Combined Thermodynamic, Theoretical, and Biological Study for Investigating N-(2-Acetamido)iminodiacetic Acid as a Potential Thorium Decorporation Agent

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.