Imaging, Distribution, and Toxicity of Superparamagnetic Iron Oxide Magnetic Resonance Nanoparticles in the Rat Brain and Intracerebral Tumor

Abstract

OBJECTIVE: Superparamagnetic iron oxide nanoparticle magnetic resonance imaging (MRI) contrast agents are gaining use in the central nervous system. The purpose of this study was to evaluate the imaging characteristics, distribution, time course, and neurotoxicity of the clinical agents ferumoxtran-10, ferumoxides, and ferumoxytol, and the laboratory preparation MION-46 in rat brain. METHODS: Iron oxide agents were administered by intracerebral inoculation or intraarterially after osmotic blood-brain barrier opening in normal rats and intravenously in nude rats with intracerebral tumor xenografts. Rat brains were imaged by MRI at multiple time points and then were assessed for iron histochemistry and pathological features. RESULTS: After intracerebral injection, MRI signal changes declined slowly over weeks to months. After transvascular delivery, transient (3 d) enhancement was seen with ferumoxtran-10 or ferumoxytol, whereas ferumoxides induced long-term (28 d) signal dropout. No pathological brain cell or myelin changes were detected after delivery of the clinical iron oxide agents to normal brains. In tumor models, ferumoxtran-10 enhanced one small-cell lung carcinoma intracerebral tumor, which correlated with iron staining in cells with macrophage morphological features at the tumor margin. Little enhancement was seen in two other models. CONCLUSION: These studies demonstrate the safety and efficacy of iron oxide-based MRI contrast agents in the brain and provide imaging parameters and time course data for future studies in brain tumors and neurological lesions.