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.

治疗由脏弹或其他事件造成的大量人口的放射性同位素污染将需要 由于各种可能的放射性核素及其 化学/生物特性。披露是减少某些公司风险的唯一途径。 放射性同位素裂变产物镧系元素和锕系元素是其中最难处理的 元素分解。而二乙烯三胺五乙酸（DTPA）一直是标准治疗 自美国原子能委员会开发和使用以来， 在五十年代，它的功效是有限的。已经开发了一种新的螯合剂家族， 基于钚（IV）和铁（III）的类似生化运输性质的仿生设计， 铁载体细菌的天然铁螯合剂这些螯合剂更具选择性， 对钚（IV）和许多其他锕系金属离子的亲和力。广泛的毒性和有效性研究 已经发表了使用小鼠模型的研究，并且在狗和狒狒中进行了有限的测试。的 结果表明，几种新的药剂比DTPA有效得多，与DTPA不同， 可以是口服活性的。本项目拟以两个先导化合物3，4，3-LI-1，2-HOPO（anoctadentate 配体）和5-LIO-Me-3，2-HOPO（四齿配体）通过按比例放大合成而用于临床用途， 建立适合良好生产规范（GMP）的制备方法， 在小鼠模型中对两种螯合剂的组合的功效和毒性研究，完成毒性 在人细胞系中的研究，并在良好的实验室下建立候选配体的临床前安全性 }实践（GLP）指南。 本研究的目的是成功地研制出两种新型的除臭剂， 加速其发展到IND前阶段，在此阶段，在完整IND之前仅保留灵长类动物研究 应用程序.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拥有专业知识，SRI国际， 拥有GLP测试和将药品推向市场的专业知识。

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