Investigating the Role of Sulfate Groups for the Binding of Gd3+ Ions to Glycosaminoglycans with NMR Relaxometry. (12th May 2022)

• Record Type: Journal Article
• Authors: Werner, Patrick; Schuenke, Patrick; Krylova, Oxana; Nikolenko, Heike; Taupitz, Matthias; Schröder, Leif
• Is Part Of: ChemMedChem. Volume 17:Number 13(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-05-12
• Subjects: MRI contrast agent -- gadolinium -- chelation -- glycosaminoglycans -- GBCA; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202100764
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Glycosaminoglycans (GAGs) are highly negatively charged macromolecules with a large cation binding capacity, but their interaction potential with exogeneous Gd 3+ ions is under‐investigated. 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 approach 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 T1 ‐weighted MR images. Abstract : A combined approach of MRI‐based relaxometry and isothermal titration calorimetry shows that the chelation process of Gd 3+ into glycosaminoglycans (GAGs) is not just a long‐range electrostatic interaction as proposed for the Manning model, but presumably a site‐specific binding. Further evidence shows that the potential of a specific GAG to engage in this mechanism increases with its degree of sulfation.