Lipid- and Polymer-Based Drug Delivery Vehicles

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 ÌøåÀå_transition escapeÌøåÀå_ 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 Ì_å_g/mL, paclitaxel-polymersome formulations showed comparable activity in inhibiting the growth of MCF-7 cells.