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.

说明(申请人提供)：在过去几年里，随着核恐怖主义威胁变得更加可信，环境污染和人类暴露于放射性同位素的风险增加，人们对放射性核素化学和生物学的研究产生了紧迫感和新的兴趣。尽管裂变产物镧系元素和氡系元素是最难处理的放射性核素之一，但要想减少内含的榄系元素/镧系元素污染对健康造成的严重后果，唯一实用的治疗方法是用形成可排泄的络合物的螯合剂治疗。虽然几十年来，二乙烯三胺五乙酸(DTPA)一直是治疗榄系元素/镧系元素脱孔的标准疗法，但它的疗效有限，目前还没有口服使用。本实验室研制的羟基吡啶酸类隔离剂具有选择性，对钚(IV)、铟(III)等金属离子和稀土离子具有较高的亲和力。已经发表了对小鼠的广泛疗效研究，并在狗和狒狒身上进行了有限数量的测试，证实了所设计的两种药物，3，4，3-Li(1，2-HOPO)和5-LiO(Me-3，2-HOPO)的效果比DTPA高30倍，而且与DTPA不同，它们是口服活性的。此外，最新的大规模合成方法、大鼠临床前毒性研究和体外细胞毒性研究表明，所选择的螯合剂具有低毒性，有望成为无毒的口服可用鳗系元素/稀土元素脱孔剂。这项为期两年的项目申请的目标是维持一项大规模的跨学科研究计划，该计划将推进用于紧急使用的精选的临床前治疗榄系元素/镧系元素脱孔剂的开发，并使能够建立一个可行的基础设施，致力于研究和了解生物系统中鳗系元素和镧系元素的络合作用。将与劳伦斯伯克利国家实验室、SRI国际和洛夫莱斯呼吸研究所(LRRI)的科学家合作，进行化合物表征、在小鼠和狗身上进行的吖系元素去除效果研究、在大鼠和狗身上进行的临床前安全性研究以及使用大鼠肠道组织进行的渗透性评估。最后，我们将为我们的配体开发计划获得FDA的早期投入，以便及时和成功地提交IND申请。正如国家过敏和传染病研究所(NIAID)辐射对策方案所强调的那样，放射性核素脱孔剂的开发满足了保护普通民众免受大规模接触放射性核素后果的迫切需要。在发生放射性/核恐怖事件时，预期的去孔化治疗必须适合于治疗可能暴露于各种可能造成高伤亡人数的各种制剂的大量人口。该项目的重点是满足NIAID所列的用于临床前开发的鳗系元素和镧系元素脱孔剂的标准，其中包括(I)螯合和消除一系列鳗系元素/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。