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.

治疗大量人口受到脏弹或其他事件的放射性同位素污染将需要 鸡尾酒脱孔剂，因为可能的放射性核素种类繁多， 化学/生物特性。去孔化是减少某些公司暴露的唯一方法 放射性同位素。裂变产物镧系元素和吖系元素是其中最难处理的。 要取消孔洞的元素。而二乙烯三胺五乙酸(DTPA)已成为标准疗法 自美国原子能委员会开发和使用以来，用于鳗系元素/镧系元素的脱孔 在20世纪50年代的S，它的疗效有限。一种新的隔离剂家族已经开发出来，它使用一种 基于钚(IV)和铁(111)相似生物化学传输特性的仿生设计 铁载体，细菌的天然铁络合剂。这些螯合剂具有更高的选择性和更高的 对钚(IV)和一些其他鳗系金属离子的亲和力。广泛的毒性和有效性研究 已经发表了使用老鼠模型的实验，并在狗和狒狒身上进行了有限的试验。这个 结果表明，一些新的药物比DTPA有效得多，而且与DTPA不同的是， 可以是口服药。该项目建议采用两种先导化合物3，4，3-Li-1，2-HOPO(十八齿 配体)和5-LiO-Me-3，2-HOPO(四齿配体)通过放大合成而用于临床， 建立适用于良好生产规范(GMP)的准备方法，开展有限度的 两种螯合剂联合应用于小鼠完全毒性模型的疗效和毒性研究 在人类细胞系中的研究，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。 本研究的目标是成功地同时推出两种新的脱脂剂 加速他们的发展到IND之前的阶段，在那里只有灵长类研究在完整的IND之前保持 申请。这将通过劳伦斯伯克利国家实验室的有效合作来实现 (LBNL)，与SRI国际公司合作，拥有配体设计、合成和实验室测试方面的专业知识 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