Water-Mediated Nanostructures for Enhanced MRI: Impact of Water Dynamics on Relaxometric Properties of Gd-DTPA

Abstract

Recently, rational design of a new class of contrast agents (CAs), based on biopolymers (hydrogels), have received considerable attention in Magnetic Resonance Imaging (MRI) diagnostic field. Several strategies have been adopted to improve relaxivity without chemical modification of the commercial CAs, however, understanding the MRI enhancement mechanism remains a challenge. Methods: A multidisciplinary approach is used to highlight the basic principles ruling biopolymer-CA interactions in the perspective of their influence on the relaxometric properties of the CA. Changes in polymer conformation and thermodynamic interactions of CAs and polymers in aqueous solutions are detected by isothermal titration calorimetric (ITC) measurements and later, these interactions are investigated at the molecular level using NMR to better understand the involved phenomena. Water molecular dynamics of these systems is also studied using Differential Scanning Calorimetry (DSC). To observe relaxometric properties variations, we have monitored the MRI enhancement of the examined structures over all the experiments. The study of polymer-CA solutions reveals that thermodynamic interactions between biopolymers and CAs could be used to improve MRI Gd-based CA efficiency. High-Pressure Homogenization is used to obtain nanoparticles. Results: The effect of the hydration of the hydrogel structure on the relaxometric properties, called Hydrodenticity and its application to the nanomedicine field, is exploited. The explanation of this concept takes place through several key aspects underlying biopolymer-CA's interactions mediated by the water. In addition, Hydrodenticity is applied to develop Gadolinium-based polymer nanovectors with size around 200 nm with improved MRI relaxation time (10-times). Conclusions: The experimental results indicate that the entrapment of metal chelates in hydrogel nanostructures offers a versatile platform for developing different high performing CAs for disease diagnosis.

A Microfluidic Platform to design Multimodal PEG - crosslinked Hyaluronic Acid Nanoparticles (PEG-cHANPs) for diagnostic applications

“…Indeed, by definition, in the process of solvation, molecules are surrounded by concentric shells of solvent 66 . It can directly affect the mobility of water molecules that are coordinated around Gd-DTPA 67 .…”

Theranostic Design of Angiopep-2 Conjugated Hyaluronic Acid Nanoparticles (Thera-ANG-cHANPs) for Dual Targeting and Boosted Imaging of Glioma Cells

“…The ability of hydrogel matrices to boost the relaxivity of Gd-chelates has been widely described by the hydrodenticity theory [ 29 , 30 , 31 , 32 , 33 , 47 ].…”

“…In addition, this natural interaction can be useful to provide an early and more accurate MRI and, in this perspective, it has already been reported that hydrogels, in particular HA, boost relaxometry properties of MRI CAs [ 28 , 29 ]. In detail, Russo et al, demonstrated that HA matrices are able to boost the relaxivity of Gd-based CAs for MRI by a hydrodenticity effect [ 30 , 31 , 32 , 33 ]. Indeed, hydrodenticity effect arises from the establishment of a complex equilibrium between the elastodynamics of polymer chains of the hydrogel and water molecules which are packed around Gd-chelates forming gado-meshes that, improving the hydration degree of the CA, boost its relaxivity.…”

New Strategies in the Design of Paramagnetic CAs

“…Further advances in the T 1 boosting have been reported using biocompatible hydrogels, taking advantage of their hydrophilicity. Indeed, hydrogel matrices made up of hydrophilic polymers are able to accumulate a large amount of water inside the structure, increasing interactions between water molecules and the metal chelate and, consequently, promoting a relaxivity boosting of the T1 CAs [ 25 , 26 , 28 – 30 ]. The effect has been very well described by Russo et al in the Hydrodenticity concept [ 31 ].…”

“…This effect is called Hydrodenticity [ 31 ]. In particular, when a complex equilibrium between elastodymanic forces of the polymer chains, water osmotic pressure, and hydration degree of Gd-CAs is reached, SBM correlation times go through a change [ 28 ]. The improved relaxation rate is the result of an increased residence lifetime of water molecules within the crosslinked polymer matrix, a restricted molecular tumbling, and a resulting faster exchange rate with metal ions (see Figure 2 ).…”