Ultrasound Sensitive Liposomes
|dc.contributor.advisor||Tucker, Ian George|
|dc.identifier.citation||Mujoo, H. (2016). Ultrasound Sensitive Liposomes (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/6667||en|
|dc.description.abstract||Context: On a conceptual level, triggering drug release from liposomes using ultrasound (US) involves the liberation of encapsulated drug by acoustic energy at a predetermined site and time. Depending upon the parameters of US and composition of the liposome, this concept may offer a solution for pharmacokinetic challenges such as non-specificity in drug distribution and suboptimal drug exposure to target tissues. Objective: The objective of the experiments in this thesis was to explore the effect(s) of ultrasound (US) on liposomes and how the sensitivity of liposomes to US is influenced by the constituents of the liposomes. The ultimate aim is to optimize the design of liposome and US combinations for triggered delivery of drugs. Methods:The US-sensitivity of liposomes was investigated using both phenomenological and mechanistic approaches. The phenomenological approach was to compare the sonosensitivity of various liposomal preparations composed of differing lipid combinations to varying US parameters (30 kHz and 1.1 MHz). These investigations employed the carboxyfluorescein (CF) assay that was used to measure the release of encapsulated content during exposure of liposomes to US. The mechanistic approach investigated potential parameters of sonosensitivity and how different parameters influence US-triggered release from liposomes. The mechanistic investigation required complex methodologies that were individually tailored for the investigation of a specific liposomal response to US exposure. The combination of liposomal responses that were explored to understand the mechanistic basis for sonosensitivity included thermal sensitivity, mechanical sensitivity, membrane destabilisation, lipid motion, membrane rupture, membrane permeability and pressures variations across the liposomal wall. Results: The release-response of liposomes to US depended on the parameters of US (frequency, energy) and the composition of the phospholipid bilayers. Furthermore, the thermal and mechanical mechanisms by which US triggered the release of liposomal content also depended on the combination of US parameters and liposomal composition. The thermal sensitivities of liposomes arose as a result of heat-induced phase transition from gel to liquid crystalline phase. On the other hand, the mechanical sensitivities of liposomes to the US arose because mechanically active lipids altered the phase behavior and created structural defects in the liposomal bilayers. Through the use of a combination of fluorometric techniques, it was found that US at high intensity and low frequency increased the mobility of phospholipids within the lipid bilayer and US at low frequency caused rupture of the bilayer. Computational studies supported these findings and further suggested formulation strategies to improve the sonosensitivity of liposomes. Conclusion: This thesis illustrates how the application of a combination of methods can increase the understanding of US sensitive liposomes. It was tentatively concluded that the physical responses of the phospholipid bilayer, such as membrane rupture and lipid mobility, underlie the mechanism with which US triggers the release of drug from US sensitive liposomes.|
|dc.publisher||University of Otago|
|dc.rights||All items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.|
|dc.title||Ultrasound Sensitive Liposomes|
|thesis.degree.discipline||School of Pharmacy|
|thesis.degree.name||Doctor of Philosophy|
|thesis.degree.grantor||University of Otago|
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