Biomedical Engineering Reference
In-Depth Information
Gold nanoparticles have recently been shown to increase the lysosomal pH in rat kidney cells, caus-
ing lysosomal dysfunction; this fact supports the alkalization mechanism of toxicity (Ma et al. 2011).
14.3.4.8 Toxicity of Dendrimers
Nephrotoxicity consistent with biodistribution studies has been reported, revealing a high kidney
accumulation for G3 PAMAM dendrimers (IP) (Roberts et al. 1996), G3 and G4 PAMAM den-
drimers (IV or IP) (Malik et al. 2000), biotinylated-PAMAM dendrimers (G0-4) (IV) (Wilbur et al.
1998), and PEG-polyester dendritic hybrids (IV) (DeJesus et al. 2002).
14.3.4.9 Toxicity of Fullerenes
Fullerenes are another category of carbon-based nanoparticles. The most common type of fullerenes
have a molecular structure of C
60
which takes the shape of a ball-shaped cage of carbon particles
arranged in pentagons and hexagons. In an
in vivo
study, Chen et al. administered a water-soluble,
polyalkylsulfonated C
60
dispersion orally, intraperitoneally, and intravenously. No lethal damage
was observed through oral administration, but the median lethal dose (LD
50
) was estimated to be
600 mg/kg in intraperitoneal administration. C
60
injected intraperitoneally or intravenously accu-
mulated in the kidney and induced nephropathy (Chen et al. 1998).
14.4
TOXICITY OF NANOMATERIALS ON SPLEEN
14.4.1 s
pleeN
M
orphology
The spleen is a large, highly irrigated, lymphatic organ. It participates in the storage of spent blood
components as well as in the maturation and recycling of lymphocytes. Anatomically, the spleen
is confined and protected by a fibrous capsule, and fibrous trabeculae shape its inner structure
(Figure 14.5a). Splenic blood flow is divided into two circulation pathways: one fraction transits
through closed vasculature, as seen in other organs, and the remainder reaches the open circulation,
where small arteries empty directly into the parenchyma (Figure 14.5b) (Moghimi 1995; Mebius
and Kraal 2005). Spleen parenchyma is divided between red and white pulps. The red pulp is
formed by a network of reticular fibers containing macrophages and senescent RBCs. It is engaged
in the filtration of pathogens and old erythrocytes from the blood (Figure 14.5c). White pulp, situ-
ated in the vicinity of the arteries, is involved in the proliferation of lymphocytes (both B and T
types). The marginal zone, delimiting the outer border of the white pulp, is composed of specialized
macrophages. Efferent lymph vessels leave the spleen to reach lymphatic circulation. The spleen
architecture varies between species (Demoy et al. 1999; Mebius and Kraal 2005). The most evident
distinction is the existence of sinusoidal (human, rat) and nonsinusoidal (mice) splenic circula-
tions. Judicious interpretation must be applied when comparing results between animal models. For
example, distinct regions of the spleen contribute differently to particle retention in sinusoidal and
nonsinusoidal spleens (Demoy et al. 1999).
CDC retention in the spleen is usually undesired because it can lead to immunogenic reac-
tions (Dobrovolskaia and McNeil 2007). Because of the differences in the blood flow between the
liver and spleen, splenic delivery is inversely related to hepatic uptake (Allen and Hansen 1991).
Therefore, PEGylated CDCs that avoid uptake in the liver are delivered to the spleen in higher
amounts compared to non-PEGylated colloids (Moghimi 1995; Peracchia et al. 1999). The architec-
ture of the splenic parenchyma is highly tortuous and its reticular fiber meshwork decrease blood
shear rates, maximizing interactions between blood components and splenocytes (Figure 14.5c).
Moreover, extravasated colloids must squeeze through the elongated fenestrations of the sinusoids
to reenter venous circulation. Physiologically, this process results in the splenic retention (and sub-
sequent phagocytosis) of senescent erythrocytes (Mebius and Kraal 2005).
For CDCs, the physicochemical factors that limit passage through the sinusoidal sieve (high
rigidity, large size (N200 nm) and elongated or irregular shapes) will therefore contribute to their
