Nanoparticles for Stem-Cell Engineering - Stem-Cell Nanoengineering - page 136

Nanoparticle Toxicity to Stem Cells
Particles in the 50-500 nm size range are readily internalized by cells [94-98]. Internalization
can significantly affect toxicity of NPs toward stem cells in regenerative medicine [99, 100].
Furthermore, the interaction of NPs with blood components, protein adsorption on NPs,
and NP aggregation can affect the toxicity of NPs [98]. Gold [101, 102], magnetic ferrous
oxides [103], silica [104], calcium phosphate [105], and graphene [106] NPs, cadmium-
telluride (CdTe) quantum dots [107], and carbon nanotubes [108] are used in imaging,
detection, and gene delivery to cells. Asharani et al. compared the toxicity of silver, gold, and
platinum NPs in developing zebrafish embryos [109]. They reported that silver and titanium
NPs induced a concentration-dependent increase in mortality rate, hatching delays, and
other phenotypic changes whereas gold NPs did not show any toxicity [109]. Vallabani et al.
reported that thermally exfoliated graphite oxide flakes induce cytotoxicity and apoptosis
in human lung cells [110]. Sasidharan et al. reported that pristine graphene accumulated on
the membrane of kidney epithelial cells, which induced apoptosis, whereas carboxyl-
functionalized graphene was internalized with no apparent toxic effect [111]. Chng et al.
observed a correlation between the oxygen content of the functional groups of graphene
oxide prepared by different oxidative methods and their toxicity when tested with lung epi-
thelial cells [112]. Walkey et al. investigated the effect of PEGylation of gold NPs and par-
ticle size on serum protein adsorption and uptake by macrophages [98]. For NPs ranging
15-90 μm in size, smaller NPs had a higher adsorption of serum proteins and the adsorbed
protein density decreased significantly with increasing PEGylation of the NPs, such that
the adsorbed protein density was generally < 5% for poly(ethyleneglycol) (PEG) densities
of > 1 nm 2 . The uptake of the NPs by macrophages correlated with the PEG density, with
rapid decrease in macrophage uptake with increasing PEG density. However, uptake by
NPs was not eliminated even at relatively high PEG densities. Walkey et al. attributed the
residual NP uptake at high PEG densities to a serum-independent uptake mechanism [98].
Samberg reported that silver NPs, 10-120 nm in size, are taken up by human adipose tissue
derived stem cells (hASCs) but did not have a significant effect on cell morphology, cell via-
bility, and differentiation [100]. Park et al. reported that silica NPs in the 10-30 nm size
range inhibited the differentiation of mouse embryonic stem cells (mESCs) to contracting
cardiomyocytes, whereas those in the 80-400 nm size range did not have a noticeable effect
on differentiation [113].
Toxicity of gold NPs toward stem cells depends on size, zeta potential, and surface func-
tionality [101, 102, 114-116]. Mironava et al. reported that citrate-coated gold NPs were
internalized by adipose derived stromal cells (ADSCs), increased population doubling time,
decreased cell motility, and reduced adipogenesis, but the effect was reversed when the NPs
were removed from the culture medium [115]. Zhang et al. concluded from their results that
the toxicity of PEG-coated gold NPs is complex and smaller NPs are not necessarily more
toxic than larger but there may be a cause for concern with regard to metabolism and liver
uptake of the NPs for all sizes [114]. Taken together, the results suggest that PEG-coated
gold NPs are relatively inert. Liu et al . reported no in vitro or in vivo toxicity associated with
FePt@Fe 2 O 3 core-shell magnetic NPs coated with PEG and functionalized with folic acid
for targeting to cell-surface folate receptors [117]. Hafeli et al. investigated the toxicity of
magnetic ferrous NPs of 10 nm size coated with poly(ethylene oxide) (PEO) triblock copol-
ymers with human umbilical vein endothelial cells (HUVECs) and human retinal pigment
epithelial cells (HRPEs). They reported that PEG-coated ferrous magnetic NPs with PEO
lengths > 2 kDa are nontoxic for in vivo applications [118]. Sadaf et al . investigated the tox-
icity of cadmium telluride (CdTe) and silica-coated CdTe quantum dot NPs in mice [119].
They reported increased level of white blood cells and mild nephrotoxicity in CdTe treated