Oluwasanmi, Adeolu (2017) Diels Alder-mediated release of gemcitabine from nanoparticles: developing improved methods for pancreatic cancer drug delivery. Doctoral thesis, Keele University.

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Abstract

Pancreatic cancer or pancreatic ductal adenocarcinoma (PDAC), is the deadliest type of cancerous malignancy with a survival rate of only 3.7 % after 5 years. The first line current treatment is a drug called gemcitabine, which has been shown to display effectiveness in only 23.8 % of patients. Hybrid nanoparticles (HNPs) comprised of an iron oxide core and outer gold coat have shown great potential for anti-cancer therapies. The magnetic iron oxide cores and the surface plasmon resonance (SPR) properties of the gold surface provide the HNPs with the capabilities of diagnostic imaging and drug delivery, making them true theranostic agents.

A novel thiolated thermally labile drug (TTLD) analogue of gemcitabine was successfully synthesized and attached to the surface of HNPs forming a novel drug formulation called TTLD+HNP. This TTLD compound is comprised of a gemcitabine molecule with a Diels Alder cycloadduct. Gem-Mal, a maleimide derivative of gemcitabine is released during retro Diels Alder (rDA). The mode of release involves heat-activation of the rDA reaction facilitated by the SPR of the gold shell. TTLD was characterised with mass spectrometry, nuclear magnetic spectroscopy and IR spectroscopy.

Preliminary studies determined that the TTLD compound doesn’t undergo rDA at 20 °C and a subsequent 4 week study displayed no rDA occurring at 20 °C. Afterwards in vitro experiments including the MTT and trypan blue assay determined that Gem-Mal is 4.6 times less cytotoxic than gemcitabine but is taken up by cells 11 fold faster when attached to the HNPs. Upon heat-activation at 44 °C, the TTLD+HNP formulations cytotoxicity increased by 56 % outperforming gemcitabine by 26 %, confirming its temperature driven activity. The TTLD+HNP drug formulation is the first of its kind and has displayed superior anti-cancer activity to the current first line drug gemcitabine after heat mediated controlled release.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: Theranostics, Thermoresponsive drug delivery, Diels Alder, Pancreatic cancer
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
Depositing User: Lisa Bailey
Date Deposited: 07 Jun 2017 10:27
Last Modified: 07 Jun 2017 10:27
URI: http://eprints.keele.ac.uk/id/eprint/3560

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