Biomedical Engineering Reference
In-Depth Information
toxicities (three IP injections every 3 weeks over 6 weeks) (Neerman et al. 2004). The acute study
indicated that the lethal dose was 160 mg/kg, giving rise to 100% mortality 6-12 h post injection.
In both acute and subchronic studies, the hepatic function was normal at up to 10 mg/kg dendrimer
as evaluated by changes in serum alanine transaminase activity. However, a significant increase in
serum alanine transaminase activity was noticed for both acute and subchronic groups at the dose
level of 40 mg/kg. In addition, the histopathological investigation showed extensive liver necrosis.
In vivo
dendrimer toxicity profiles are closely related to the chemical structure of the dendrimer;
size and generation; exposure duration; biodistribution; and the rate, location, and mechanism of
metabolism. Dendrimer toxicity is influenced by the nature of the terminal groups. Full generation
polyamidoamine dendrimers with cationic amine terminal groups are more toxic than half-genera-
tion dendrimers with anionic carboxylic acid terminal groups. High generation dendrimers and high
doses of cationic dendrimers usually lead to a greater
in vivo
tox icit y.
14.2.3.5 Toxicity of Carbon Nanotubes
The size of aggregated CNTs is thought to be a primary concern for toxicity. Pristine (nonfunc-
tionalized) CNTs are inherently hydrophobic; as a result, aggregation is expected and observed
in
vivo
. For injection, pristine CNTs are suspended in biocompatible surfactants such as Tween 80 or
Pluronic F108 (Cherukuri et al. 2006; Yang et al. 2008). Several studies have been conducted on the
in vivo
distribution of IV injected pristine single-walled carbon nanotubes (SWCNTs). The accumu-
lation of CNTs was primarily determined to be in the liver, but is also found in the spleen and lungs.
Acute toxicity was not observed in any tissue up to 24 h (Cherukuri et al. 2006; Yang et al. 2007,
2008). The accumulation in the liver was suggested to be due to a rapid surfactant displacement
followed by the opsonization of serum proteins (Cherukuri et al. 2006). Yang et al. followed up dis-
tribution studies by looking at serum biomarkers of damage. Furthermore, they looked at markers
for oxidative stress (glutathione and malondialdehyde) in liver samples post dose. Elevated levels
of lactose dehydrogenase and alanine aminotransferase were concluded to be due to hepatic injury
from accumulation in the liver. They also observed an increase in malondialdehyde and a decrease
in glutathione in liver samples at the dose of 1.0 mg/mouse, which was indicative of increased levels
of oxidative stress. Though no acute toxicity was determined histologically up to 90 days post dose,
biomarkers representing hepatic injury due to oxidative stress should be further investigated (Yang
et al. 2008). Recent studies have shown that once in the bloodstream, the slow clearance, a tendency
to aggregate, and intrinsic properties can lead to oxidative stress especially in the liver, lungs, and
spleen, eventually resulting in inflammation.
Histopathological evaluations of livers exposed to multi-walled carbon nanotubes (MWCNTs)
showed remarkable morphological alterations such as individual cell necrosis indicated by kary-
orhxis as well as sinusoid dilation, hepatocyte disruption, vacuolation and swelling, fatty changes,
hemorrhagic clots, and necrotic changes when compared to controls. Kupffer cells are the resident
macrophages of the liver and play an important role in its normal physiology and homeostasis.
These cells participate in acute and chronic responses of the liver to toxic compounds. Activation
of Kupffer cells by toxic agents, both directly and indirectly, results in the release of an array of
inflammatory responses, growth factors, and ROS. This activation appears to control acute hepato-
cyte injury along with chronic liver responses. The role of Kupffer cells in these diverse responses
is the key to understanding the mechanisms involved in liver injury (Roberts et al. 2007).
14.2.3.6 Toxicity of Europium Hydroxide Nanorods
Chitta and coworkers synthesized europium hydroxide nanorods by microwave irradiation and
characterized them using several analytical tools. They found that synthesized europium hydrox-
ide nanorods are nontoxic to endothelial cells observed by the apoptosis assay. The IP injection of
europium hydroxide nanorods at several doses in mice showed normal blood hematology and serum
clinical chemistry except the slight elevation of liver enzymes. The histopathological examination
of the liver, kidney, spleen, and lungs from every mouse, assayed on day 8 or day 60 after nanorod
