Stimuli-Responsive Surface Coating Properties of T₂ MRI Contrast Agents

Iron oxide nanocrystals (IONCs) are FDA approved Magnetic Resonance Imaging (MRI) contrast agents with high biocompatibility, hepatobiliary clearance, and contrast performance. It has been demonstrated that polymeric nanocrystal surface coatings have a significant impact on T₂contrast performance (relaxivity). These non-magnetic polymers at IONC interfaces can influence the diffusion of bulk water within the local magnetic field of the nanocrystal core – thus impacting relaxation dynamics. Specific environmental or molecular stimuli can induce changes in contrast performance, increasing signal-to-noise and highlighting pathological areas of interest. The result is a “smart” molecular imaging contrast agent that exhibits stimuli-responsive contrast changes. “Smart” T₂ contrast agents currently rely on <i>interparticle</i> clustering effects to increase relaxivity. Compared to an individual IONC, clusters increase their effective diameter and generate greater magnetic field inhomogeneities and promote T₂ relaxation. However, clustering is clinically problematic due to aggregation and toxicity concerns. Thus, “smart” T₂ contrast agents that exhibit <i>intraparticle</i> changes in surface coating to modulate relaxivity are promising candidates for clinical applications. For example, IONCs that can decrease their hydrodynamic diameter or polymeric grafting density in the presence of environmental or molecular stimuli can improve their relaxometric properties and display higher signal-to-noise. Particularly when cleavable peptide sequences are incorporated into IONC surfaces, the coatings can undergo substantial changes when in the presence of certain proteases which are established biomarkers of cancer, traumatic brain injury, or other pathologies. Proteases cleave a target portion of the IONC surface coating, directly modulating its thickness, stability, and/or grafting density.<br/><br/>Here, we highlight a shift in optimizing contrast performance by modulating surface coating properties instead of magnetic core properties. Additionally, a novel framework for conceptualizing the impact of surface coatings on water diffusion and resulting contrast performance was developed. This framework provides a more detailed explanation for contrast performance trends found in the literature and informs the rational design of high-performance contrast agents. The effects of grafting density and thickness on relaxivity were measured for various surface coatings. The impacts of physiologically relevant pH ranges and metal cation concentrations on contrast performance were evaluated for a range of surface coatings. Contrast performance was also evaluated upon IONC conjugation to a target peptide sequence. Stimulus-responsiveness was probed by introducing clinically relevant proteases to the conjugated IONC system and measuring changes in relaxivity.