| This thesis describes the preparation, characterization and biological study of block copolymer aggregates as drug delivery vehicles. A novel method is described for the synthesis of biodegradable and biocompatible copolymers of polycaprolactone-b-poly(ethylene oxide). The copolymers and their aggregates are then characterized with special attention given to properties which are of most interest to applications in drug delivery such as copolymer composition, thermal behavior, critical water content, critical micelle concentration, partition coefficient of hydrophobic solubilizates, morphology of the aggregates and in vitro biocompatibility. The polycaprolactone-b-poly(ethylene oxide) copolymer micelles are first explored as a delivery vehicle for the neurotrophic agents FK506 and L-658,818. The in vitro delivery and biological activity of the micelle-incorporated drugs are confirmed in PC12 cell cultures. The in vivo biological distribution of the micelle-incorporated FK506 was assessed in Sprague Dawley rats both 6 and 24 hours following intravenous administration. Also, the biological activity of the micelle-incorporated FK506 was shown to be retained in vivo using the sciatic nerve crush model of peripheral neuropathy in Hanover Wistar rats. The question of whether or not the cellular internalization of the polycaprolactone- b-poly(ethylene oxide) micelles proceeds by an endocytotic mechanism is addressed in PC12 cell cultures. Finally, the polycaprolactone- b-poly(ethylene oxide) micelles are explored as a delivery vehicle for dihydrotestosterone. We report on several of the physico-chemical characteristics of the micelle-incorporated dihydrotestosterone as well as in vitro delivery in HeLa cells which have been cotransfected with the MMTV-LUC reporter gene and the androgen receptor. |
