Biomedical Engineering Reference
In-Depth Information
Transcellular passages by passive diffusion appear to be rare: Although the passage of cells by
22 nm TiO
2
particles was suggested to occur passively (Geiser et al. 2005), other researchers dem-
onstrated that Au-NPs in sizes of 5-8 nm could not enter cells by passive diffusion (Stoeger et al.
2006). The likely mode of cellular uptake for metal and metal oxide nanomaterials is believed to
actively occur through endocytosis. Various endocytotic routes have been characterized, which are
classified on the basis of the coating with clathrin and the involvement of dynamin in uptake. The
chief mechanisms are termed as clathrin-mediated endocytosis, caveolae-dependent mechanism,
and macropinocytosis. Various classifications are used for the clathrin-independent and caveolae-
independent routes. The classification by Sahay et al. is mainly based on the GTPases involved
(RhoA-dependent, Arf6-dependent, and Cdc42/Arf1-dependent endocytosis) and on the coat protein
(flotillin dependent) (Sahay et al. 2010). Another nomenclature employs the term clathrin-dependent
carriers/glycophosphatidylinositol (GPI)-anchored protein-enriched compartment (GEEC)-type
endocytosis as a synonym for Cdc42/Arf1-dependent endocytosis and IL-2Rβ-dependent endocyto-
sis for RhoA-dependent endocytosis (Doherty and McMahon 2009).
Independent of the route of entry, the cargo is mainly transported via endosomes to lysosomes
(Figure 13.3). TiO
2,
nonfunctionalized silver, and SiO
2
particles are mainly taken up by clathrin-
mediated endocytosis (Chung et al. 2007; Greulich et al. 2011; He et al. 2009; Huang et al. 2005;
Singh et al. 2007; Sun et al. 2008). NPs can leave the cells either by exocytosis or by transcytosis.
Exocytosis of NPs is not well studied and conflicting results were obtained: Exocytosis of quan-
tum dots was not consistently seen in the studies (Clift et al. 2008; Jiang et al. 2010). On the other
hand, transcytosis can occur through receptor-mediated uptake or via adsorptive-mediated uptake.
Receptors for BSA (bovine serum albumin), transferrin, and opioid peptide-functionalized nano-
materials are expressed on several cell types and BSA-coated NPs have been shown to transcytose
Macropinocytosis
Clathrin
Caveolin
RhoA
Cdc42
Arf6-dep.
Flotillin
RE
CC
EV
MP
GEEC
Cav
EE
LE
L
TV
ER
TV
Cyto
FIGURE 13.3
Active uptake mechanisms of nanomaterials into cells. Macropinocytosis, clathrin-mediated
endocytosis, and caveolae-mediated and non-clathrin, non-caveolae-mediated uptake are the major routes
identified. The latter are subclassified into RhoA- (or IL-2Rβ-) dependent endocytosis, Cdc42/Arf1 or clath-
rin-independent cargo/GPI-anchored protein-enriched compartment-dependent (GEEC) endocytosis, flotil-
lin-dependent endocytosis, and Arf6-dependent endocytosis. Early endosomes (EE) and late endosomes (LE)
transport the contents of macropinosomes (MP), clathrin-coated vesicles (CC), and GEEC to the lysosomes
(L). Material taken up by caveolae-mediated endocytosis is transported via caveolosomes (Cav) either to the
endoplasmic reticulum (ER) or to early endosomes. Nanomaterials may be removed from the cells by exocy-
totic vesicles (EV). Early endosomes may also fuse with the plasma membrane directly or through recycling
endosomes (RE). In polarized cells, transcytosis occurs via transport vesicles (TV). Cyto: cytoplasm.
