*Article* **Glycosaminoglycans and Contrast Agents: The Role of Hyaluronic Acid as MRI Contrast Enhancer**

**Alfonso Maria Ponsiglione 1,2 , Maria Russo 2,**† **and Enza Torino 2,3,\***


Received: 26 September 2020; Accepted: 26 November 2020; Published: 28 November 2020 -

**Abstract:** A comprehensive understanding of the behaviour of Glycosaminoglycans (GAGs) combined with imaging or therapeutic agents can be a key factor for the rational design of drug delivery and diagnostic systems. In this work, physical and thermodynamic phenomena arising from the complex interplay between GAGs and contrast agents for Magnetic Resonance Imaging (MRI) have been explored. Being an excellent candidate for drug delivery and diagnostic systems, Hyaluronic acid (HA) (0.1 to 0.7%*w*/*v*) has been chosen as a GAG model, and Gd-DTPA (0.01 to 0.2 mM) as a relevant MRI contrast agent. HA samples crosslinked with divinyl sulfone (DVS) have also been investigated. Water Diffusion and Isothermal Titration Calorimetry studies demonstrated that the interaction between HA and Gd-DTPA can form hydrogen bonds and coordinate water molecules, which plays a leading role in determining both the polymer conformation and the relaxometric properties of the contrast agent. This interaction can be modulated by changing the GAG/contrast agent molar ratio and by acting on the organization of the polymer network. The fine control over the combination of GAGs and imaging agents could represent an enormous advantage in formulating novel multifunctional diagnostic probes paving the way for precision nanomedicine tools.

**Keywords:** hyaluronic acid; glycosaminoglycan; hydrogel; MRI; hydrodenticity; precision medicine
