Gold target tumor cells (35). GNPs have also

Gold
has been considered to be a precious material for centuries and have intrigued
mankind. There are suggested reports that colloidal gold nanoparticles have
been used by artists as these particles were able to interact with visible
light thereby leading to the formation of radiant colors. Gold nanoparticles
have a broad range of applications in divergent fields. Gold nanoparticles
applications include therapeutic agents, sensory probes, and drug delivery
platforms among others. Due to its higher surface area to volume ratio,
therapeutic biomarkers can be coated on the surface of GNPs (34). When
excited by 700-800 nm wavelength of light, GNPs could generate heat that could
potentially target tumor cells (35). GNPs
have also been used to diagnose cancers, heart diseases and infectious agents
undermining the versatility of GNPs (36). Despite
their biological applications, anti-inflammatory properties of GNPs have been
characterized fairly recently (37). In this
study we determined whether gold nanoparticles can be used as immunomodulators
to treat inflammation linked with cancer.

Owing
to its size, GNPs have the capacity to pass through blood vessel and eventually
blood-brain barrier (38).
However, both in vitro and in vivo data suggest that GNP can be
used as diagnostics to be used in parenteral routes (39). This
study used bio-conjugates of GNPs and tested their toxicity in human PBMCs,
HUVECs, PMNs and erythrocytes. Such in
vitro studies coupled with in vivo
experiments did not show any toxic effects and exhibited ROS scavenging
property when rat neutrophils were stimulated with LTB4 or PMA along with GNP
bioconjugate (39). We
observed reduction in ROS production when A549 cells were pre-treated with GNP
and then stimulated with either LPS or CpG-ODN (Figure 4, S2). However, when we
stimulated A549 cells with PMA there was increased ROS production, but pre-treatment
with GNP did not result in significant reduction in ROS production (data not
shown) suggesting that GNPs might be inducing immunomodulation by specifically
targeting TLR pathway in lung cancer (A549) cell lines. Furthermore,
GNP-bioconjugate could also potentially have superior ROS scavenging trait
owing to efficient cellular uptake of such conjugates. In our studies, we
observed that the 5 nm GNP was most efficiently internalized by A549 cells (Figure
2). Future studies would involve comparison between the efficacy of GNP and
GNP-bioconjugate in ROS scavenging function.

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Cytotoxicity
of nanoparticles depends on the size of the nanoparticles (40). When
different sized silver nanoparticles were compared for cytotoxicity, it was
observed that the 20 nm silver nanoparticles were more toxic than the 80 and
113 nm particles (41). This
effect could again be cell-type specific as this effect was evident in L929 cells
but not in RAW264.7 cells (41). When the
cytotoxicity of 1-2 nm GNPs was tested using fibroblasts, macrophages,
epithelial cells, drastic changes in IC50 values were observed (42). In
contrast, 15 nm GNPs were nontoxic to a 60-fold higher concentration of 1-2 nm
GNPs (42). Similar
results were observed when SK-Mel-28 melanoma cells were used (42). However,
in our study spherical GNPs of 5, 15 and 30 nm size did not display any
significant toxicity in A549 cells (Fig 4). This effect could be dependent on
the cell type being used. Similarly, when GNPs (5-200 µg/mL) were tested for
cytotoxicity in human DCs after 48h incubation, necrosis was not induced even at
a high concentration of 200 µg/mL (43). Consistent
with our study, bare non-conjugated gold nanoparticles of various sizes such as
4, 11, 19, 35 and 45 nm GNPs did not induce cytotoxicity in murine RAW264.7
cells indicating that the cytotoxicity of various sized GNPs is also cell line
specific and varies depending on the type of cells used (16). Shape of
nanoparticles also impacts cell viability due to modifications in geometry.
Additionally, distinct chemical and physical interactions with cell membrane
also impact cell viability. Gold nanospheres (10 nm) and gold nanorods (41 nm)
displayed dose and time-dependent toxicity in HEK293T and HeLa cell lines (44). However,
nanoprisms (160 nm), gold nanostars (240 nm), and nanoflowers (370 nm) did not
demonstrate appreciable level of toxicity in HeLa cells implying the sensitivity
of HEK293T cells (44).
Similarly, needle-shaped, but not the spherical-shaped
PEGylated PLGA polymer NPs were found to induce significant cytotoxicity in
HepG2 cell lines (45).Apart from TLR4 and TLR9, other
TLRs are expressed by A549 cells including TLR7, which is also expressed in the
endosome. The role of TLR7 in lung cancer has not been understood completely (68). TLR7 activation has a pro-tumorigenic
role has been associated with poor prognosis in non-small cell lung cancer (69). Type I
IFN activates the immune system to target the process of metastasis (70). Whether GNPs can target TLR7
pathway and modulate downstream molecules including MyD88 and
interferon-inducible genes need to be ascertained.

Thus,
modulation of TLR4-mediated inflammatory responses by 5 nm GNPs suggests their potential
use an adjunct therapy to treat inflammation-linked lung cancer. Conjugation of
standard anti-cancer drug on the surface of immunomodulatory (5 nm) GNPs
(GNP-anticancer drug conjugates) might be a promising strategy to treat lung cancer
with increased efficacy and minimal side-effects. GNPs in such conjugates might
serve as drug delivery carriers as well as might prevent overt inflammation and
associated cancer progression owing to their immunomodulatory potential. Thus, GNP-anticancer
drug conjugates might aid in maintaining balanced immune responses to kill
cancer cells as well as prevent hyper-inflammation-mediated tumor promotion.