Nitroxide Radical Contrast Agents for Metal-Free MRI: Materials Design and Biomedical Applications

Abstract

Magnetic resonance imaging (MRI) is a widely used clinical diagnostic modality; however, conventional metal-based contrast agents, particularly gadolinium-based contrast agents, have raised concerns about long-term tissue retention and potential metal-associated toxicity. Nitroxide radical contrast agents (NRCAs) have been investigated as promising metal-free alternatives because persistent nitroxide radicals can shorten proton longitudinal relaxation times and thereby produce positive contrast on T1-weighted MRI without metal deposition. Moreover, nitroxide radical–based Overhauser-enhanced MRI (OMRI) can be used as a complementary approach to redox-sensitive functional imaging via dynamic nuclear polarization. Nevertheless, small-molecule nitroxides are limited by rapid bioreduction, short circulation times, and relatively low relaxivity. To address these limitations, various nanoscale engineering strategies, including polymer conjugation, dendrimer construction, supramolecular assembly, biomacromolecular scaffolding, and biomimetic delivery, have been developed to improve radical stability, increase relaxivity, and prolong in vivo retention. This review summarizes recent advances in the molecular design of NRCAs, radical stabilization, nanomaterial engineering, and their biomedical applications in cancer, inflammation, and ischemia–reperfusion (I/R) injury. Current challenges and future perspectives regarding the development of next-generation metal-free MRI contrast agents are also discussed.