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.

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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