title: Reducing Tumour Hypoxia via Oral Administration of Oxygen Nanobubbles.
abstract: Hypoxia has been shown to be a key factor inhibiting the successful treatment of solid tumours. Existing strategies for reducing hypoxia, however, have shown limited efficacy and/or adverse side effects. The aim of this study was to investigate the potential for reducing tumour hypoxia using an orally delivered suspension of surfactant-stabilised oxygen nanobubbles. Experiments were carried out in a mouse xenograft tumour model for human pancreatic cancer (BxPc-3 cells in male SCID mice). A single dose of 100 μL of oxygen saturated water, oxygen nanobubbles or argon nanobubbles was administered via gavage. Animals were sacrificed 30 minutes post-treatment (3 per group) and expression of hypoxia-inducible-factor-1α (HIF1α) protein measured by real time quantitative polymerase chain reaction and Western blot analysis of the excised tumour tissue. Neither the oxygen saturated water nor argon nanobubbles produced a statistically significant change in HIF1α expression at the transcriptional level. In contrast, a reduction of 75% and 25% in the transcriptional and translational expression of HIF1α respectively (p<0.001) was found for the animals receiving the oxygen nanobubbles. This magnitude of reduction has been shown in previous studies to be commensurate with an improvement in outcome with both radiation and drug-based treatments. In addition, there was a significant reduction in the expression of vascular endothelial growth factor (VEGF) in this group and corresponding increase in the expression of arrest-defective protein 1 homolog A (ARD1A).
authors.affiliation: Oxford Institute of Biomedical Engineering, University of Oxford, Oxford, United Kingdom.
authors.forename: Joshua
authors.initials: J
authors.lastname: Owen
authors.affiliation: Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Conor
authors.initials: C
authors.lastname: McEwan
authors.affiliation: Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Heather
authors.initials: H
authors.lastname: Nesbitt
authors.affiliation: Oxford Institute of Biomedical Engineering, University of Oxford, Oxford, United Kingdom.
authors.forename: Phurit
authors.initials: P
authors.lastname: Bovornchutichai
authors.affiliation: Avrox Technologies Ltd. Copgrove, Harrogate, North Yorkshire, United Kingdom.
authors.forename: Raymond
authors.initials: R
authors.lastname: Averre
authors.affiliation: Department of Mechanical Engineering, University of Colorado, 1111 Engineering Drive, Boulder, CO, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Borden
authors.affiliation: Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: McHale
authors.affiliation: Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, United Kingdom.
authors.forename: John F
authors.initials: JF
authors.lastname: Callan
authors.affiliation: Oxford Institute of Biomedical Engineering, University of Oxford, Oxford, United Kingdom.
authors.forename: Eleanor
authors.identifier: http://orcid.org/0000-0003-3371-5929
authors.initials: E
authors.lastname: Stride
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D053758:Nanoparticles / Q000008:administration & dosage*; D049329:Nanostructures / Q000627:therapeutic use*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010100:Oxygen / Q000008:administration & dosage*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072258:Tumor Hypoxia / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D010100:Oxygen