17 research outputs found
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Optimization of Gold Nanoparticles for Radiotherapy
Radiotherapy is currently used in around 50% of cancer treatments. Although highly effective it is also damaging to surrounding healthy tissues and needs to be improved by better targeting of cancer cells. Improved radiotherapy outcomes can be achieved by using nanoparticles, especially those with high atomic number (Z), that interact with ionising radiation to generate secondary electrons and reactive species that increase cellular damage. One of the most promising elements to use is gold, in the form of gold nanoparticles (AuNPs) because of its biocompatibility and amenability to surface modification. For example, surface modification of AuNPs with simple sugars can improve their solubility and cellular uptake. Furthermore, positively charged AuNPs are thought to have an improved cellular uptake because of their interactions with negatively charged cell membranes.
This thesis is focussed on two research areas: (1) the development of dual action chemo-radiosensitising AuNPs and (2) the development of oligonucleotide-AuNPs for radiosensitisation.
(1) It is shown that sugar-PEGamine coated AuNPs demonstrate selective uptake and toxicity toward skin cancer cells with an IC50 of 1 ÎŒg/ml [Au], without damaging normal skin cells at this concentration. Oxidative stress and caspase-dependent apoptosis both play a key role in the toxicity of these AuNPs. Moreover, AuNPs coated with sugar and PEGamine show a strong radiosensitisation effect in combination with kilovoltage X-rays and a smaller effect with megavoltage X-rays.
(2) Oligonucleotide-phosphine-coated AuNPs are shown to demonstrate a limited uptake in the cellular cytoplasm compared to the previous AuNPs but increase AuNPs uptake into the cell nucleus. The limited uptake into the cells, as well as the DNA triplex forming oligonucleotides (TFOs) attached to the AuNPs, is still responsible for a radiosensitisation effect, although smaller than with sugar:PEGamine AuNPs. In the future, the uptake of the oligonucleotides AuNPs may possibly be improved by varying their size (from 3.5 to 2 nm) and/or adding a spacer between the NP and the TFO
Cancer-selective, single agent chemoradiosensitising gold nanoparticles
Two nanometre gold nanoparticles (AuNPs), bearing sugar moieties and/or thiol-polyethylene glycol-amine (PEG-amine), were synthesised and evaluated for their in vitro toxicity and ability to radiosensitise cells with 220 kV and 6 MV X-rays, using four cell lines representing normal and cancerous skin and breast tissues. Acute 3 h exposure of cells to AuNPs, bearing PEG-amine only or a 50:50 ratio of alpha-galactose derivative and PEG-amine resulted in selective uptake and toxicity towards cancer cells at unprecedentedly low nanomolar concentrations. Chemotoxicity was prevented by co-administration of N-acetyl cysteine antioxidant, or partially prevented by the caspase inhibitor Z-VAD-FMK. In addition to their intrinsic cancer-selective chemotoxicity, these AuNPs acted as radiosensitisers in combination with 220 kV or 6 MV X-rays. The ability of AuNPs bearing simple ligands to act as cancer-selective chemoradiosensitisers at low concentrations is a novel discovery that holds great promise in developing low-cost cancer nanotherapeutics
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Selective cancer cell toxicity and radiosensitization with gold nanoparticles
Place de la pharmacie d'officine dans la prise en charge des patients cancereux (Ă©tat des lieux et prospectives aprĂšs le plan cancer et la loi HPST)
BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF
Clonogenic assay dose-response of adherent MCF-7 and MCF-10 cells exposed for 3 h to different concentrations of 50:50 or 0:100 αGal:PEG-amine AuNPs.
<p>The graphs represent the percentage of cell colonies compared to the no-nanoparticle control ±SEM.</p
Clonogenic assay of HSC-3 cells, demonstrating a partial rescue of 50:50 αGal:PEG-amine AuNP-induced cell death by 50 ΌM Z-VAD-FMK caspase inhibitor.
<p>10 ΌM Antimycin A was used as an apoptosis positive control. For each condition, n = 3 and data are presented ±SEM. * Denotes a significant difference (P<0.05 ANOVA, Tukey multiple comparisons post-test).</p
Clonogenic assay dose-response curves for three different 50:50 sugar:PEG-amine AuNPs on adherent HSC-3 and HaCaT cells.
<p>Cells were loaded with a range of AuNP concentrations for: A) 1 h, B) 3 h, C) 6 h and D) 24 h. The graphs represent the percentage of cell colonies compared to the no-nanoparticle control for each sugar:PEG-amine AuNP ±SEM.</p
Clonogenic assay dose-response of different ratios of αGal:PEG-amine AuNPs, citrate-capped AuNPs, αGal only, or PEG-amine only, loaded for 3 h on adherent cells.
<p>a) HSC-3 cells, b) HaCaT cells. The graphs represent the percentage of cell colonies compared to the no-nanoparticle control ±SEM.</p