Polymer cross-linking: a nanogel approach to enhancing the relaxivity of MRI contrast agents

Polymer cross-linking was explored as an approach for increasing the relaxivity of macromolecular contrast agents for magnetic resonance imaging. Poly(ethylene glycol) methyl ether methacrylate, N-(2-aminoethyl) methacrylamide hydrochloride, and the cross-linker ethylene glycol dimethacrylate were copolymerized under free radical conditions. By tuning the cross-linker content and reaction concentration, it was possible to obtain 10 nm nanogels in a single synthetic step. The pendant amine moieties were functionalized with an isothiocyanate derivative of diethylenetriaminepentaacetic acid (DTPA) and Gd(III) was chelated. In comparison with a linear control polymer prepared under the same conditions in the absence of the cross-linking agent, the nanogel contrast agent did exhibit enhanced relaxivity with an r(1) of 20.8 +/- 0.2 at 20 MHz and 17.5 +/- 0.4 at 60 MHz (corresponding to the clinical field strength of 1.5 T). The nuclear magnetic resonance dispersion profile was modeled to demonstrate that the enhanced relaxivity was a result of the nanogel agent's increased rotational correlation time, that is proposed to result from the constraint on motion imparted by the cross-linking. T-1 weighted imaging in mice showed enhanced contrast and vascular circulation for the nanogel relative to Gd(III)-DTPA (Magnevist) demonstrating the future promise of these new agents.