Biomimetic Actinide Decorporation: Characterization and Preclinical Development

仿生锕系元素装饰：表征和临床前开发

• 批准号: 7937967
• 负责人: Rebecca J Abergel
• 金额: $ 214.01万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937967
• 关键词: Acids; Actinoid Series Elements; Address; Affinity; Behavior; Biological Availability; Biological Models; Biology; Biomimetics; Businesses; Canis familiaris; Cells; Cellular biology; Chelating Agents; Chemistry; Collaborations; Complex; Data; Development; Development Plans; Dose; Drug Kinetics; Effectiveness; Emergency Situation; Environmental Pollution; Event; Excision; Exhibits; Exposure to; Future; Gastrointestinal tract structure; General Population; Goals; Health; Human; In Vitro; Inorganic Chemistry; Interdisciplinary Study; International; Intestines; Investigational Drugs; Investigational New Drug Application; Ions; Kinetics; Laboratories; Lanthanoid Series Elements; Lead; Ligand Binding; Ligands; Methods; Mus; Mutagenicity Tests; National Institute of Allergy and Infectious Disease; Nuclear; Oral; Oral Administration; Papio; Permeability; Phase I Clinical Trials; Plutonium; Population; Practice Guidelines; Program Development; Protocols documentation; Publishing; Radiation; Radioisotopes; Rattus; Research Infrastructure; Research Institute; Risk; Route; Safety; Schedule; Scientist; Series; Site; Specificity; Terrorism; Testing; Therapeutic; Thermodynamics; Time; Tissues; Toxic effect; Toxicology; absorption; biological systems; chelation; cytotoxicity; design; exposed human population; good laboratory practice; in vitro Model; in vivo; interest; meetings; metal complex; oxidation; pre-clinical; preclinical toxicity; programs; prospective; research and development; respiratory; safety study; solid solution; tool

DESCRIPTION (provided by applicant): In the last several years, a sense of urgency and a renewed interest in the study of radionuclide chemistry and biology have emerged, as threats of nuclear terrorism have become more plausible, and the risk of environmental contamination and human exposure to radioisotopes consequently increased. The only practical therapy to reduce the dramatic health consequences of internal actinide/lanthanide contamination is treatment with chelating agents that form excretable complexes, although fission product lanthanides and the actinides are among the most intractable radionuclides to decorporate. While diethylenetriaminepentaacetic acid (DTPA) has been the standard therapy for actinide/lanthanide decorporation for several decades, it has limited efficacy and is not yet orally available. Hydroxypyridonate sequestering agents developed in our laboratory are selective and have a high affinity for plutonium(IV), americium(III), a number of other actinide ions, and lanthanide ions. Extensive efficacy studies in mice have been published and a limited number of tests have been performed in dogs and baboons, establishing that two of the designed agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2- HOPO), are up to 30 times more effective than DTPA and, unlike DTPA, are orally active. In addition, recent methods for large-scale synthesis, preclinical toxicity studies in rats and in vitro cytotoxicity studies using human cells have demonstrated that the selected chelators exhibit low toxicity and hold promise as non-toxic orally available actinide/lanthanide decorporation agents. The objective of this two-year project application is to sustain a large-scale interdisciplinary research program that will carry forward the pre-clinical development of both selected therapeutic actinide/lanthanide decorporation agents for emergency use and to enable the establishment of a viable infrastructure dedicated to the study and understanding of actinide and lanthanide chelation in biological systems. Compound characterization, actinide removal efficacy studies in mice and dogs, pre-clinical safety studies in rats and dogs and permeability assessment using rat intestinal tissues will be performed in collaboration with scientists from the Lawrence Berkeley National Laboratory, SRI International, and the Lovelace Respiratory Research Institute (LRRI). Finally, early input from the FDA will be obtained for our ligand development plan to enable the timely and successful filing of an IND application. As underlined by the National Institute of Allergy and Infectious Diseases (NIAID) Radiation Countermeasures Program, the development of radionuclide decorporation agents responds to the urgent need to protect the general population from the consequences of a large-scale exposure to radionuclides. In the event of a radiological/nuclear terrorist event, prospective decorporation treatments must be suitable to treat a large population that could be exposed to a variety of agents with a potentially high number of casualties. This project focuses on meeting the criteria listed by NIAID for the pre-clinical development of actinide and lanthanide decorporation agents, which include (i) chelation and elimination of a range of actinides/lanthanides, (ii) oral administration, (iii) effectiveness when administration is delayed, and (iv) safety for all potential populations.

描述（由申请人提供）：在过去几年中，随着核恐怖主义的威胁变得更加可信，环境污染和人类暴露于放射性同位素的风险随之增加，人们对放射性核素化学和生物学研究产生了紧迫感和新的兴趣。减少内部锕系元素/镧系元素污染的严重健康后果的唯一实用疗法是用形成可排泄络合物的螯合剂治疗，尽管裂变产物镧系元素和锕系元素是最难清除的放射性核素之一。虽然二亚乙基三胺五乙酸（DTPA）几十年来一直是锕系元素/镧系元素脱矿的标准疗法，但其疗效有限，并且尚未口服。我们实验室开发的羟基吡啶酮螯合剂具有选择性，对钚（IV）、镅（III）、许多其他锕系元素离子和镧系元素离子具有高亲和力。已经发表了在小鼠中的广泛功效研究，并且已经在狗和狒狒中进行了有限数量的测试，确定了两种设计的药剂，3，4，3-LI（1，2-HOPO）和5-LIO（Me-3，2- HOPO），比DTPA有效多达30倍，并且与DTPA不同，是口服活性的。此外，最近的大规模合成方法，在大鼠中的临床前毒性研究和使用人细胞的体外细胞毒性研究已经证明，所选择的螯合剂表现出低毒性，并有希望作为无毒的口服可利用的锕系元素/镧系元素脱硝剂。这个为期两年的项目申请的目的是维持一个大规模的跨学科研究计划，将推进两个选定的治疗性锕系元素/镧系元素decoration剂的临床前开发，以供紧急使用，并使一个可行的基础设施的建立，致力于研究和了解生物系统中的锕系元素和镧系元素螯合。将与劳伦斯伯克利国家实验室、SRI国际和Lovelace呼吸研究所（LRRI）的科学家合作，进行化合物表征、小鼠和犬中锕系元素清除有效性研究、大鼠和犬临床前安全性研究以及使用大鼠肠组织进行渗透性评估。最后，我们的配体开发计划将获得FDA的早期输入，以确保及时和成功地提交IND申请。正如国家过敏症和传染病研究所辐射对策方案所强调的那样，开发放射性核素消毒剂是为了满足保护公众免受大规模放射性核素照射后果的迫切需要。在发生放射性/核恐怖事件时，预期的去辐射治疗必须适合于治疗可能暴露于各种制剂并可能造成大量伤亡的大量人群。该项目的重点是满足NIAID列出的锕系元素和镧系元素去离子剂临床前开发标准，包括（i）螯合和消除一系列锕系元素/镧系元素，（ii）口服给药，（iii）延迟给药时的有效性，以及（iv）对所有潜在人群的安全性。