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Title: Pro-drug strategies for pancreatic cancer therapy
Author: Alfahad, Mohanad Abdul-Satar Mahmood
ISNI:       0000 0004 7227 6401
Awarding Body: Keele University
Current Institution: Keele University
Date of Award: 2018
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Pancreatic cancer is the fourth main cancer in the western world. Currently the only chemotherapy available clinically is gemcitabine. However, gemcitabine treatment only proves effective in 23.8% of patients. Nano-structures (< 120 nm) are capable of entering the highly permeable blood capillaries which supply the rapidly growing tumours. Once inside the capillaries they accumulate and are retained in the tumour as a result of the poor lymphatic drainage. This allows for a deeper tissue penetration which is otherwise difficult to achieve. Hybrid nanoparticles with an iron oxide core covered by gold shell (HNPs) 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 prodrug of gemcitabine has been developed by a regioselective coupling of gemcitabine and lipoic acid, itself a potent antioxidant. Gemcitabine-N-lipoate (GL) was obtained in a one-pot synthesis and the optimum conditions for the reaction were established. GL prodrug loading on to the HNPs surface was confirmed and the release profile of gemcitabine from the GL-HNPs formulation was studied at pH 3.6, 5.6 and 7.4 utilising different temperature conditions (20, 37, 44 °C) using RPMI serum free media under sink conditions. The data showed the stability of the formulation at pH 7.4, 20 °C while the optimum release conditions for gemcitabine from the GL-HNPs formulation were at pH 5.6, 44 °C with the highest release of 41.1% recorded after 24 hrs. III Preliminary in vitro MTT assay together with the drug uptake study show the superior inhibitory effect of the GL-HNPs formulation on the cell viability over gemcitabine after 24 hrs which indicates faster uptake of the formulation, however the overall effect of gemcitabine is greater after 48 hrs which is mainly due to the slow release of gemcitabine from the formulation. The behaviour of the GL-HNPs formulation as a drug delivery system shows a great potential for the system to act as a theranostic tool and to overcome the significant drawbacks associated with gemcitabine.
Supervisor: Curtis, Anthony D. M. ; Hoskins, C. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RS Pharmacy and materia medica