Biomedical Engineering Reference
In-Depth Information
doses are much shortened compared to the values observed with the first injection. The ABC effect
gradually decreases over 2-4 weeks. The ABC effect is more evident when CDCs are PEGylated.
Even without prior sensitization, non-PEGylated CDCs are rapidly opsonized and captured by the
liver. The induction of circulating antibodies, therefore, does not affect their clearance. Conversely,
PEGylated CDCs are designed to slow down nonspecific capture by the MPS. The presence of spe-
cific interacting antibodies greatly enhances their clearance.
The secreted antibodies are mainly immunoglobulin-M (IgM) (Ishihara et al. 2009), but -G
has also been reported (Judge et al. 2006). The specific epitopes targeted by the Ig's are still
unclear, because high doses of non-PEGylated CDCs (N5 mg/kg) can induce an ABC effect on
subsequently administered PEGylated CDCs (Laverman et al. 2001; Ishida et al. 2004). As with
most immunization processes, the factors affecting the ABC induction phase rely on a subtle
balance between immune responses and tolerance. Particulate CDCs possess characteristics, sub-
micrometer sizes, and repetitive surface architectures similar to those of pathogens, which can
stimulate immunogenic reactions (Bachmann and Jennings 2010). Nucleic acids further enhance
immunogenicity (Judge et al. 2006; Tagami et al. 2009) while cytotoxic drugs have a deleterious
effect on splenocytes and prevent the initiation of ABC (Laverman et al. 2001; Ishida et al. 2006).
Interestingly, high doses (N5 mg/kg) of PEGylated CDCs seem to induce tolerance (Ishida et al.
2005, 2006; Tagami et al. 2009).
14.4.3 p
oteNtIal
r
Isk
of
N
aNoMaterIals
oN
the
s
pleeN
The spleen is an important organ in the immune system and a constituting part of the RES (Xiaoyong
et al. 2009). The slow clearance and tissue accumulation of potential free radical producing nano-
materials as well as the prevalence of numerous phagocytic cells in the organs of the RES make
organs such as the liver and spleen to be the main targets of oxidative stress (Sumit et al. 2012).
14.4.3.1 Toxicity of Metal Nanoparticles
The
in vivo
renal clearance, biodistribution, and toxicity of gold nanoclusters were studied by Xiao-
Dong et al. They concluded that gold nanoparticles have a high level of accumulation in the liver and
spleen, and these accumulations can induce genetic changes and liver necrosis (Cho et al. 2010; Lipka
et al. 2010). QDs larger than 15 nm can bypass renal excretion and can be accumulated in the liver
and the spleen (Fischer et al. 2006; Cho et al. 2010; Zhou et al. 2011). It was found that gold nanoclu-
sters (Au25 NCs) caused an acute immune response with a decreasing thymus index. Subsequently,
the continuous Au accumulation in the liver and spleen destroys the immune system and causes irrep-
arable damage. Furthermore, the liver and kidneys cannot obtain protection by the immune system.
These damages can be reflected by clinical hematology and biochemistry (Xiao-Dong et al. 2012).
Jong et al. demonstrated the size-dependent tissue distribution of gold nanoparticles with the
smallest (10 nm) nanoparticles showing the most widespread distribution (blood, liver, kidney,
spleen, testis, heart, lung, thymus, and brain) whereas the larger particles (50, 100, and 250 nm)
were detected only in the blood, liver, and spleen (Jong et al. 2008, Sumit et al. 2012).
Lankveld et al. carried out a kinetics study of the tissue distribution of different-sized silver
nanoparticles and found that following a single exposure, the highest silver concentrations per gram
organ were found in the spleen followed by the liver for both, 80 and 110 nm particles. They found
that the accumulation of silver nanoparticles was present in all organs, but most significantly in
the liver, lungs, and spleen and, thus, these organs may be potential target organs for toxicity after
repeated exposures (Lankveld et al. 2010).
14.4.3.2 Toxicity of Nanorods
Yang et al. (2013) studied the long-term
in vivo
biodistribution and toxicity of Gd(OH)
3
nanorods.
Biodistribution results by both,
in vivo
SPECT imaging and l-counter experiments showed that most
of the Gd(OH)
3
nanorods were quickly cleared from the bodies of mice. However, the excretion
