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Title: The impact of hypoxia on nanomedicine uptake and efflux in human breast cancer cells
Author: Brownlee, William J.
ISNI:       0000 0004 8502 8191
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2018
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In women, breast cancer is the most frequently diagnosed neoplasm, with a recognised high mortality burden. Breast cancer cells adapt to the hypoxictumoral environment by undergoing changes in metabolism, cell signalling, endo-lysosomal receptor uptake and recycling. The resulting hypoxic cellphenotype has the potential to undermine the therapeutic efficacy of nanomedicines designed for endocytic uptake and specific intracellular trafficking (Chapter 1). The aim of this thesis was to examine the impact of hypoxia and simulated reperfusion on the in vitro uptake and release of nanomedicines by human breast cancer cells. Cells were exposed to a hypoxic preconditioning treatment in 1% oxygen for 6 and 24 hours to induce temporal changes in the hypoxic circuit (e.g. HIF1α expression). The preconditioned cells were then dosed with nanoparticles for 45 or 180 minutes emulating nanomedicine access following tumor reperfusion. Hypoxic preconditioning significantly increased nanoparticle retention by up to 10% when compared to normoxic cultures (p<0.001), with the greatest relative difference between normoxic and hypoxic cultures occurring with a45 minute dosing interval (Chapter 3). Similarly, 24 hours hypoxic conditioning significantly increased nanoparticle uptake, in MDA-MB-231 cells, where HIF1α was partially inhibited by digoxin (p<0.001, Chapter 4). Exocytosis studies indicated that the preconditioned cells had a significantly increased nanoparticle efflux (up to 9%, p<0.001) when compared tonormoxic cells (Chapter 3). Overall, this thesis has demonstrated thathypoxic preconditioning regulates both the endocytosis and exocytosis of nanomedicines in human breast cancer cells (Chapters 3 and 4).
Supervisor: Seib, Philipp ; Wilson, Clive Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral