Gadolinium-based contrast agents (GBCAs) have been used in clinical Magnetic Resonance Imaging (MRI) for more than 30 years. However, there is increasing evidence that their dissociation in vivo leads to long-term depositions of gadolinium ions in the human body. In vitro experiments provide critical insights into kinetics and thermodynamic equilibria of underlying processes, which give hints towards the in vivo situation. We developed a time-resolved MRI relaxometry-based approach that exploits distinct relaxivities of Gd3+ in different molecular environments. Its applicability to quantify the transmetallation of GBCAs, the binding of Gd3+ to competing chelators, and the combined transchelation process is demonstrated. Exemplarily, the approach is applied to investigate two representative GBCAs in the presence of Zn2+ and heparin, which is used as a model for a macromolecular and physiologically occurring chelator. Opposing indirect impacts of heparin on increasing the kinetic stability but reducing the thermodynamic stability of GBCAs are observed. The relaxivity of resulting Gd-heparin complexes is shown to be essentially increased compared to that of the parent GBCAs so that they might be one explanation for observed long-term MRI signal enhancement in vivo. In forthcoming studies, the presented method could help to identify the most potent Gd-complexing macromolecular species.
Glycosaminoglycans (GAGs) are highly negatively charged macromolecules with a large cation binding capacity, but their interaction potential with exogeneous Gd 3 + ions is underinvestigated. These might be released from chelates used as Gadolinium-based contrast agents (GBCAs) for clinical MR imaging due to transmetallation with endogenous cations like Zn 2 + . Recent studies have quantified how an endogenous GAG sequesters released Gd 3 + ions and impacts the thermodynamic and kinetic stability of some GBCAs. In this study, we investigate and compare the chelation ability of two important GAGs (heparin and chondroitin sulfate), as well as the homopolysaccharides dextran and dextran sulfate that are used as models for alternative macromolecular chelators. Our combined ap-proach of MRI-based relaxometry and isothermal titration calorimetry shows that the chelation process of Gd 3 + into GAGs is not just a long-range electrostatic interaction as proposed for the Manning model, but presumably a site-specific binding. Furthermore, our results highlight the crucial role of sulfate groups in this process and indicate that the potential of a specific GAG to engage in this mechanism increases with its degree of sulfation. The transchelation of Gd 3 + ions from GBCAs to sulfated GAGs should thus be considered as one possible explanation for the observed long-term deposition of Gd 3 + in vivo and related observations of long-term signal enhancements on T 1 -weighted MR images.
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