Abstract
Superparamagnetic iron-oxide particles (SPIO) are used in different ways as contrast agents for magnetic resonance imaging (MRI): Particles with high nonspecific uptake are required for unspecific labeling of phagocytic cells whereas those that target specific molecules need to have very low unspecific cellular uptake. We compared iron-oxide particles with different core materials (magnetite, maghemite), different coatings (none, dextran, carboxydextran, polystyrene) and different hydrodynamic diameters (20–850 nm) for internalization kinetics, release of internalized particles, toxicity, localization of particles and ability to generate contrast in MRI. Particle uptake was investigated with U118 glioma cells und human umbilical vein endothelial cells (HUVEC), which exhibit different phagocytic properties. In both cell types, the contrast agents Resovist, B102, non-coated Fe3O4 particles and microspheres were better internalized than dextran-coated Nanomag particles. SPIO uptake into the cells increased with particle/iron concentrations. Maximum intracellular accumulation of iron particles was observed between 24 h to 36 h of exposure. Most particles were retained in the cells for at least two weeks, were deeply internalized, and only few remained adsorbed at the cell surface. Internalized particles clustered in the cytosol of the cells. Furthermore, all particles showed a low toxicity. By MRI, monolayers consisting of 5000 Resovist-labeled cells could easily be visualized. Thus, for unspecific cell labeling, Resovist and microspheres show the highest potential, whereas Nanomag particles are promising contrast agents for target-specific labeling.
Highlights
Small supraparamagnetic iron oxide particles are increasingly used in magnetic resonance imaging (MRI) either as direct contrast agents in vivo, as conjugates for monitoring specific molecules in vitro and in vivo, or for ex vivo-labeling of cells and tracking their fate in vivo [1,2]
Cells were washed twice briefly with phosphate buffered saline (PBS) and the iron uptake was quantified by photometrical determination Alternatively, internalized iron was visualized by Prussian Blue Staining, electron microscopy or MRI
Different cell numbers were cultured as monolayers on polyethylene terephthalate (PET) membrane filters (VWR International GmbH, Darmstadt, Germany) in medium, incubated with different iron oxide nanoparticles for 24 h, washed twice with PBS and fixed with 4% paraformaldehyde for 20 min
Summary
Small supraparamagnetic iron oxide particles are increasingly used in magnetic resonance imaging (MRI) either as direct contrast agents in vivo, as conjugates for monitoring specific molecules in vitro and in vivo, or for ex vivo-labeling of cells and tracking their fate in vivo [1,2]. As compared with (non-polymeric) gadolinium complexes, magnetic iron oxide particles appear to yield higher detection sensitivities [3,4], but have the disadvantage for molecular imaging (or the advantage to monitor phagocytic cells) to be rapidly internalized by phagocytosis. Little is known about how these modifications influence toxicity, phagocytosis and cellular retention of these particles. We compared these properties for several supraparamagnetic particles with magnetite and maghemite cores and different coatings. We analyzed the internalization kinetics of the particles, their cellular localization after uptake, their in vitro toxicity, and their contrast properties in vitro under the aspects of suitability for ex vivo cellular labeling and/or for selective molecular imaging for in vivo MRI visualization
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