Superparamagnetic Iron Oxide Nanoparticles Stabilized with Multidentate Block Copolymers for Optimal Vascular Contrast inT₁-Weighted Magnetic Resonance Imaging

Ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) have been used as vascular contrast agents in magnetic resonance imaging (MRI), mainly for their capacity to generate negative contrast. To use USPIOs as positive contrast agents, it is necessary to achieve increased colloidal stability and signal-enhancement performance. Their molecular coatings must be carefully chosen, so that the vascular blood-pool contrast agents lead to long blood turnover times. However, to avoid long-term toxicological effects, they must also be cleared rapidly through the urinary or gastrointestinal pathways. In this context, highly stable USPIOs showing “positive” contrast in MRI and optimal clearance rates call for the development of robust biocompatible molecular coatings. In the present study, USPIOs were stabilized with a multidentate block copolymer (MDBC), using a one-pot polyol synthesis method in the presence of a MDBC. Two types of MDBCs having pendant COOH groups in the anchoring block were developed: a polymer with linear-poly(ethylene glycol) (PEG) blocks and a polymer containing brushed-PEG blocks. The synthesized superparamagnetic Fe 3 O 4 crystals were uniform (5–8 nm in diameter), showed ultrasmall hydrodynamic diameters in dynamic light scattering, and were stable in physiological liquids. MDBC-coated USPIOs were analyzed in relaxometry, and the formulations showing the strongest potential for T 1 -weighted vascular imaging ( r 2 / r 1: ∼4) were selected for in vivo MRI. Intravascular injections performed in the mouse model indicated long blood retention times and high signal enhancement in MRI for nanoparticles coated with linear-PEG block coatings. These results also indicate that MDBC/USPIOs could be used in vascular MRI applications, where the nanoparticles must transit the blood for several hours, followed by an efficient clearance in the next days following injection. The use of MDBCs as nanoparticle coatings could open new possibilities in the design of USPIOs for targeted molecular MRI.