1H NMR Relaxometric Study of Chitosan-Based Nanogels Containing Mono- and Bis-Hydrated Gd(III) Chelates: Clues for MRI Probes of Improved Sensitivity

Abstract

Hydrogel nanoparticles composed of chitosan and hyaluronate and incorporating Gd-based MRI contrast agents with different hydration number (e.g., [Gd(DOTA)(H₂O)]^- and [Gd(AAZTA)(H₂O)₂]^-) were prepared and fully characterized. In particular, ¹H NMR relaxometric data, acquired as a function of temperature and applied magnetic field strength, were for the first time thoroughly analyzed using a theoretical model that includes the effects of a static zero-field splitting and an anisotropic molecular tumbling. The paramagnetic nanoparticles show excellent stability in aqueous solution for over 150 h and do not release the load of Gd(III) chelates. These nanoparticles exhibit enhanced efficacy (relaxivity) as relaxation agents, over 6 times that of the free complexes, thanks to the combination of a restricted molecular dynamics in the presence of a fast exchange of metal-bound water molecule(s) and between the water inside the nanogel and the bulk water. The knowledge of the molecular parameters that control the effectiveness of these MRI nanoprobes and those that limit their further increase will be crucial for the development of optimized systems with high sensitivity and stability.

Keywords: MRI nanoprobes; cyclic ligands; gadolinium (III); nanogels; relaxometry.