Investigation of blood-brain barrier permeability to magnetite-dextran nanoparticles (MD3) after osmotic disruption in rats

The permeability of experimentally disrupted blood-brain barrier (BBB) to superparamagnetic nanoparticles (MD3) was studied in rats. BBB opening was induced by intracarotid injection of mannitol. One hundred eighty rats were used for the study. Rats were examined at two time points, 30 minutes and 12 hours after intracarotid mannitol injection. Different preparations intravenously injected 30 minutes before rat sacrifice were used for characterization of BBB disruption. BBB integrity was determined with Tc-99m-diethylenetriamine pentaacetic acid (DTPA) and Tc-99m-albumin. Iron oxide-glucose particles (12-nm mean diameter), Tc-99m-labeled lecithin-cholesterol liposomes of three different sizes (50, 100, and 200 nm), and polyethylene glycol (PEG)-coated Tc-99m liposomes (50 nm) were used for investigations of the dependence of BBB permeability on particle system size or surface. Magnetite-dextran nanoparticles (MD3) were evaluated as superparamag netic contrast agent to monitor with magnetic resonance imaging (MRI) the BBB breakdown. In vitro T-1 and T-2 relaxation times of the brain tissue were measured at 40 MHz and 37 degrees C, and T-2-weighted MR images were acquired at 0.5 T. After intracarotid mannitol infusion, as expected, the BBB breakdown was immediate and temporary as judged by soluble molecule diffusion. MD3 nanoparticles crossed the BBB 12 hours after intravenous mannitol injection, at a time when brain permeability for molecules or small particles returns to normal. Magnetite crystals were found in cytoplasmic vesicles of glial cells. On MRI, signal intensity decreased after injection of MD3, even 12 hours after mannitol injection. This particularity could be useful in the study of focal pathological lesions accompanied by BBB permeability modifications. In such conditions, superparamagnetic particle contrast agents could be caught by the BBB, allowing the observation of impaired BBB areas without detectable cellular lesions.