Received for publication January 27, 2006.
Revised April 7, 2006.
Accepted for publication April 10, 2006.

Interaction of functionalized superparamagnetic iron oxide nanoparticles with brain structures

Abstract

Super Paramagnetic Iron Oxide Nanoparticles (SPIONs) combined with MRI are under clinical evaluation to enhance detection of neurodegenerative diseases. A major improvement would be to link therapeutic drugs to the SPIONs to achieve targeted drug delivery, either at the cell surface or intracellularly, together with active disease detection, without inducing cell reaction. Our objectives were to define the characteristics of SPIONS able to achieve cell-specific interaction with brain-derived structures. Our system consisted in an ironoxide core (9-10 nm diameter) coated either with dextran (Sinerem and Enorem) or various functionalized polyvinylalcohols (PVA) (PVA-SPIONs). We investigated the cellular uptake, cytotoxicity and interaction of these various nanoparticles with brain-derived endothelial cells, microglial cells and differentiating 3-dimensional aggregates. None of the nanoparticles coated with dextran or the various PVAs was cytotoxic or induced the production of the inflammatory mediator NO used as a reporter for cell activation. AminoPVA-SPIONs were taken up by isolated brain-derived endothelial and microglial cells at a much higher level than the other SPIONs, and no inflammatory activation of these cells was observed. AminoPVA-SPIONs did not invade brain cells aggregates lower than the first cell layer and did not induce inflammatory reaction in the aggregates. Fluorescent aminoPVA-SPIONs derivatized with a fluorescent reporter molecule and confocal microscopy demonstrated intracellular uptake by microglial cells. Fluorescent aminoPVA-SPIONs were well tolerated by mice. Therefore functionalized aminoPVA-SPIONs represent biocompatible potential vector systems for drug delivery to the brain which may be combined with MRI detection of active lesions in neurodegenerative diseases.

Key words: blood-brain barrier, brain, cell uptake, iron oxide, microglia, nanoparticles