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|Title: ||Targeted Delivery of a Platinum Anticancer Complex to Tumours Using Carrier-DNA Tethered Aptamers|
|Authors: ||Upadhyay, Parth J.|
|Issue Date: ||8-May-2015|
|Publisher: ||University of Sydney|
Faculty of Pharmacy
|Abstract: ||DNA-based aptamers have been proposed as a simultaneous active targeting agent and delivery vehicle for anticancer drugs. PHENSS is a platinum-based anticancer complex that reversibly binds to DNA. Previous research has shown reduced targeting ability of aptamers when platinum compounds are bound to them. This study aimed to attach PHENSS to a DNA-based-aptamer, AS1411, using a high affinity carrier segment based on adenosine bulge secondary DNA structures. Drug-carrier segment binding was studied using DNA melting, circular dichroism spectrophotometry and 1D and 2D NOESY 1H NMR. In vitro cytotoxicity assays were performed against on-target MCF-7 and off-target HEK-293 cell lines. DNA melting experiments appeared to demonstrate PHENSS intercalation into the carrier segment, although, there was no apparent increase in the melting temperature. Circular dichroism, however, confirmed PHENSS binding in a drug-carrier segment ratio of 2:1, consistent with the two adenosine bulge sites. The binding was also confirmed by 1H NMR, where the large upfield shifts of the PHENSS proton resonances (0.75-0.95 and 0.8 ppm) were consistent with an intercalative mode of binding. Broadening of both the PHENSS and carrier segment resonances indicate fast-to-intermediate exchange kinetics, on the NMR timescale. The in vitro cytotoxicity assay showed a statistically insignificant reduced activity of PHENSS when bound to the aptamer vehicle (IC50: 2.37 ± 0.91 µM) compared with PHENSS alone (IC50: 0.72 ± 0.23 µM) in the MCF-7 cell line and a statistically insignificant increase in HEK-293 cells (IC50: 2.21 ± 1.01 µM and 4.29 ± 2.71 µM, respectively, (p>0.05). Overall, while a PHENSS-aptamer complex was formed using a carrier DNA segment, the results show that it did not improve the cytotoxicity or selectivity of the platinum complex.|
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|Rights and Permissions: ||The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.|
|Type of Work: ||Masters Thesis|
|Type of Publication: ||Master of Philosophy M.Phil|
|Appears in Collections:||Sydney Digital Theses (University of Sydney Access only)|
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