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Type of Document	Dissertation
Author	Li, Shuliang
URN	etd-04012006-121707
Title	Lipid- and Polymer-Based Drug Delivery Vehicles
Degree	Doctor of Philosophy
Department	Chemical Engineering
Advisory Committee	Advisor Name Title Adre F. Palmer Committee Member
Keywords	polymer vesicles drug delivery vehicles AFM liposomes polymer micelles
Date of Defense	2006-03-31
Availability	unrestricted
Abstract The objective of this dissertation was to develop novel classes of mechanically stable lipid- and diblock copolymer based drug delivery vehicles. Liposome based drug delivery vehicles were created by encapsulating a polymeric actin matrix. The structure of actin-containing liposomes was studied using a combination of static light scattering and atomic force microscopy (AFM). It was observed that actin-containing liposomes possessed the ability to adopt non-spherical ellipsoidal shapes in solution. Further experiments showed that the aspect ratio of these ellipsoidal-shaped liposomes was controlled by the encapsulated actin concentration. In vivo circulatory studies in rats showed greater than 50% of administered actin-containing liposomes were retained in the circulatory system after 72 hours. Actin-containing liposomes were further applied towards the development of a long-circulating artificial blood substitute by encapsulating bovine hemoglobin (Hb) inside the aqueous core of actin-containing liposomes (LEAcHb). The potential of LEAcHb dispersions to function as a cellular hemoglobin-based oxygen carrier (HBOC) was evaluated by measuring several key physical properties: vesicle size distribution, Hb encapsulation efficiency, oxygen binding properties (as indicated by P50 and cooperativity coefficient), encapsulated methemoglobin level, and in vivo circulatory half-life. LEAcHb exhibited satisfactory physical properties and circulatory half-life consistent with the design criteria of a cellular-based artificial blood substitute. In the second half of this dissertation, amphiphilic diblock copolymer poly(butadiene)-b-poly(ethylene oxide) (PB-b-PEO) self-assembled colloids, were investigated as novel mechanically stable drug delivery vehicles. AFM was employed to probe the morphology and mechanical response of PB-b-PEO self-assemblies. It was observed that the structure of these colloids ranged from spherical micelles, worm-like micelles, to polymersomes depending on the diblock composition and method of preparation. AFM force imaging of closely packed micelles on glass surfaces showed a sharp downward deflection, which implied the existence of a �transition escape� most probably due to a conformational change in the PEO hydrophilic brush upon AFM tip compression. Paclitaxel was successfully incorporated into PB-PEO polymersomes of various molecular weights. The loading capacity of paclitaxel inside polymersomes ranged from 6.7-13.7% w/w. Paclitaxel-polymersome (OB4) formulations were colloidally stable for 4 months, and exhibited slow steady release of paclitaxel over a 5 week period. Evaluation of the in vitro cytotoxicity of paclitaxel-polymersome formulations showed that the ability of paclitaxel-loaded polymersomes to inhibit proliferation of MCF-7 human breast cancer cells was less compared to free paclitaxel. By increasing the concentration of paclitaxel in polymersomes to 0.2 μg/mL, paclitaxel-polymersome formulations showed comparable activity in inhibiting the growth of MCF-7 cells.
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