Thermodynamics of Decorporol Complexes with Sr²⁺ and Ca²⁺ Ions─A Combined Isothermal Titration Calorimetry and DFT Study

Nuclear incidents release hazardous ⁹⁰Sr, posing risks to health. Seeking chelating agents capable of removing ⁹⁰Sr is critical for nuclear safety and development. In our work, the main goal was to develop a substantial yet straightforward method to support the design of viable, in vivo stable chelating agents for radiostrontium. To investigate, we implemented the highly accurate density functional theory (DFT)-based r²SCAN-3c composite method and isothermal titration calorimetry (ITC). Our methods were validated through the characterization of calcium (Ca²⁺) and strontium (Sr²⁺) chelation by ethylenediaminetetraacetic acid (EDTA). The chosen DFT model was able to approximate the literature value (ΔΔ<i>G</i> _DFT of 15.4 kJ/mol for the ion exchange reaction from Ca-EDTA to Sr-EDTA, compared to the literature value of 11.0 kJ/mol), while the thermodynamic parameters obtained from the ITC study of calcium EDTA chelation were almost identical to those found in the literature. With the validated methods, strontium chelation by (7,16-bis-malonate)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-bis-malonic acid (Decorporol) was first synthesized and then examined. Our DFT calculations revealed that the exchange reaction from Ca²⁺ to Sr²⁺ with Decorporol has an exergonic (-14.1 kJ/mol) Gibbs free energy profile, which is also approved by the experimental Gibbs free energy change of -34.5 ± 1.1 kJ/mol obtained from the ITC measurements. Measurements at elevated temperatures and physiological conditions did not impact chelation significantly; therefore, in vivo application of the chelating agent is feasible.