Evaluating Size-Dependent Relaxivity of PEGylated-USPIOs to Develop Gadolinium-Free T1 Contrast Agents for Vascular Imaging

Ultra-small superparamagnetic iron oxide (USPIO) nanoparticles provide a safer alternative to gadolinium-based contrast agents (GBCAs) in T 1 -weighted MR imaging. MRI contrast behavior of USPIOs depends on their magnetic properties, which in turn depend on their physicochemical composition. Identifying and tailoring USPIO structural characteristics that influence proton relaxation in MRI is crucial to developing effective gadolinium-free T 1 contrast agents. Here, we present a systematic empirical evaluation of the relationship between USPIO size and MRI relaxivity ( r 1 and r 2 values). Monodisperse USPIO cores, with precisely controlled core diameter ( d C ) were synthesized via the thermal decomposition of iron(III)-oleate precursor. USPIOs with d C = 6.34, 7.58, 8.58, and 9.50 nm, were dispersed in aqueous phase via ligand exchange with silane or dopamine-modified polyethylene glycol (PEG) polymers. Relaxivity characterization in a 1.5 T clinical MRI scanner showed the r 2 / r 1 ratio increased linearly with USPIO core diameter ( R 2 = 0.95), but varied little with both hydrodynamic diameter ( d H ) and PEG molecular weight. One sample, DOPA-6-20 (6.34 nm USPIO cores coated with 20 kDa dopamine-modified PEG), provided the lowest r 2 / r 1 value (3.44) and thus promise as a potential T 1 contrast agent. In a preliminary study, we evaluated DOPA-6-20 for in vivo angiography imaging in a mouse with a 7 T scanner and observed strong T 1 -weighted enhancement of the mouse blood pool. Key anatomical features in the vascular network were visible even 5 min after intravenous administration. Using empirical data, we have presented the basis of a structure-property relationship that can help develop optimized USPIO-based T 1 contrast agents.