Gd3+ Complexes Conjugated to Cyclodextrins: Hydroxyl Functions Influence the Relaxation Properties

Abstract

In the search for improvement in the properties of gadolinium-based contrast agents, cyclodextrins (CDs) are interesting hydrophilic scaffolds with high molecular weight. The impact of the hydrophilicity of these systems on the MRI efficacy has been studied using five β-CDs substituted with DOTA or TTHA ligands which, respectively, allow for one (q = 1) or no water molecule (q = 0) in the inner coordination sphere of the Gd3+ ion. Original synthetic pathways were developed to immobilize the ligands at C-6 position of various hydroxylated and permethylated β-CDs via an amide bond. To describe the influence of alcohol and ether oxide functions of the CD macrocycle on the relaxation properties of the Gd3+ complexes, 1H Nuclear Magnetic Relaxation Dispersion (NMRD) profiles, and 17O transverse relaxation rates have been measured at various temperatures. The differences observed between the hydroxylated and permethylated β-CDs bearing non-hydrated GdTTHA complexes can be rationalized by a second sphere contribution to the relaxivity in the case of the hydroxylated derivatives, induced by hydrogen-bound water molecules around the hydroxyl groups. In contrast, for the DOTA analogs the exchange rate of the water molecule directly coordinated to the Gd3+ is clearly influenced by the number of hydroxyl groups present on the CD, which in turn influences the relaxivity and gives rise to a very complex behavior of these hydrophilic systems.

Design of High-Relaxivity Polyelectrolyte Nanocapsules Based on Citrate Complexes of Gadolinium(III) of Unusual Composition

“…An increase in relaxivity (which is equivalent to the increase in the contrast of MRI images) could improve the diagnostic accuracy and decrease the dosage of CAs, which are nephrotoxic [38]. Employment of the compositions, which provide binding of gadolinium with macromolecular ligands or utilize supramolecular interactions [39][40][41][42][43][44], including those with poly(ethylene imine) [45], is a promising approach to the increase in the relaxivity of CAs. The authors of this paper previously analyzed the potential of the design of such compositions based on Mn(II) complexes with DTPA in PEI solutions [32]; however, high relaxivity was observed in the solutions beyond physiological range and the compositions decomposed in the presence of 150 mM NaCl.…”