Tunable, High-Relaxivity Gd(III)-Conjugated Lipoic Acid Hydrogels for Magnetic Resonance Imaging

A lipoic acid(LA)-base hydrogel polymerization, viscosity, and relaxivity were explored by varying several different bases, additives, Gd³⁺ chelates, and with or without a reducing agent (tris(2-carboxyethyl)phosphine, TCEP). The polymerization of LA was greatly improved by using TCEP to convert the more inert disulfides into thiol initiators. The base deprotonation of LA was found to be essential to solubilize LA for polymer propagation. The various bases and TCEP additions had a substantial effect on viscosity, with values ranging from 1 × 10⁸ to 1 × 10³ mPa·s. This can enable targeting of many different applications that depend on viscosity, such as topical ointments or injectable hydrogels. The relaxivity effects of the LA-hydrogels were explored by varying the Gd³⁺ chelates' inner-sphere coordination or by adding one or two sulfur atoms, thereby allowing for a terminal or internal-linking Gd³⁺ chelate. It was found that the inner sphere and microenvironment dominate the relaxivity of Gd³⁺ chelates in the LA-hydrogel, with a high relaxivity of r₁ = 49.2 ± 1.2 mM^-1 s^-1 at 1.4 T and 37 °C. Cellular uptake was confirmed by confocal fluorescence microscopy, and contrast was assessed in vivo at 9.4 T.