Nanotherapeutics as a localised drug delivery system for the treatment of GBM

Vasey, Catherine E (2021) Nanotherapeutics as a localised drug delivery system for the treatment of GBM. PhD thesis, University of Nottingham.

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Abstract

Glioblastoma multiforme (GBM) (recently classified by the World Health Organisation as glioblastoma isocitrate dehydrogenase wild-type or mutant), is the most common, malignant brain tumour in adults, mainly due to its rapid proliferation and ability to penetrate and diffusely infiltrate healthy brain parenchyma. Standard of care treatment consists of surgical debulking of the tumour, followed by an intense course of concomitant chemotherapy and radiotherapy. However, despite these multimodal treatment methods, and a greater understanding of disease biology, prognosis remains bleak with a median survival of 14 months from diagnosis.

This front-line treatment whereby tumours are neurosurgically-resected, poses a distinct opportunity for the consideration of localised, intracranial therapy for GBM patients, hereby overcoming the blood-brain barrier (BBB) and enabling the delivery of therapeutics directly to the site of the infiltrative disease left behind following surgical resection. The overarching aim of this thesis is to design and synthesise drug-loaded nanocarriers which can be incorporated into a pre-existing microparticulate paste to act as a localised drug delivery system for the treatment of GBM.

Chapter 2 details the design and synthesis of a library of these drug-loaded nanocarriers, optimising an established ring-opening polymerisation (ROP) method to enable a user-friendly approach with a fast reaction time, resulting in polymers with highly predictable final molecular weights and narrow molar mass dispersities (Đ). The introduction of a functionalisable monomer enabled the conjugation of doxorubicin (DOX), a relevant chemotherapeutic, to the polymeric backbone. The resultant polymers were able to reproducibly self-assemble to form kinetically-trapped nanoparticles (NPs) with narrow polydispersity indexes (PDIs).

Chapter 3 details the cytotoxicity of the DOX-NPs on a range of GBM cell lines. Considering the inevitable recurrence of GBM is due to the infiltrative cells left behind following surgical removal of the original tumour, the NPs were tested upon a range of patient derived cell lines isolated from this infiltrative region, allowing a more clinically-relevant insight into the activity of the formulations.

Overall, the results from this thesis highlight the potential of incorporating drug-loaded NPs into a pre-existing microparticulate paste, for the first time in neuro-oncology, building a platform technology for future in vivo studies to investigate the potential efficacy of this delivery system as a localised treatment method for GBM.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Rahman, Ruman
Alexander, Cameron
Smith, Stuart J
Keywords: Glioblastoma multiforme, Nanotherapeutics, Drug-loaded nanocarriers
Subjects: R Medicine > RS Pharmacy and materia medica
Faculties/Schools: UK Campuses > Faculty of Science > School of Pharmacy
Item ID: 64137
Depositing User: Vasey, Catherine
Date Deposited: 31 Jul 2021 04:40
Last Modified: 31 Jul 2021 04:40
URI: http://eprints.nottingham.ac.uk/id/eprint/64137

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