Cell-permeable MR contrast agents with increased intracellular retention

Magnetic resonance imaging (MRI) is a technique used in both clinical and experimental settings to produce high-resolution images of opaque organisms without ionizing radiation. Currently, MR imaging is augmented by contrast agents, and the vast majority these small molecule Gd(III) chelates are confined to the extracellular regions. As a result, contrast agents are confined to vascular regions reducing their ability to provide information about cell physiology or molecular pathology. We have shown that polypeptides of arginine have the capacity to transport Gd(III) contrast agents across cell membranes. However, this transport is not unidirectional, and once inside the cell, the arginine-modified contrast agents efflux rapidly, decreasing the intracellular Gd(III) concentration and corresponding MR image intensity. By exploiting the inherent disulfide reducing environment of cells, thiol compounds, Gd(III)-DOTA-SS-Arg₈ and Gd(III)-DTPA-SS-Arg₈, are cleaved from their cell-penetrating peptide transduction domains upon cell internalization. This reaction prolongs the cell-associated lifetime of the chelated Gd(III) by cleaving it from the cell transduction domain.