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McCrorie, Phoebe (2021) Developing a sprayable drug delivery system for the local delivery of nanoparticles in glioblastoma multiforme. PhD thesis, University of Nottingham.

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Abstract

Glioblastoma multiforme (GBM) is a World Health Organisation classified grade 4 tumour with a dismal median survival time of 14 months from diagnosis and a 16% 2-year survival rate. Current treatment consists of debulking surgery followed by concurrent radiotherapy and temozolomide chemotherapy. Relapse from residual disease cells is inevitable, with 80% of tumours recurring within 2 cm of the primary tumour resective margin. This gives high precedence for a local drug delivery system (DDS) to target residual disease within neighbouring brain parenchyma. A spray device and formulation (polymer-coated nanoparticles (PCNPs) and hydrogel) has been developed to achieve further penetration of drug into this 2 cm target area.

Etoposide (ETO) and olaparib (OLA) have been loaded into novel mPEG5000-PLA100 PCNPs with a drug loading of 32- and 33%, respectively. These PCNPs have been concentrated using gaseous N2 to a final drug concentration of 0.30 and 0.24 mg/mL for ETO and OLA, respectively. The PCNPs have shown good stability to storage (>6 weeks) and stability at 37 C in PBS, artificial cerebrospinal fluid and culture media. Finally, in the presence of 0.1% (w/v) Pluronic F127, the PCNPs survive the shear stress of a 50 L spray device.

The PCNPs have been loaded into a 200 M pectin hydrogel, which has demonstrated biocompatibility and biodegradability in vitro and in vivo. This pectin formulation sprays successfully using the Aptar Pharma spray device, forming a gel in the presence of endogenous levels of calcium found within the brain. This formulation has been successfully sprayed into ex vivo brain tissue and the penetration of drugs and Cy5 fluorescent labelled nanoparticles have been optimised on Orbitrap-secondary ion mass spectrometry (OrbiSIMS) and confocal microscopy, respectively. To our knowledge, this is the first data generated on a sprayable DDS utilising drug-loaded polymeric nanoparticles for the enhanced delivery of chemotherapeutics to GBM surgical resections. This work provides a platform for further developing sprayable DDS for this application.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Rahman, Ruman Marlow, Maria
Keywords:	Glioblastoma multiforme, Drug delivery system, Nanoparticles
Subjects:	R Medicine > RS Pharmacy and materia medica
Faculties/Schools:	UK Campuses > Faculty of Science > School of Pharmacy
Item ID:	64553
Depositing User:	McCrorie, Phoebe
Date Deposited:	31 Jul 2021 04:40
Last Modified:	31 Jul 2021 04:40
URI:	https://eprints.nottingham.ac.uk/id/eprint/64553

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