Biomedical Engineering Reference
In-Depth Information
10.4
IN VIVO
EVALUATION OF NANOPARTICLE TOXICITY
In vivo
systems are extremely complex, and the interactions between nanomaterials and biological
components can cause unique biodistributions, clearances, immune responses, and metabolisms.
The major challenges for
in vivo
assays include dosimetry, the optimization of dispersion, the evalu-
ation of interactions and biodistribution, and so on.
10.4.1 adMe
of
N
aNopartIcles
The assessment of pharmacokinetics (PK) provides information regarding nanotoxicity and guides
future investigations. The time and concentration of the exposure is determined by PK studies. The
residence time and accumulation locations of nanoparticles can mean the difference between avoid-
ing and experiencing toxic responses.
The small size of nanoparticles allows them to enter tissues easily but, unfortunately, they still
cannot go freely into all biological systems. Nanoparticles barely enter the brain because of the
protection of the blood-brain barrier, unless aided by tailored surface functionalizations. Whenever
nanoparticles enters into the body via six major ways (oral, intravenous, dermal, subcutaneous,
inhalation, and intraperitoneal), they interact with biological components (proteins and cells) first,
and then distribute to various organs or tissues with the same or modified/metabolized structure.
Afterwards, they reside in the cells of the organ for an unknown amount of time and dose before
leaving. Excretion can happen at any time after absorption via the kidneys and liver/bile duct.
Although the number of current studies is not sufficient to draw any conclusion about nanophar-
macokinetics, new information appears from time to time. For example, a study regarding organ
coefficients of TiO
2
in mice indicated that the coefficients of the liver, kidney, and spleen increased
while the coefficients of the lung and brain dropped with an increasing dose of nano-anatase TiO
2
(Liu et al., 2009). In addition, some
in vivo
PK data found a correlation of nanostructure-protein
interactions. These data allow setting up a system to examine and predict structure-activity rela-
tionships (Fischer and Chan, 2007).
10.4.2 a
NIMal
M
odels
Mice, rats, zebra fish,
Caenorhabditis elegans
, and rainbow trout are often-seen models. These mod-
els are employed to investigate the biodistribution and clearance of nanoparticles, environmental haz-
ards, carcinogenicity, and acute toxicity. A DNA microarray of 207 stress-related genes performed in
rainbow trout found that 13% of tested genes responded to both dissolved and nano-Ag, while about
12% of genes changed upon nano-Ag treatment specifically; the levels of vitellogenin-like proteins
and DNA strand breaks were significantly reduced by both forms of Ag (Gagne et al., 2012). An
in
vivo
measurement of nano-Zn, Fe, and Si acute toxicity in mice compared to microsized particles
demonstrated that the low-level toxicity of nanoparticles was due to the presence of the inorganic par-
ticles themselves, not to the nanometer size (Cha and Myung, 2007). An acute toxicity of Cu-NP was
reported in zebra fish, indicating that the gill was the primary target and the transcriptional response
induced by Cu-NP was highly divergent (Griffitt et al., 2007).
In vivo
studies with adult Sprague-
Dawley rats showed that Ag-NP did not induce genetic toxicity in either male or female rat bone
marrow, but it did damage the liver (Kim et al., 2008). In contrast, tests of Ag-NPs on
Caenorhabditis
elegans
highlighted that the toxicity of Ag-NP was not greater than silver ions when investigating the
mechanisms of toxicity via pharmacological, genetic, and physicochemical ways (Yang et al., 2011).
10.4.3 c
arcINogeNIcIty
s
tudIes
of
N
aNopartIcles
Carcinogenicity can be induced through genotoxic and nongenotoxic ways. Some scientists assume
that, due to their unique properties, all nanoparticles may be carcinogenic no matter what their
