Ultrasmall maghemite nanoparticles as MRI contrast agent: Unique combination of aggregation stability, low toxicity, and tumor visualization.

Iron oxide nanoparticles are a promising candidate for the dual-mode MRI contrast agent, however most of them have limited circulation time and predominant negative contrast. We developed citric acid stabilized superparamagnetic maghemite nanoparticles (CA-SPMNs) with size 3.2 ± 0.7 nm with intense positive contrast. Co-precipitation reactions under well-controlled conditions in the automatic chemical reactor have carried out the synthesis. We found an encouraging correlation between aggregate formation kinetics in biological media and in vitro cytotoxicity results and in vivo circulation time. A cytotoxicity test showed the mouse fibroblast viability over 80 % for iron doses exceeding 1 mg/mL. CA-SPMNs have a low r/r ratio, exhibiting positive contrast. Using in vivo MRI we demonstrated that CA-SPMNs circulate in the blood for 12-24 h, enabling blood vessel and tumor visualization, and partial renal clearance. Finally, CA-SPMNs show promise as effective MRI contrast agents, enabling differentiation between normal and pathological tissues.