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Title: Development of liposomes as pharmaceutical carriers for antibiotic and gene delivery
Author: Dallal Bashi, Yahya Haseeb Yahya
ISNI:       0000 0004 6425 0674
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2017
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An inhaled dry powder azithromycin liposomal formulation for the treatment of cystic fibrosis (CF) lung infection was developed based on a previously developed liposome composition by Yusuf (2014). The formulation contains liposomes composed of dimethyldioctadecylammonium bromide, soy-phosphatidylcholine, tocopherol polyethylene glycol 1000 succinate, antibiotic drug azithromycin and pharmaceutical excipients trehalose and L-leucine. A spray-drying method was. optimized and used to produce adry respirable powder product with a low range of water content, a high glass transition (Tg) value. After spray drying the liposomes within the formulation exhibited an average liposome size of less than 120 nm, a size uniformity of 0.3, a zeta potential value of more than +60 mV, an encapsulation efficiency of more than 50% and a prolonged drug release profile. This liposomal formulation enhanced the anti-biofilm activity of azithromycin by 2- to 8-fold against pseudomonal biofilms grown from bacterial strains obtained from the sputum of CF patients. The most promising formulation exhibited good stability profiles over two months at 40 C and one year at 20 C. The formulation showed rapid delivery into bacterial cells, and fast interaction with human cells with no cytotoxic effect in an in vitro setting. The dry-loaded liposomal formulation showed a good cellular uptake following administration to mice via various routes of administration. The in vitro respiratory deposition pattern for this powder formulation was evaluated by performing a next generation impactor (NGI) deposition test using the Aerolizer dry powder inhaler device. The parameters of NGI test were adjusted to mimic the inhalation profile in CF patients. Together, NGI results and the above data indicated that this formulation could potentially be a good inhaled azithromycin delivery system to improve the lung function in CF patients. For gene therapy purpose, a freeze-dried formulation was developed using the same liposome components but loaded with plasmid DNA (pDNA). Following the optimzation of liposome to pDNA ratio, in vitro transfection at lipid to pDNA ratios of 4.7:1 to 9.4:1 was conducted with no cytotoxic effect. In mice, the liposome-pDNA complexes showed local and systemic gene expression that was detectable 48 hours post administration via the intramuscular, intraperitoneal, intravenous and intranasal route. The lyophilized liposome-pDNA complexes exhibited accepted Tg and water content values, that could be optmized further. Finally, these results support the possibility of using this efficient, safe and affordable liposomal formulation in delivering different active compounds for both antibiotic and gene delivery purposes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available