Ligand-Driven Optimization of Iron Oxide Nanoprobes forIn Vivo MRI Enhancement at Ultra-High Field

Abstract

Ultra-high-field magnetic resonance imaging (UHF-MRI, B0 > 7 T) combined with contrast enhancement (CE-MRI) offersunmatched spatial resolution, but high-field effects limit the performance of negative contrast agents. Here, we report a ligand-driven strategy to modulate the T2 relaxivity (r2 ) of monodisperse 12 nm iron oxide-based contrast agents synthesized by thermaldecomposition. Five surface chemistries–polyacrylic acid (PAA), poly(isobutylene-alt-maleic anhydride) (PMA), poly(maleicanhydride-alt-1-octadecene) (PMAO), citric acid (CA), and silica (SiO2 )─ were investigated under physiological conditions andin vivo using relaxometry (1.4 T), clinical (3 T), and UHF (9.4 T) MRI, achieving up to a 333 mm−1 s−1 increase in r2 . CA-coated T2contrast agents exhibited record-high r2 values (522 mm−1 s−1 at 3 T; 381 mm−1 s−1 at 9.4 T) in spherical iron oxide MNPs withinthe superparamagnetic size range (d < 20 nm). Correlations of r2 with hydrodynamic size, ζ-potential, and coating thicknessrevealed that ligand chemistry–specifically hydrophilicity and anionic surface charge–dominates over physical shell dimensionsin governing water accessibility and magnetic dephasing. This scalable ligand-exchange strategy enables precise T2 tuning at UHF,with phantom results reliably predicting in vivo UHF-MRI performance in rat brain models, advancing the design of neuroimaging nanoprobes.