As silica nanoparticles (SiO 2 NP) gain increasing interest for medical applications it is important to understand their potential adverse effects for humans. Here we prepared well-defined core-shell fluorescently labelled SiO 2 NP of 15, 60 and 200 nm diameter and analyzed their cytotoxicity in THP-1 derived macrophages, A549 epithelial cells, HaCaT keratinocytes and NRK-52E kidney cells. We observed a size-dependent cytotoxicity in all cell types in serumfree conditions. HaCaT cells were least and macrophages or lung derived A549 cells were highly sensitive towards SiO 2 NP treatment. Differences in cytotoxicity could be correlated with different uptake rates. By using flow cytometry and confocal microscopy we quantified the uptake. Furthermore we used specific inhibitors for clathrin-and caveolinmediated endocytosis to elucidate the uptake mechanisms, which were found to be dependent on the NP size and the cell type. Clathrin-mediated endocytosis was involved in the uptake of SiO 2 NP of all sizes and was the major pathway for 60 nm or 200 nm SiO 2 NP. Caveolin-mediated endocytosis contributed to the uptake of 60 and 200 nm SiO 2 NP in THP-1 macrophages but only to uptake of 200 nm SiO 2 NP in A549. However, in the presence of serum all SiO 2 NP were non-toxic. The presence of serum furthermore could alter the uptake mechanism. In summary, this study demonstrates size-and cell type dependent differences in SiO 2 NP uptake and toxicity.
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