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Title: Development of graphene nanostructures for use in anti-cancer nanomedicine
Author: Tabish, Tanveer Ahmad
ISNI:       0000 0004 7232 3036
Awarding Body: University of Exeter
Current Institution: University of Exeter
Date of Award: 2018
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Nanomedicine utilises biocompatible nanomaterials for therapeutic as well as imaging purposes, for the treatment of various diseases including cancer, neurological disorders and wound infections. Graphene, a material composed of a single layer of carbon atoms, has recently shown great potential to improve diagnostics and therapeutics, owing to its small size, large surface-area-to-volume ratio and unique physicochemical properties. However, the limited fabrication, in vitro and in vivo functionalities published in the literature indicate inconsistencies regarding the factors affecting metabolic fate, biodistribution as well as toxicity patterns of graphene. This thesis focuses on the biological effects of graphene-based materials, including graphene oxide (GO), reduced graphene oxide (rGO), graphene nanopores (GNPs), graphene quantum dots (GQDs) and three-dimensional graphene foam (GF). These can be used to closely mimic therapeutic functions and thereby open up new pathways to anticancer nanomedicine. In this work, a biocompatible GO-based anti-metastatic enzyme cancer therapy approach has been introduced for the first time to target the extracellular pro-metastatic and pro- tumourigenic enzymes of cathepsin D and cathepsin L, which are typically overexpressed in ovarian and breast cancers. Definitive binding and modulation of cathepsin- D and -L with GO has revealed that both of the enzymes were adsorbed onto the surface of GO through its cationic and hydrophilic residues under the biologically relevant condition of acidic pH. It has been demonstrated that low concentrations of rGO were shown to significantly produce late apoptosis and necrosis rather than early apoptotic events in lung cancer cells (A549 and SKMES-1), suggesting that it was able to disintegrate the cellular membranes in a dose-dependent manner. GNPs at lower concentrations (250μg/ml) induce upregulation of phosphatidylserine on cell surface membrane (i.e. early apoptotic event), which does not significantly disintegrate the cell membrane in the aforementioned lung cancer cells, while higher concentrations of GNPs (5 and 15 mg/kg) in rats (when intraperitoneally injected) exhibited sub-chronic toxicity in a period of 27 days. The interaction of GQDs and trypsin has revealed the strong bonding capacity of GQDs with trypsin, owing to their surface charge and surface functionalities evidencing the high bioavailability of GQDs in enzyme engineering. Finally, 3D GF was developed to probe the role of graphene-based scaffold cues in the field of regenerative medicine revealing their cell attachment to in vitro cell cultures. Furthermore, GF was shown to maintain remarkable biocompatibility with in vitro and in vivo toxicity screening models when exposed for 7 days at doses of 5, 10 and 15 mg/l. Taken together, graphene and its modified structures developed in this thesis promise to revolutionise clinical settings across the board in nanomedicine which include, but are not limited to, ultra-high sensitive enzyme adsorbents, high throughput biosensors, enzyme modulators and smart scaffolds for tissue regeneration.
Supervisor: Zhang, Shaowei ; Xia, Yongde Sponsor: EPSRC ; University Of Exeter
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Graphene ; nanomedicine ; cancer diagnosis and treatment