Small molecule-stabilized exceedingly small magnetic iron oxide nanoparticles as a contrast agent of T₁-weighted...

Exceedingly small magnetic iron oxide nanoparticles (ES-MIONs) with high biocompatibility have been developed as T₁-weighted magnetic resonance imaging (MRI) contrast agents (CAs) with potential to replace commercial Gd chelates. To overcome the key problem of clinical transformation (high viscosity at high concentration) for reported ES-MIONs stabilized by polymers, herein, we propose a new concept to synthesize ES-MIONs stabilized by small molecules, but not polymers. Typically, sodium citrate (SC) was used as the stabilizer to synthesize ES-MION-SC through a co-precipitation method. After optimization of large-scale synthesis conditions, ES-MION-SC24 was considered as the optimal sample because of its high r₁ value (7.03 ± 0.05 mM^-1 s^-1, 3.0 T). At 100 mM of C_Fe, the viscosity of ES-MION-SC24 (only 1.0 CP) is much lower than that of ES-MION stabilized by polyacrylic acid (PAA) (∼11.0 CP), which exhibits promising potential for clinical application of ES-MION-SC24. The MTT assay, live/dead cells assay, blood routine analysis, and histological analysis show ES-MION-SC24 exhibits favorable biosafety. T₁-weighted MRI at 3.0 T indicates ES-MION-SC24 can accumulate in tumors and maintain high brightness for an extended period up to 2.0 h enabling multiple scans post-injection, which is much longer than commercial MRI CAs.