Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.692932
Title: Butylglyceryl-modified polysaccharide nanoparticles for drug delivery to the brain
Author: Bin Bostanudin, Mohammad Fauzi
ISNI:       0000 0004 5920 7620
Awarding Body: University of Portsmouth
Current Institution: University of Portsmouth
Date of Award: 2016
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Abstract:
The limited access to the brain of a large number of therapeutic actives due to the presence of the blood-brain barrier (BBB) has led to intensive research toward the development of nanotechnology-based approaches. Polysaccharides such as chitosan, guar gum, pectin and pullulan have been selected as starting materials for this study due to their biocompatibility, biodegradability, good drug carrier properties, and ease of chemical modification with short chain alkylglycerol-like moieties (expected to enhance drug permeability through the BBB). A series of butylglyceryl-modified polysaccharides were prepared and characterised using chromatographic, spectroscopic and thermal analysis techniques prior to formulation into nanoparticles (NPs) by means of a selection of methods that include reverse emulsification, nanoprecipitation, and ionotropic gelation. Dynamic Light Scattering, Nanoparticle Tracking Analysis, Electrophoretic Mobility Measurements and Electron Microscopy were employed to characterise all NPs (overall size range 120–200 nm, and zeta potential values ranging from -27 to +39 mV). Modified pullulan (PUL-OX4) and guar gum (GG-OX4) NPs were found to be most stable at physiological pH (7.4), in contrast to chitosan (CS-OX4) NPs that demonstrated an increase in size as a result of aggregation. PUL-OX4 NPs (< 145 nm) had the highest Angiotensin II model peptide loading (8.46 %), while GG-OX4 NPs showed the highest loading degree with Doxorubicin (19.11 %) and Rhodamine B (3.78 %). Drug release studies demonstrated that PUL-OX4 NPs released fastest all the model actives tested, while GG-OX4 NPs were able to retain them for the longest period of time. The in vitro interactions of NPs with mouse brain endothelial cells (bEnd3) were investigated using a Transwell permeability model, with results suggesting an increased model membrane permeability in the presence of the modified polysaccharide nanoparticles. The cytotoxicity of these NPs at physiologically-relevant concentrations was studied using MTT assays; all NPs were non-toxic at concentration below 2 mg/mL, however a decrease in cell viability was noticed at higher concentrations. PUL-OX4 nanoparticles were found to be the least toxic, having the lowest LC50 value (9.48 mg/mL; for comparison, CS-OX4 has 7.30 mg/mL). Haemolysis study demonstrated that at concentration below 12 mg/mL, all the NPs studied did not induce a haemolysis effect significantly when compared to PBS control, however an increase in the effect was observed at higher concentration. PUL-OX4 nanoparticles exhibited the highest LC30 value of 19.87 mg/mL while the lowest value was exhibited by CS-OX4 nanoparticles (13.95 mg/mL). Confocal microscopy and flow cytometry investigations confirmed that all modified polysaccharide NPs were successfully taken up by bEnd3 cells, becoming localised in the cytoplasm.
Supervisor: Barbu, Eugen ; Gorecki, Dariusz Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Thesis
EThOS ID: uk.bl.ethos.692932  DOI: Not available
Keywords: Biomedical Sciences ; Pharmacy
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