Decreased reticuloendothelial system clearance and increased blood half-life and immune cell labeling for nano- and micron-sized superparamagnetic iron-oxide particles upon pre-treatment with Intralipid.

BACKGROUND: Superparamagnetic iron-oxide nanoparticles are useful as contrast agents for anatomical, functional and cellular MRI, drug delivery agents, and diagnostic biosensors. Nanoparticles are generally cleared by the reticuloendothelial system (RES), in particular taken up by Kupffer cells in the liver, limiting particle bioavailability and in-vivo applications. Strategies that decrease the RES clearance and prolong the circulation residence time of particles can improve the in-vivo targeting efficiency. METHODS: Intralipid 20.0%, an FDA approved nutritional supplement, was intravenously administered in rats at the clinical dose (2g/kg) 1h before intravenous injection of ultra-small superparamagnetic iron-oxide (USPIO) or micron-sized paramagnetic iron-oxide (MPIO) particles. Blood half-life, monocyte labeling efficiency, and particle biodistribution were assessed by magnetic resonance relaxometry, flow cytometry, inductively-coupled plasma MS, and histology. RESULTS: Pre-treatment with Intralipid resulted in a 3.1-fold increase in USPIO blood half-life and a 2-fold increase in USPIO-labeled monocytes. A 2.5-fold increase in MPIO blood half-life and a 5-fold increase in MPIO-labeled monocytes were observed following Intralipid pre-treatment, with a 3.2-fold increase in mean iron content up to 2.60pg Fe/monocyte. With Intralipid, there was a 49.2% and 45.1% reduction in liver uptake vs. untreated controls at 48h for USPIO and MPIO, respectively. CONCLUSIONS: Intralipid pre-treatment significantly decreases initial RES uptake and increases in-vivo circulation and blood monocyte labeling efficiency for nano- and micron-sized superparamagnetic iron-oxide particles. GENERAL SIGNIFICANCE: Our findings can have broad applications for imaging and drug delivery applications, increasing the bioavailability of nano- and micron-sized particles for target sites other than the liver.

Quantitative temporal profiles of penumbra and infarction during permanent middle cerebral artery occlusion in rats.

The basic premise of neuroprotection in acute stroke is the presence of salvageable tissue, but the spatiotemporal volume profiles of the penumbra and infarction remain poorly defined in preclinical animal models of acute stroke used to evaluate therapies for clinical application. Our aim was to define these profiles using magnetic resonance imaging (MRI) quantitative cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) for dual-parameter voxel analysis in the rat suture permanent middle cerebral artery occlusion (pMCAO) model. Eleven male Sprague Dawley rats were subjected to pMCAO with MRI measurements of quantitative CBF and ADC at baseline, over the first 4 h (n=9) and at 7, 14, and 21 days (n=4). Voxel analysis of CBF and ADC was used to characterize brain tissue ischemic transitions. Penumbra, core, and hyperemic infarction volumes were significantly elevated (P<0.05) and unchanged over the first 4 h of pMCAO while the total lesion volume progressively rose. At 7, 14, and 21 days, tissue compartment transitions reflected infarction, tissue cavitation, and selective ischemic neuronal necrosis. Anatomical distribution of penumbra and core revealed marked heterogeneity with penumbra scattered within core and penumbra persisting even after 4 h of permanent MCAO.