Building a Better Magnetic Resonance Imaging Contrast Agent Using Macromolecular Architecture

In vivo imaging enables us to peer deeply within living subjects and is producing tremendous opportunities both for the study of cancer biology and clinical diagnostics. Rapid advances in fluorescent imaging, magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography (CT), and ultrasound imaging promise to translate the insights from basic science at the single-cell level to clinical application. Among these imaging modalities, MRI is among the most prominently used in medical diagnostics. Metal-based contrast materials have been widely adopted to clearly visualize the functional architecture of physiological structures. At present, Johnson and co-workers exploit a potential substitute in the form of nitroxide-based macromolecular contrast agents with unprecedented transverse relaxivity and stability for MRI of tumors. MRI is a noninvasive, nonionizing modality offering anatomical, physiological, and even molecular information within the bodies of living subjects. Standard MRI inherently suffers from low sensitivity stemming from the mechanism of signal detection which typically measures the relaxation rates of water protons. Contrast agents are thus used to alter the water proton relaxation rates and highlight anatomical and pathological features in the imaged tissues by enhancing images contrast (Figure 1). On the basis of the physical MR mechanism that enables them to generate a signal, two primary classes of MR contrast agents are T1 and T2 contrast agents. T1 contrast agents (e.g., Gd 3+ or Mn chelates, and analogous paramagnetic complexes) decrease protons’ longitudinal relaxation time (spin−lattice, T1) and result in a faster signal decay and a brighter region in the image (positive contrast). T2 contrast agents (e.g., superparamagnetic iron oxide nanoparticles) reduce the transverse relaxation time (spin−spin, T2) and induce localized darker spots (negative contrast). T1 contrast agents generally contain metals with a large number of unpaired electrons (Gd with seven unpaired electrons and Mn with five unpaired electrons) and have significantly improved MRI performance. Despite their wide employment, key problems remain, particularly issues associated with the toxicity of metals coupled to their tendency to accumulate in biological tissues. Metal-free MRI contrast agents can overcome these disadvantages and enable to MRI be performed in people with high risk for the side effects of traditional contrast agents. Paramagnetic nitroxide-based organic radical contrast agents (ORCAs), chemical exchange saturation transfer (CEST) contrast agents, hyperpolarized C and F MRI probes, have become new innovative tools with critical applications in MRI. Among these metal-free MRI contrast agents, nitroxide ORCAs are in principle most likely to translate to the clinic since they acquire an MRI signal using standard water relaxation mechanisms. F MRI and CEST agents have problems in their inherent insensitivity, while hyperpolarized C agents suffer from complex preparation processes and limited imaging times. For these reasons, an increasing number of studies have been devoted to developing nitroxide ORCAs, but until now their low relaxivity values compared to metals and their fast in vivo reduction to diamagnetic hydroxylamines with half-lives on the order of minutes have restricted their clinical application. Modifying MRI contrast agents with a rigid macromolecular scaffold, such as the spirocyclohexyl nitroxide derivative “chex”, is one of the most efficient ways to increase the relaxivity. Johnson’s group further stepped up the relaxivity values, by appending chex to the core of