Biomimetic Actinide Decorporation: Characterization and Preclinical Development

仿生锕系元素装饰：表征和临床前开发

基本信息

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
项目类别：
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

项目摘要

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）：在过去的几年中，随着核恐怖主义的威胁变得更加合理，对放射性核素化学和生物学的研究产生了一种紧迫感和重新兴趣，并且对环境污染的威胁变得越来越合理，并且受到环境污染的风险以及人类对放射性病的暴露。唯一减少肌动蛋白/灯笼污染的急剧健康后果的实际疗法是用螯合剂的治疗，尽管裂变产物腺苷酸和肌动蛋白是装饰最棘手的放射性核素之一。虽然二乙烯酸苯甲酸乙酸乙酸（DTPA）一直是肌动剂/兰烷化装饰的标准疗法，但它具有有限的疗效，尚未口服。在我们的实验室中开发的羟基吡啶甲酸盐隔离剂具有选择性，并且对p，对p，美国（III），许多其他actinide离子和灯笼离子具有很高的亲和力。在小鼠中的广泛疗效研究已经发表，并且在狗和狒狒中进行了数量的测试，确定其中两种设计的药物，3,4,3-LI（1,2-HOPO）和5-LIO（ME-3,2- HOPO），比DTPA和DTPA高达30倍。此外，使用人类细胞的大鼠和体外细胞毒性研究的大规模合成，临床前毒性研究的最新方法表明，所选的螯合剂表现出低毒性，并且具有无毒的口服阳式阳离子/灯笼/灯笼的含量。这项为期两年的项目应用程序的目的是维持一项大规模的跨学科研究计划，该计划将继续前进的临床前开发，既选择了精选的Actinide/lanthanide装饰剂，供紧急使用，并能够建立可行的基础设施，以研究和理解Actinide和Lanthanide和Lanthandhanide和Lanthandhanide和Lanthandhanide和Lanthanthanide和Lanthandhanide和Lanthanthanide In In Icy In In In In In In In In In Icy Incological Incological Incological Incological Incological in Colicoical Systems。将与劳伦斯·伯克利国家实验室，SRI International以及Lovelace呼吸研究所（LRRRI）合作进行，将在小鼠和狗中进行复合表征，肌动剂去除功效研究，大鼠和狗的临床前安全研究以及使用大鼠肠道组织的渗透性评估。最后，将为我们的配体开发计划获得FDA的早期投入，以允许及时和成功提交IND申请。正如美国国家过敏和传染病研究所（NIAID）辐射对策计划所强调的那样，放射性核素装饰剂的发展迫切需要保护普通人群免受大规模暴露于放射性核素的后果。如果发生放射线/核恐怖主义事件，前瞻性装饰治疗必须适合治疗大量人群，这些人群可能会暴露于潜在的人员伤亡的各种特工。该项目的重点是符合NIAID在脱骨和灯笼装饰剂的临床前开发中列出的标准，其中包括（i）螯合和消除一系列actinides/lanthanides，（ii）口服给药，（iii）在给药时（延迟给药时）的有效性，以及（IV）的所有潜在人口安全性。