Al-Ameri, Jenan Jasim Mohammed (2020) Development of a novel doxorubicin delivery system for pancreatic cancer. Doctoral thesis, Keele University.

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Abstract

Pancreatic cancer is considered as the 4th most aggressive cancer in the Western world. There is a direct link between
pancreatic cancer diagnosis and patient age with high occurrence of the disease happening in the 65-75-year age group. The majority of cases are diagnosed at the advanced stages, making curing of this disease unattainable and leading to high mortality rates. Problems related to treatment of cancer using traditional systemically delivered drugs are as a result of an ineffective absorption, bioavailability or high systemic toxicity resulting in unwanted side effects. Thus there is an unmet need for better, more efficient delivery systems causing an increased patient quality of life.
In this work a poly(allylamine) graft polymer modified with 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-thiol hydrophobic pendant groups was developed. This polymer was capable of incorporation of metallic hybrid iron oxide-gold nanoparticles. The resultant magnetomicelles were capable not only of laser triggered heating but also carrying lipophilic drug molecules which we exploited in this work. In order to produce a heat triggered drug delivery system, a two new analogues of doxorubicin was created modifying the molecule with spermine or lipoic acid forming DOX-SP and DOX-LA respectively.
Magnetomicelle synthesis was confirmed using nuclear magnetic resonance spectroscopy, inductively coupled spectra - optical emission spectroscopy and fourier transform infrared spectroscopy. The aggregation behaviour was confirmed using photon correlation spectroscopy. Reversible drug incorporation was realised via
linkage between the drug analogue linkers and the hybrid nanoparticle surface in the magnetomicelle. The magnetomicelles developed exhibited up to 59.21% drug release noticed at 44 °C after 24 h.
Cytotoxicity of the doxorubicin analogue formulations was tested on human pancreatic adenocarcinoma (BxPC3) cells. The unloaded nano-aggregates were incubated for 24 h with the cells and the cell viability was compared to control wells. The result revealed that 50% of the total cell number was viable (IC50) at 50 gmL-1 (PAA-Ox5-HNPs). These values revealed that the incorporation of the metallic HNPs into the polymer backbone did not result in any significant increase in toxicity (p>0.001).

Item Type: Thesis (Doctoral)
Subjects: R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy and Bioengineering
Contributors: Hoskins, C (Thesis advisor)
Curtis, Anthony (Thesis advisor)
Depositing User: Lisa Bailey
Date Deposited: 20 Mar 2020 14:56
Last Modified: 20 Mar 2020 14:56
URI: https://eprints.keele.ac.uk/id/eprint/7822

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