Biomedical Engineering Reference
In-Depth Information
that the larger particle size (200 nm) PLGA did not trigger any negative response. Relatively more
toxic TiO
2
nanoparticles triggered cell death and other responses such as ROS generation, mito-
chondrial depolarization, plasma membrane damage, intracellular calcium concentration increase,
and size-dependent TNF-a release. The authors concluded that the cytotoxic effects could be due to
the size-dependent interaction between nanoparticles and biomolecules, as smaller particles tend to
adsorb more biomolecules [68].
In another study, the cationic branch-like macromolecules polyamidoamine (PAMAM) dendrimers
used as drug delivery systems for gene-based therapies such as RNA interference were studied. The
study reveals that the effect of PAMAM dendrimers on their interactions with cellular signal transduc-
tion pathways such as the epidermal growth factor receptor (EGFR) is an important area to examine
the toxicity of these nanoparticles. The EGFR is an important signaling cascade that regulates cell
growth, differentiation, migration, survival, and apoptosis. In this study, the impact of naked unmodi-
fied Superfect (SF), a commercially available generation 6 PAMAM dendrimer, on the EGFR tyrosine
kinase-extracellular-regulated kinase 1/2 (ERK1/2) signaling pathway in human embryonic kidney
(HEK 293) cells was investigated. It was found that the SF PAMAM dendrimer delivery system,
at doses routinely recommended for transfection of nucleic acids, can stimulate the EGFR-ERK1/2
signal transduction pathway in human cells via an oxidative-stress-dependent mechanism. It is a well-
known fact that EGFR is an important signaling pathway for important life processes such as cell
growth, differentiation, and migration as well as mediating several pathologies, most notably cancer.
These findings have important implications for the safe use of PAMAM dendrimers [69].
7.3.2.2 Interaction of PNs and SLNs with Biological Systems
It is very important to study the interaction of PNs and SLNs with a biological system as it can be
the major route for nanotoxicity of these systems. Only few studies have documented the interac-
tions of PNs with the biological systems. A study of enhanced transfection by an antioxidative
polymeric gene carrier that reduces polyplex-mediated cellular oxidative stress looked into the role
of transfection-induced cellular ROS in nanoparticle-mediated oxidative stress and showed that tox-
icity might be a concern. The authors studied the cellular stress during transfection for polycation-
based nonviral gene delivery. It was found that polyplexes can induce cellular ROS production even
at subtoxic concentrations. The study emphasizes that the effect on cellular ROS stresses should be
considered while designing polycation-based nonviral gene delivery systems, especially for clinical
applications where a substantial amount of polyplex may be administered [70]. Efficient transfec-
tion and low cytotoxicity are prerequisite properties for nonviral gene carriers to reach clinical
settings. Since polycation-based gene delivery systems rely mostly on the formation of nanosized
polyplexes with nucleic acid drugs such as plasmid DNA (pDNA) and siRNA, it is likely that the
polyplex will induce oxidative stress after cellular uptake. Polyethylenimines (PEIs) are among the
most extensively studied cationic polymers for nonviral gene delivery because of their ability to
form nanosized particles with nucleic acid drugs and to mediate consistent transfection in several
cell types [71]. However, like most polycations used in nonviral transfection protocols, the relatively
high cytotoxicity of PEI is considered a major drawback. The interactions of PEI with cellular mem-
branes may reduce membrane fluidity by facilitating the formation of huge clusters on the surface
of the membrane, leading to necrotic cell death. In addition, it was recently reported that PEI and
its copolymer can induce oxidative stress responses in epithelial cells and macrophages. Grandinetti
et al. [72] also showed that PEI/DNA polyplexes localized to mitochondria after transfection. The
interaction of PEI polyplex with mitochondria seems to be related with the interference of mito-
chondrial function and loss of mitochondrial membrane potential. The mitochondrial damages by
polyplexes could stimulate the additional production of ROS due to the uncoupling of electron
transport machineries, leading to significant increase in cellular oxidative stress [73]. Subtle altera-
tions in the expression of cellular signal transporters induced by ROS may either directly or indi-
rectly affect the reporter gene expression.
