Toxicological Effects of Metal Nanomaterials - Safety of Nanomaterials along Their Lifecycle - page 192

the released silver ions, demonstrating the contribution of solubility to nanoparticle
toxicity (Bouwmeester et al. 2011). A correlation of ROS induction and apoptosis
was found by Foldbjerg et al. using two sizes of nanosilver (60-70 and 149 nm) and
A549 cells (Foldbjerg, Dang, and Autrup 2011). Haase et al. assessed four differ-
ent silver nanoparticle variants, a 40 nm sized silver nanoparticle as well as three
variants of 20 nm sized nanosilver (uncoated, citrate-coated, and peptide-coated)
in THP-1-derived macrophages. The 20 nm nanosilver displayed stronger cytotoxic
effects and induced a stronger oxidative stress response compared to the 40 nm sized
silver nanoparticles. Similar to the results of Braydich-Stolle et al., the observed
effects depended on the coating, in which the influence of citrate coating was less
pronounced (Braydich-Stolle et al. 2010; Haase et al. 2011). In summary, nanosil-
ver has the potential to induce cytotoxic effects in vitro , which seem to be ion and
size dependent and which often involve oxidative stress and inflammation. However,
none of these studies attributed effects to the intracellular concentration of particles
or dissolved silver species which would be an important issue in the understanding
of these effects.
The increasing use of gold nanomaterials in biomedical applications has been
paralleled by an increase in research activity in the biodistribution and toxicity of
gold nanoparticles. Albeit most of the in vivo studies conducted so far has focused
on the biodistribution of gold nanomaterials, a few cytotoxicity studies have com-
prehensively assessed the impact of size (Pan et al. 2007), surface modification
(Uboldi et al. 2009; Connor et al. 2005; Sun, Liu, and Wang 2008), and aggregation
(Albanese and Chan 2011).
Different groups have adjusted the perception that gold nanoparticles can be
considered as inert like their bulk counterparts. Li et al. demonstrated that gold
nanoparticles of 20 nm diameter induce oxidative stress and inhibit cell prolifer-
ation in lung fibroblasts (MRC-5 cells; Li et al. 2008). Likewise, Pan et al. have
shown size- and concentration-dependent cytotoxicity of gold nanoparticles (rang-
ing from 0.8 to 15 nm). Gold clusters of 1.4 nm were found to induce cell death
in four different cell lines (HeLa cells, J774A1 mouse macrophages, L929 mouse
fibroblasts, and SK-Mel-28 melanoma cells), with IC 50 values ranging from 30 µM to
56 µM, whereas IC 50 values of 0.8, 1.2, and 1.8 nm gold clusters were considerably
higher (250, 140, and 230 µM, respectively) and 15 nm sized colloidal gold particles
(Au15MS) were found to be completely nontoxic up to 6,300 µM (Pan et al. 2007).
By studying the major cell death pathways, Pan et al. found indicators of oxidative
stress and proposed that the toxicity of the 1.4 nm gold nanoparticles depended on
their ability to trigger the intracellular formation of ROS from dioxygen (Pan et al.
2009). In another study, different aggregates of transferrin-coated gold nanoparticles
of 16 nm size were generated and found to display different uptake patterns in HeLa
cells, A549 lung epithelial cells, and melanoma cells (MDA-MB-435; Albanese and
Chan 2011). These results demonstrate that cell type and mechanism of interactions
may contribute to nanoparticle uptake and toxicity. Connor et al. studied the meta-
bolic activity of a human leukemic cell line (K562) after three days of continuous
exposure to gold nanoparticles of average diameters of 4, 12, or 18 nm with different
surface modifications (Connor et al. 2005). They found citrate- and biotin-modified
particles at concentrations of up to 250 µg/ml as well as preparations with glucose or