Investigating the Role of Sulfate Groups for the Binding of Gd³⁺ Ions to Glycosaminoglycans with NMR Relaxometry

Abstract

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.

Inorganic Phosphate-Induced Extracellular Vesicles from Vascular Smooth Muscle Cells Contain Elevated Levels of Hyaluronic Acid, Which Enhance Their Interaction with Very Small Superparamagnetic Iron Oxide Particles

“…Negatively charged surface structures are of interest for monitoring pathophysiological alterations by magnetic resonance imaging (MRI). Gadolinium-containing contrast agents preferably bind to sulfated dextran molecules compared to non-sulfated dextran [ 19 ]. And VSOP are suggested to interact with inflamed tissues by the binding of their cationic iron oxide cores to negatively charged sulfate groups on surfaces [ 20 ].…”

Polyelectrolyte Chondroitin Sulfate Microgels as a Carrier Material for Rosmarinic Acid and Their Antioxidant Ability

“…It has been reported that CS as an anionic biopolymer interacts with chitosan [ 12 ], peptides [ 28 ], pectin [ 29 ], and cationic tannin [ 18 ] for various biomedical purpose. For example, CS-based polyelectrolytes have been prepared through the interactions of CS polymer chains with metal ions, such as Gd(III) ions as a magnetic resonance imaging (MRI) enhancer [ 30 ], with Al(III) ions as a polyphenolic carrier [ 31 ], and with Zn(II) ions to provide antibacterial ability [ 32 ].…”