Biomedical Engineering Reference
In-Depth Information
NPs
ROS
?
alcium channel
NPs
Endocytosis
ROS
Calcium
ROS
Lysosomal
proteases/cathepsin
Activation of mark
Mitochondrial damage
Activation of NFκB, lkB
Activation of caspases
Activation of transcription factors
ARE
Phase II enzymes
(GST, NQO-1)
Antioxidant enzymes
(HO-1)
DNA damage
Cell cycle arrest
FIGURE 9.6
Schematic of biointeractions of nanoparticles with the cell and cell membrane. (Reproduced
with permission from Marano F et al. Nanoparticles: Molecular targets and cell signalling.
Archives of
Toxicology.
2011;85(7):733 - 41.)
nanoparticle uptake, results in lysosomal localization, such as demonstrated in the case of silver
and SiO
2
nanoparticle uptake [102,103]. The size of the nanoparticle also plays role in determining
its location in the cell; it has been shown that gold nanoparticle translocation is limited by size as it
diffuses throughout the cell [104]. Further, nanoparticles also have an ability to accumulate in the
nucleus [105-107]. The mechanism of translocation to the nucleus may involve diffusion, but it has
also been shown that gold nanoparticles close to 39 nm in size can be transported into the nucleus
by nuclear pore complexes [108].
In the cell, as a result of protein-nanoparticle interactions, protein confirmations may occur and
more significant alterations can be expected with a larger-sized nanoparticle [92,109]. These protein
conformation changes may be irreversible and can result in the loss of function and induce, there-
fore, cytotoxicity [110-112]. Furthermore, the nanoparticles have the ability to penetrate into the
nucleus and may alter the structure and function of nuclear proteins. For instance, SiO
2
nanoparti-
cles have been shown to cause the aggregation and fibrillation of nucleoplasmic proteins, impacting
nuclear function [113]. However, the nanoparticles may also result in increased enzymatic activity.
The effect of the interactions depends on the location and nature of the binding. If the interaction is
close to the active site, the protein will be inactivated, but if the protein is encapsulated or otherwise
stabilized, the activity of the enzyme may be increased [114-116]. The ability of the nanoparticles
to stabilize proteins and trigger refolding can also facilitate therapeutic intervention for diseases
caused by misfolded proteins or their aggregates, such as Alzheimer's [117].
Cell signaling may be effected as a result of nanoparticle and cellular protein interactions [118].
As almost any foreign object entering a body, the induction of an inflammation response is one
of the most common adverse effects of nanoparticles considered. Following the uptake by cells
such as epithelial cells or macrophages, nanoparticles directly or indirectly produce biological
responses that involve the generation of intra- or extracellular reactive oxygen and nitrogen species
(ROS and NOS) (Figure 9.6) [119,120]. Some of the nanoparticles, namely, fullerenes and CNTs,
are shown to favor localization in mitochondria, where they may facilitate the generation of ROS
in connection with the leakage of electrons from the electron transport chain [121,122]. Through
the generation of ROS, an inflammation signaling pathway (NF-kB, AB-1) may be activated,
