Thermodynamics-based rules of thumb to evaluate the interaction of chelators and kinetically-labile metal ions in blood serum and plasma.

Metal ions play a very important role in nature and their homeostasis is crucial. A lot of metal-related chemical research activities are ongoing that concern metal-based drugs or tools, such as chelation therapy, metal- and metabolite sensors, metallo-drugs and prodrugs, PET and MRI imaging agents, . In most of these cases, the applied chelator/ligand (L) or metal-ligand complex (M-L) has at least to pass the blood plasma to reach the target. Hence it is exposed to several metal-binding proteins (mainly serum albumin and transferrin) and to all essential metal ions (zinc, copper, iron, .). This holds also for studies in cultured cells when fetal calf serum is used in the medium. There is a risk that the applied compound (L or M-L) in the serum is transformed into a different entity, due to trans-metallation and/or ligand exchange reactions. This depends on the thermodynamics and kinetics. For kinetically-labile complexes, the complex stability with all the ligands and all metal ions present in serum is decisive in evaluating the thermodynamic driving force towards a certain fate of the chelator or metal-ligand complex. To consider that, an integrative view is needed on the stability constants, by taking into account all the metal ions present and all the main proteins to which they are bound, as well as the non-occupied metal binding site in proteins. Only then, a realistic estimation of the complex stability, and hence its potential fate, can be done. This perspective aims to provide a simple approach to estimate the thermodynamic stability of labile metal-ligand complexes in a blood plasma/serum environment. It gives a guideline to obtain an estimation of the plasma and serum complex stability and metal selectivity starting from the chemical stability constants of metal-ligand complexes. Although of high importance, it does not focus on the more complex kinetic aspects of metal-transfer reactions. The perspective should help for a better design of such compounds, to perform test tube assays which are relevant to the conditions in the plasma/serum and to be aware of the importance of ternary complexes, kinetics and competition experiments.