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Title: Bioreactivity of ZnO and Ag nanostructures in the lung
Author: Theodorou, Ioannis
ISNI:       0000 0004 6059 1631
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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One-dimensional nanomaterials (NMs) have become the focus of intensive research due to their unique physicochemical properties and their application in the fabrication of nanoscale devices. Silver (Ag) and zinc oxide (ZnO) nanowires (NWs) are considered as potential building blocks for the next generation of optical, electronic and sensing devices. However, there is currently limited information on human health effects from Ag and ZnO NW exposures, but concerns have been raised about a potentially greater toxicity compared to their non-fibrous counterparts. Inhalation of Ag and ZnO NWs represents one of the primary routes for human exposure. Due to their size, these NMs are expected to preferentially deposit in the alveolar region of the lungs, where any damage would not only impact pulmonary homeostasis but would also determine possible translocations to other organs. Therefore, the interactions of Ag and ZnO NWs with the pulmonary epithelium urgently need to be addressed, in order to predict their adverse effects and provide guidelines for their safe use. Along with concerns about the toxic effects of Ag NMs, there is also potential for enormous benefit via highly efficacious antibacterial modality. Bacterial infections of the pulmonary system, such as tuberculosis, are increasing; especially infections caused by bacterial strains resistant to existing conventional antibiotics. AgNPs represent exciting candidates for the development of novel platforms for the treatment of pulmonary bacterial infections. Whilst the biological activity of silver has been well demonstrated, the mechanisms by which AgNPs degrade at the bio-nano interface and how these processes correlate to their bioreactivity are poorly understood. The motivation of this thesis is to investigate the bioreactivity of Ag and ZnO nanostructures in the lungs. The main objective of the work presented here is to examine the bioreactivity of Ag and ZnO NWs with human lung epithelial cells from the perspective of their putative toxicity. For inhaled NMs that reach the alveoli, the lung lining fluid (LLF) that covers their surface represents a first line of defence of the lungs. Therefore, the emphasis of this work is placed on characterizing the impact of the LLF on the physicochemical properties of Ag and ZnO NWs. The formation of a phospholipid/protein corona is shown to modify the ion release kinetics and aggregation states of the NWs. These effects are correlated with the cellular uptake and toxicity of the NWs to human lung epithelial cells. Furthermore, the mechanisms by which Ag and ZnO NWs degrade within epithelial cells are investigated. In the case of AgNWs, intracellular dissolution precedes the precipitation of highly insoluble silver sulfide, which could significantly limit their short-term toxicological effects. ZnO NWs, on the other hand, rapidly dissolve intracellularly and cell death correlates with the amount of free Zn2+ ions released. Furthermore, the antibacterial effects of AgNPs against Mycobacterium tuberculosis (M.tb) are examined. A set of analytical transmission electron microscopy techniques are employed to investigate the ultrastructural damage in bacterial cells and the mechanisms by which AgNPs induce cell damage. The antimicrobial effects of AgNPs are also examined in M.tb-infected macrophages, to explore the potential use of AgNPs as therapeutic agents for pulmonary bacterial infections.
Supervisor: Porter, Alexandra ; Ryan, Mary Sponsor: Natural Environment Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral