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@PHDTHESIS{Leifert:197580,
author = {Leifert, Annika},
othercontributors = {Simon, Ulrich},
title = {{S}yntheses and characterization of biologically active
gold nanoparticles},
address = {Aachen},
publisher = {Publikationsserver der RWTH Aachen University},
reportid = {RWTH-CONV-143435},
pages = {VI, 165 S. : Ill., graph. Darst.},
year = {2012},
note = {Prüfungsjahr: 2012. - Publikationsjahr: 2013; Aachen,
Techn. Hochsch., Diss., 2012},
abstract = {In this work, the biological activity of a variety of gold
nanoparticles (AuNPs) was investigated. Water soluble AuNPs
in a size range from 1–15 nm were synthesized and
characterized via UV/Vis spectroscopy, electron microscopy,
dynamic light scattering, elemental analysis, infrared (IR)
and nuclear magnetic resonance (NMR) spectroscopy. Within a
DFG funded cooperation project, the AuNPs were tested for
their cytotoxicity against several cell lines including HeLa
cells. For phosphine-stabilized AuNPs, stabilized with
3-(diphenylphosphino)-benzenesulfonate sodium salt (TPPMS),
a size dependent toxicity with a maximum of toxicity for 1.4
nm sized AuNPs was found. Furthermore, the influence of the
ligand binding strength was investigated. It was found that
thiol-stabilized AuNPs are considerably less toxic and, in
opposite to phosphine-stabilized small AuNPs, do not induce
oxidative stress. By electron paramagnetic resonance
spectroscopy, it was analyzed with an oxidizable stable
radical as substrate if the toxicity of AuNPs correlates
with their catalytic activity for oxidation reactions. This
was however not the case. With DNA samples from cells that
were incubated with AuNPs, the potential of the particles to
damage DNA was investigated. For this, the DNA samples were
enzymatically digested, and by gas chromatography and
subsequent mass spectrometry the concentrations of DNA base
oxidation products (lesions) were quantified. Here, no
correlation with cytotoxicity was found. For cytotoxic
phosphine-stabilized as well as for non-toxic
thiol-stabilized AuNPs, no significantly enhanced
concentrations of DNA lesions were found, and in contrary,
for both cases, the concentrations of two lesions were
decreased. A possible correlation with an activation of
certain repair enzymes could not yet be proven within this
work. It was further investigated whether the cytotoxic
gold(I) complex TPPMS-Au(I)-Cl is potentially present as an
impurity in AuNP samples and could thus be partially
responsible for the cytotoxicity. By 31P-NMR spectroscopy,
this question could not be answered unambiguously. A
dialysis experiment revealed that the gold complex is not
present besides the AuNPs in significant amounts. With
31P-NMR spectroscopy, the equilibrium between associated and
dissociated TPPMS ligand molecules of AuNPs in solution
could be confirmed. Patch clamp experiments with potassium
ion (hERG) channel expressing cells revealed that the small
phosphine-stabilized AuNPs block the ion channels
irreversibly. Thiol-stabilized AuNPs again showed no effect.
In reference experiments in the presence of an excess of
TPPMS, the blocking could be inhibited. This result
indicates that the blocking species is a gold core which has
partially or completely stripped off its TPPMS ligand shell.
This hypothesis could be supported by theoretical
calculations from one of the cooperation partners. Besides
TPPMS, more phosphines were synthesized and used as ligands
for AuNPs. A trisulfonate (TPPTS), a carboxylic acid
derivative (TPPMC) and a mixed charged ligand with a
carboxylic acid and an amine function (TPPMCMA) could
successfully be used as AuNP ligands. The resulting species
did however not show considerable changes in cytotoxicity.
Further, it was attempted to use diphosphine molecules as
ligands for 1.4 nm sized AuNPs to investigate the
correlation between ligand binding strength and cytotoxicity
in more detail. With
3,3‘,3‘‘,3‘‘‘-(ethane-1,2-diylbis-(phosphintriyl))tetrabenzenesulfonate
sodium salt (DPPETS), water soluble AuNPs could be
synthesized. In a KCN degradation experiment, these showed
lower stability than TPPMS-stabilized AuNPs. In differential
scanning calorimetry measurements however, a clearly higher
thermic stability of the diphosphine-stabilized AuNPs could
be verified. A geometric estimation revealed that DPPETS
could possibly, due to the chain length of the ethyl group
between the two phosphorus atoms, not act as a bidentate
ligand. For this reason, more AuNPs with the propyl- and
butyl-analogous ligands (DPPPTS and DPPBTS) were
synthesized. These showed however an impaired long term
stability and were not stable in cell culture medium. By
using larger gold colloids (11–13 nm) it could be shown
that the synthesized diphosphine ligands are in principle
applicable as AuNP ligands. For a potential therapeutic
application of toxic AuNPs, 1.4 nm sized AuNPs were
stabilized with a mixed ligand shell of TPPMS and TPPMC and
further functionalized with (Lys3)-bombesin, an oligo
peptide with high affinity towards gastrin-releasing peptide
receptors (GRPR) which are expressed by several cancer
cells. The functionalization of the AuNPs could be confirmed
by IR spectroscopy. Further, cell experiments with GRPR
expressing cells revealed that the activity of the bombesin
derivative was not inhibited by coupling to the AuNPs.},
keywords = {Anorganische Chemie (SWD) / Nanotechnologie (SWD) /
Nanopartikel (SWD) / Gold (SWD) / Biologische Aktivität
(SWD) / Anorganische Synthese (SWD)},
cin = {151310 / 150000},
ddc = {540},
cid = {$I:(DE-82)151310_20140620$ / $I:(DE-82)150000_20140620$},
typ = {PUB:(DE-HGF)11},
urn = {urn:nbn:de:hbz:82-opus-41253},
url = {https://publications.rwth-aachen.de/record/197580},
}
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