Clustered ultra-small iron oxide nanoparticles as potential T₁/T₂ dual-modal magnetic resonance imaging contrast agents and application to tumor model

Many studies have been conducted on the use of ultra-small iron oxide nanoparticles (USIONs) (d < 3 nm) as potential positive magnetic resonance imaging (MRI)-contrast agents (CAs); however, there is dearth of research on clustered USIONs. In this study, nearly monodispersed clustered USIONs were synthesized using a simple two-step one-pot polyol method. First, USIONs (d = 2.7 nm) were synthesized, and clustered USIONs (d = 27.9 nm) were subsequently synthesized through multiple cross-linking of USIONs with poly(acrylic acid-co-maleic acid) (PAAMA) polymers with many-COOH groups. The clustered PAAMA-USIONs exhibited very weak ferromagnetism owing to the magnetic interaction between superparamagnetic USIONs; this was evidenced by their appreciable r₁ = 3.9 s^‒1 mM^‒1 and high r₂/r₁ ratio of 14.6. Their ability to function as a dual-modal T₁/T₂ MRI-CA in T₁-weighted MRI was demonstrated when they simultaneously exhibited positive and negative contrasts in T₁-weighted MRI of tumor model mice after intravenous injection. They displayed positive contrasts at the kidneys, bladder, heart, and aorta and negative contrasts at the liver and tumor.