Metal Chelating Crosslinkers Form Nanogels with High Chelation Stability.

We present a series of hydrogel nanoparticles (nanogels) incorporating either acyclic or cyclic metal chelates as crosslinkers. These crosslinkers are used to formulate polyacrylamide-based nanogels (diameter 50 to 85 nm) yielding contrast agents with enhanced relaxivities (up to 6-fold greater than Dotarem®), because this nanogel structure slows the chelator's tumbling frequency and allows fast water exchange. Importantly, these nanogels also stabilize Gd within the chelator thermodynamically and kinetically against metal displacement through transmetallation, which should reduce toxicity associated with release of free Gd. This chelation stability suggests that the chelate crosslinker strategy may prove useful for other applications of metal-chelating nanoparticles in medicine, including other imaging modalities and radiotherapy.