Abstract
This dissertation presents the effect of peptide-modified 10 nm gold nanoparticles (GNPs) with chemotherapeutic drugs, bleomycin and cisplatin, and 2 Gy of 6 MV X-ray irradiation in MDA-MB-231 cells. The GNPs were modified with a peptide sequence containing an ‘RGD’ amino acid motif. Bleomycin binds to the surface of the GNPs through a thiol bond and cisplatin has no known significant interaction with the GNP surface. No significant toxicity was induced by introducing GNPs to MDA-MB-231 cells at the 0.3 nM concentration used throughout this dissertation. The surface modification with ‘RGD’ peptides increased accumulation of the GNP constructs 6~7 fold compared to the unmodified counterparts. There was no significant difference in the accumulation of GNPs in the presence of bleomycin or cisplatin. These results suggest that the presence of chemotherapeutics do not affect the accumulation of peptide modified GNPs into cells. The effect of having GNPs with chemotherapeutics was examined. The presence of GNPs with bleomycin decreased the survival of MDA-MB-231 cells by 18 ± 3 % compared to treatment with the same concentration of free bleomycin. Treating cells with GNPs and cisplatin did not have a significant difference in survival compared to the same concentration of free cisplatin treatment. This suggests that conjugating chemotherapeutics onto the GNPs can result in a more efficient delivery of the drug. If the drug does not bind to the GNP surface, having GNPs in the media does not interfere with the uptake of the drug. The effect of radiosensitization in the presence of GNPs was studied by incubating cells with 0.3 nM GNPs prior to irradiation with 2 Gy of 6 MV X-rays. The survival fraction decreased by 19 ± 6 % compared to the irradiated control condition. Lastly, the triple combined effect of GNPs, chemotherapeutics, and irradiation was investigated. The presence of GNPs had an advantage to the combined chemotherapy and radiation therapy. Based on results from these studies, GNPs can be used in addition to combined chemotherapy and radiation therapy for improved outcomes in cancer treatment
Highlights
1.1 Cell Biology of CancerCancer is a common human genetic disease caused by accumulation of several mutations [1]
The size range of colloidal Gold nanoparticles (GNPs) can be determined by the peak SPR wavelength [245, 246]
When GNPs are aggregated from irreversible inter-particle coupling, the Local Surface Plasmon Resonance (LSPR) will red-shift but the spectra will broaden
Summary
1.1 Cell Biology of CancerCancer is a common human genetic disease caused by accumulation of several mutations [1]. Peptide modified GNPs will be used in combination with bleomycin, a chemotherapeutic agent that conjugates onto the surface of GNPs, or cisplatin, a chemotherapeutic agent that acts as a radiosensitizer, with 2 Gy, 6 MV radiation to demonstrate the presence of relatively low concentrations of peptide modified GNPs improves the therapeutic outcome of the same dosages of chemotherapeutic agents and radiation in MDA-MB-231 cells. This is the first study where enhancement effects of GNPs and chemotherapeutics in combination with MV energy radiation are examined in vitro
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