, 1992). Transcellular passage by passive diffusion appears to be rare: although passage of cells by 22 nm TiO2 particles was suggested to occur by passive diffusion (Geiser et al., 2005), other researchers described

that Au-nanoparticles in sizes of 5–8 nm could not enter cells by passive diffusion ((Stoeger et al., 2006)). Active uptake by endocytosis is the likely mode of cellular uptake for metal and metal oxide NMs. Several endocytotic routes have been characterized, which are classified according to the coating with clathrin and the involvement of dynamin in the uptake. Main mechanisms are termed clathrin-mediated endocytosis, macropinocytosis and caveolae-dependent. Different classifications are used for the clathrin-independent and caveolae-independent routes. The classification by Sahay et al. (2010) is mainly based on the GTPases involved Selumetinib (Arf6-dependent, Cdc42/Arf1-dependent

and RhoA-dependent endocytosis) and on the coat protein (Flotillin-dependent). Another nomenclature employs the term clathrin-independent carriers/glycophosphatidylinositol (GPI)-anchored protein enriched compartment (GEEC)-type endocytosis as synonym for Cdc42/Arf1-dependent endocytosis and IL-2Rβ-dependent endocytosis for RhoA-dependent endocytosis (Doherty and McMahon, 2009). Independent of the route of entry, the cargos are mainly transported via endosomes to lysosomes (Fig. 2). Non-functionalized silver, TiO2 and SiO2 particles are mainly taken find more up by clathrin-mediated endocytosis (Chung et al., 2007, Greulich et al., 2011, He et al., 2009, Huang et al., 2005, Singh et al., Cetuximab purchase 2007 and Sun et al., 2008). Nanoparticles can leave the cells either by transcytosis or by exocytosis. Exocytosis of nanoparticles is not well studied and conflicting results were obtained: exocytosis of quantum dots was not consistently seen in the studies (Clift et al., 2008 and Jiang et al., 2010). Transcytosis

can occur through receptor-mediated uptake or via adsorptive-mediated uptake. Receptors for BSA, transferrin and opioid peptides functionalized NMs are expressed on several cell types and BSA-coated nanoparticles have been shown to transcytose through endothelial cells (Wang et al., 2009). For the gastrointestinal tract, however, this type of uptake is not relevant. Absorptive-mediated transcytosis is mediated by the interaction of positively charged substances with anionic sites of the plasma membrane: cationic nanoparticles had a greater potential than neutral or negatively charged ones (Harush-Frenkel et al., 2008). Additionally uncoated, not positively charged TiO2 nanoparticles can cross the intestinal epithelium by the transcellular route (Koeneman et al., 2010). As mentioned in Section 3.