: 2010-09
• 期刊: Health physics
• 影响因子: 2.2
• 作者: Abergel RJ;Durbin PW;Kullgren B;Ebbe SN;Xu J;Chang PY;Bunin DI;Blakely EA;Bjornstad KA;Rosen CJ;Shuh DK;Raymond KN
• 通讯作者: Raymond KN