Carter, Thomas James;
(2019)
Magnetic Hyperthermia for the Treatment of Glioblastoma.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Introduction: Glioblastoma, the most common primary adult brain malignancy, is an aggressive tumour with median survival of around one year. Despite extensive research there has been minimal improvement in prognosis and innovative new treatments are urgently required. The research within this thesis focussed on designing a novel therapeutic approach using nanotechnology to achieve in-situ immune stimulation mediated by localised hyperthermia and characterising the effects of hyperthermia within the tumour microenvironment (TME). Methods: In-situ heating was generated using superparamagnetic iron-oxide nanoparticles (SPIONs) stimulated by an alternating magnetic field (AMF); a combined process known as magnetic hyperthermia. Candidate SPIONs were first tested for biocompatibility and favourable heating properties. In-vivo experiments utilised the immunocompetent GL261 glioblastoma model and included: (i) Testing reticuloendothelial system blocking, and direct intratumoural injection to obtain sufficient intratumoural SPION concentrations; (ii) Utilising 89Zr-labelled SPIONs to evaluate in-vivo fate using PET-CT Imaging; (iii) Evaluation of SPION in-vivo heating ability using thermal imaging; (iv) Tumour growth and timed immunohistochemical (IHC) response analysis; (v) Flow cytometry analysis of the tumour infiltrating lymphocyte (TIL) populations following treatment and (vi) testing a combination therapeutic approach combining magnetic hyperthermia with immune checkpoint inhibition. Results: Perimag-COOH was identified as the lead candidate SPION, and intratumoural injection chosen as the optimal method to obtain sufficient intratumoural SPION concentrations. Perimag-COOH remained within the tumour following injection and retained ability to generate AMF-induced heat for at least 72 h post injection. Digital image analysis of IHC demonstrated a specific, localised, heat-shock protein response following hyperthermia. Tumour growth inhibition was observed up to one week following treatment and tumour flow cytometry analysis revealed changes in TIL populations suggestive of an immune response, providing a rational for a combination approach with immune checkpoint inhibition. Conclusions: SPION mediated hyperthermia is achievable in-vivo and can generate TME changes suggestive of an anti-tumour immune response.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Magnetic Hyperthermia for the Treatment of Glioblastoma |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10076950 |
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