Martin, Claire; (2004) Polymer modified liposomes for drug and vaccine delivery. Doctoral thesis (Ph.D.), University College London.

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Abstract

The aims and objectives of this thesis were: 1) to investigate the optimal formulation of liposomes alone and in combination with natural or synthetic polymers, to improve stability during preparation and storage; 2) to characterise processing conditions with jet homogenisation, and 3) to model liposomes for oral delivery of a vaccine. Methods include assessment of vesicle size and entrapment and release of small water-soluble markers after processing and a range of freezing treatments. Calibration of jet homogeniser processing conditions was conducted; size reduction of liposomes and production of stable lipidic emulsions were also examined. Modelling liposome stability in GI fluids; interactions between polymer-modified liposomes and biological substrate is characterised by a range of microscopy techniques. Finally, vaccination of mice with liposomally entrapped diphtheria toxoid is presented. Results indicate that cryoprotectant addition to liposomes as part of the bulk aqueous phase before vesicle formation, or to a suspension of ready formed liposomes, can influence size and payload retention following freezing and freeze drying. Also, the cryo- and lyo-protective efficacy of polymers loaded into liposomes and coating the exterior surface, is determined by molecular mass. The jet homogeniser has shown itself capable of reducing the size of ready formed liposomes with a minimal number of cycles, and also generating vesicles from the homogenisation of lipid emulsions. GI tract stability was shown in vitro by liposomes formulated with high phase transition lipids, a basic salt to buffer local pH and chitosan; these liposomes demonstrated superior adhesion to mucin and excised gut segments, as shown by fluorescence microscopy. Oral vaccination of mice with diphtheria toxoid gave disappointing results; intramuscular administration gave the highest serum IgG titres, followed by the nasal route. In conclusion, results have shown improved vesicle stability during preparation and processing, but alternative strategies for oral liposomal delivery of vaccines are required.

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