减轻放射性金属对人体内部暴露的毒性作用的最有效方法是金属配体(ML)螯合疗法。由于长期内部暴露,or(Th)引起的致癌作用以及对人类的其他健康危害,因此需要开发有效的Th-脱孔剂。在这方面,进行了化学和生物学研究,以评估N-(2-乙酰氨基)亚氨基二乙酸(ADA),一个相对划算的,随时可用,和生物安全的络合剂用于Th脱孔剂。在目前的工作中,详细的热力学研究了ADA与Th(IV)的络合,以了解Th-ADA相互作用,使用电位计,量热法,电喷雾电离质谱,和理论研究,其次是对Th装饰的生物学评估。热力学研究揭示了强Th-ADA配合物的形成,在焓和熵上都很受欢迎。有趣的是,密度泛函理论计算,为了获得热力学上有利的配位模式,表明ML中ADA的密度比ML2低的趋势不寻常,这已经在通过氢键稳定ML的基础上得到了解释。这也反映在Th-ADA复合物的焓的异常趋势中。使用人类红细胞的生物实验,人类全血,肺细胞表现出良好的细胞相容性和ADA能显著防止Th诱导的溶血。从红细胞中去除ADA,人血,发现正常肺细胞与二亚乙基三胺五乙酸盐(DTPA)相当,FDA批准的脱孔剂。本研究提供了有关ADA的Th络合化学及其对人红细胞的Th去穿孔功效的重要数据,血,和肺细胞。
The most effective approach to mitigate the toxic effects of internal exposure of radiometals to humans is metal-ligand (ML) chelation therapy.
Thorium (Th)-induced carcinogenesis as well as other health hazards to humans as a result of chronic internal exposure necessitates the development of efficient Th-decorporating agents. In this regard, chemical and biological studies were carried out to evaluate N-(2-Acetamido)iminodiacetic acid (ADA), a comparatively cost-effective, readily available, and biologically safe complexing agent for Th decorporation. In the present work, detailed thermodynamic studies for complexation of ADA with Th(IV) have been carried out to understand Th-ADA interaction, using potentiometry, calorimetry, electrospray ionization mass spectrometry, and theoretical studies, followed by its biological assessment for Th decorporation. Thermodynamic studies revealed the formation of strong Th-ADA complexes, which are enthalpically as well as entropically favored. Interestingly, density functional theory calculations, to obtain a thermodynamically favored mode of coordination, showed the uncommon trend of lower denticity of ADA in ML than in ML2, which has been explained on the basis of stabilization of ML by hydrogen bonding. The same was also reflected in the unusual trend of enthalpy for Th-ADA complexes. Biological experiments using human erythrocytes, whole human blood, and lung cells showed good cytocompatibility and ability of ADA to significantly prevent Th-induced hemolysis. Th removal of ADA from erythrocytes, human blood, and normal lung cells was found to be comparable with that of diethylenetriamine pentaacetate (DTPA), an FDA approved decorporating agent. The present
study contributed significant data about Th complexation chemistry of ADA and its Th decorporation efficacy from human erythrocytes, blood, and lung cells.