Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.664851
Title: Formulation and preliminary evaluation of delivery vehicles for the boron neutron capture therapy of cancer
Author: Olusanya, Temidayo Olajumoke Bolanle
ISNI:       0000 0004 5366 306X
Awarding Body: University of Portsmouth
Current Institution: University of Portsmouth
Date of Award: 2015
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Abstract:
Boron neutron capture therapy (BNCT) is a method for selectively destroying malignant (normally glioma) cells whilst sparing normal tissue. Irradiation of 10B (large neutron capture cross-section) with thermal neutrons effects the nuclear fission reaction: 10B + 1n → → 7Li+ + α + γ; where the penetration of -particles and 7Li+ is only 8 and 5 μm, respectively, i.e., within a single cell thickness, assuming 10B can be preferentially located within glioma cells. Poor selectivity is the main reason why BNCT has not become a mainstream cancer therapy. Carboranes. a third generation of high boron-containing, low-toxicity, BNCT compounds, are currently being investigated. Towards the aim of increasing malignant cell targeting specificity, this thesis investigates monodispersed dipalmitoylphosphatidylcholine (DPPC) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) SUV liposome formulations containing carboranes derivatised with delocalised lipophilic cations (DLCs), specifically the dequalinium bis nido carborane salt. AFM studies showed the loaded liposomes appeared stable (63 days, 4°C, if re-probing was employed). The integrity of the liposome membrane in serum, as reflected by %latency and %retention experiments using a fluorescent marker (calcein), was found to be high for both types of liposomes prepared using cholesterol. Successful entrapment of carboranes was demonstrated by the Nile Red method and by ICP-MS measurements. The liposomes were of sufficient size (80-100 nm) to pass through the blood brain barrier (BBB). The cationic moiety of the carborane salt allowed selective targeting of glioma mitochondria, thought to be due to differences in mitochondrial membrane potentials between malignant and non-neoplastic cells. Specific targeting of IN699 (glioma, WHO grade IV) and SC1800 (non-neoplastic astrocyte) cells with the carborane salt was evidenced by live cell (fluorescence) imaging. Spray drying was used as an alternative method of formulating agents for BNCT treatments for liver and lung cancers, where the larger (micrometre-diameter) particles do not need to pass across the BBB. Polyvinylpyrrolidone / o-carborane co-spray-dried microparticles were produced. 1H NMR studies revealed the high temperatures (180 °C) of the spray drying process did not degrade the PVP. Mean particle diameters (x90) were in the 2 – 10 μm range, with finer fractions being present (x10 ≅ 1 – 2 μm), and were therefore considered suitable for delivery to the lungs. SEM imaging showed the particles to be spherical, with dimples and cavities caused by the spray drier nozzle characteristics, as typical with the spray drying process. Some small irregularly-shaped crystalline particles, thought to be o-carborane, were observed by SEM, although the proportion accounted for less that than in the formulation (10 %w/w). An attempt was made to map the boron content in spray-dried powders on a surface using EDS, although the low atomic weight of boron made detection not possible. Cytotoxicity studies, using human glioblastoma U-87 MG (cancerous) and human fetal lung fibroblast MRC-5 (non-neoplastic) cells, revealed the PVP / o-carborane co-spray-dried particles to be non-toxic.
Supervisor: Tsibouklis, John ; Smith, James Richard Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Thesis
EThOS ID: uk.bl.ethos.664851  DOI: Not available
Keywords: Biomedical Sciences ; Pharmacy
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