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.

对于脏弹或其他事件造成的大量人口放射性同位素污染的治疗将需要 由于可能的放射性核素及其种类繁多，因此需要使用装饰剂混合物 化学/生物特性。装修是减少某些合并物暴露的唯一方法 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 来装饰的元素。虽然二乙烯三胺五乙酸 (DTPA) 已成为标准疗法 自从美国原子能委员会开发和使用以来，一直用于锕系/镧系元素的修饰 在20世纪50年代，它的功效有限。使用以下方法开发了一个新的螯合剂系列 基于钚(IV)和铁(III)相似的生化传输特性的仿生设计 铁载体，细菌的天然铁螯合剂。这些螯合剂选择性更强，具有更高的 对钚(IV) 和许多其他锕系金属离子的亲和力。广泛的毒性和功效研究 使用小鼠模型的研究已经发表，并且在狗和狒狒身上进行了有限的测试。这 结果表明，几种新药剂比 DTPA 更有效，并且与 DTPA 不同， 可以口服活性。该项目拟采用两种先导化合物3,4,3-LI-1,2-HOPO（八齿酸 配体）和 5-LIO-Me-3,2-HOPO（四齿配体）通过扩大合成规模走向临床应用， 建立适合良好生产规范（GMP）的制备方法，实施有限的 在小鼠模型中对两种螯合剂的组合进行功效和毒性研究，完成毒性 人类细胞系研究，并在良好实验室下确定候选配体的临床前安全性 }实践（GLP）指南。 本研究的目的是串联并成功地提出两种新的装饰剂 加速其发展至 IND 前阶段，在完整 IND 之前仅保留灵长类动物研究 应用。这将通过劳伦斯伯克利国家实验室的有效合作来完成 (LBNL) 拥有配体设计、合成和实验室测试方面的专业知识，与 SRI International 合作， 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