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).
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).
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DOI：
10.1097/hp.0b013e3181c21273
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发表时间：
2010-09
期刊：
影响因子：
2.2
通讯作者：
Raymond KN
中科院分区：
文献类型：
--
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
脏弹或其他重大放射性污染的威胁会造成人口受到大规模辐射照射的危险。由于这种污染的主要成分可能是锕系元素，因此必须优先考虑减少辐射暴露的锕系元素去除处理。目前用于治疗放射性核素污染的疗法是有限的，并且必须致力于开发用于紧急医疗用途的治疗性口服生物可利用的锕系元素螯合剂。使用基于钚（IV）和铁（III）的类似生化性质的仿生方法，铁载体启发的多齿羟基吡啶酮配体已被设计，并且在锕系元素亲和力，选择性和效率方面是无与伦比的。本文介绍了两种羟基吡啶酮类锕系元素脱羧剂3，4，3-LI（1，2-HOPO）和5-LIO（Me-3，2-HOPO）的临床前研究进展。这两个候选化合物的化学合成已被优化的规模。已确立了适用于大量生产的基线制备和分析方法。这两种配体显示出比目前批准的试剂二亚乙基三胺五乙酸（DTPA）高得多的锕系元素去除功效，对钚、镅、铀和镎的测试同位素具有不同的选择性。在体外处理的三种不同人体组织来源的细胞中未观察到毒性，最高配体浓度为1 mM，并且根据良好实验室规范（GLP）指南，在28天内每天以高剂量（> 100 μmol kg-1 day-1）经口给药时，两种配体在大鼠中的耐受性良好。这两种化合物都处于加速开发的临床应用途径中。
The threat of a dirty bomb or other major radiological contamination presents a danger of large-scale radiation exposure of the population. Because major components of such contamination are likely to be actinides, actinide decorporation treatments that will reduce radiation exposure must be a priority. Current therapies for the treatment of radionuclide contamination are limited and extensive efforts must be dedicated to the development of therapeutic, orally bioavailable, actinide chelators for emergency medical use. Using a biomimetic approach based on the similar biochemical properties of plutonium(IV) and iron(III), siderophore-inspired multidentate hydroxypyridonate ligands have been designed and are unrivaled in terms of actinide-affinity, selectivity and efficiency. A perspective on the preclinical development of two hydroxypyridonate actinide decorporation agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), is presented. The chemical syntheses of both candidate compounds have been optimized for scale-up. Baseline preparation and analytical methods suitable for manufacturing large amounts have been established. Both ligands show much higher actinide-removal efficacy than the currently approved agent, diethylenetriaminepentaacetic acid (DTPA), with different selectivity for the tested isotopes of plutonium, americium, uranium and neptunium. No toxicity is observed in cells derived from three different human tissue sources treated in vitro up to ligand concentrations of 1 mM, and both ligands were well tolerated in rats when orally administered daily at high doses (> 100 μmol kg−1 day−1) over 28 days under good laboratory practice (GLP) guidelines. Both compounds are on an accelerated development pathway towards clinical use.