Functional polymers as metal-free magnetic resonance imaging contrast agents

Magnetic resonance imaging (MRI) is recognized as the most powerful clinical imaging modality due to its ability to generate detailed three-dimensional anatomical images with high spatial resolution in a non-invasive manner without requiring harmful ionizing radiation. Conventionally, exogenous paramagnetic transition metal ion chelates or iron oxide nanoparticles are used as contrast agents (CAs) to enhance the image contrast of anatomical features. However, despite the wide use of these metal-based CAs, safety concerns have been raised regarding their potential toxic effects resulting from long-term in vivo accumulation. This has driven the development of organic metal-free CAs in various forms for use in MRI. Importantly, functional polymers capable of MRI via different mechanisms represent one of the most promising alternatives to current metal-based MRI CAs due to appealing features such as low toxicity, improved pharmacokinetics and biodistribution profile, and tailored structures and functionalities. Such structural and functional flexibility can enable a myriad of biomedical applications. In this review, we will highlight advances in the development of functional polymers as organic metal-free macromolecular MRI CAs based on different mechanisms including polymeric nitroxide-based 1 H MRI CAs, polymeric chemical exchange saturation transfer (CEST) MRI CAs, and polymeric heteronuclei-based MRI CAs. In addition, the review will address the challenges and future opportunities for these promising classes of metal-free polymeric MRI CAs.