Design, synthesis, and physicochemical characterization of semifluorinated triphilic surfactants with applications for hydrophobic drug delivery

The use of PEGylated amphiphiles in drug-delivery systems has found widespread use in micelle and nanoemulsion formulations due to their unique benefits: drug solubilization above its aqueous solubility; the obviation of complex syntheses through the self-assembly; high-efficacy of drug delivery due to small average particles sizes. Despite the successes of micellar and nanoemulsion systems, stability remains an issue. Triphilic surfactants --- those containing hydrophilic, lipophilic and fluorophilic moieties --- have, to date, only been objects of peripheral interest to drug delivery. This work investigates triphilic design, behavior, and potential application in delivering hydrophobic pharmaceuticals.;The incorporation of fluorinated blocks can be accomplished by various means, with Williamson ether syntheses being common. Fluorotelomer alcohols (F(CF2)x(CH2)2OH), however, show exceptional instability under basic conditions. An intramolecular hydrogen bond seems to dramatically increase the decomposition of fluorotelomer alcohols under basic conditions. Differences in decomposition among fluorotelomer alcohols of different lengths were found to depend on their respective solubility.;Syntheses for both linear and dibranched, triphilic surfactants were devised and carried out to prepare series of triphiles with various, terminal perfluoroalkoxy groups. The addition of terminal fluorinated substituents was found to lead to increases in thermodynamic (lower critical micelle concentration) and kinetic (increased resistance to dissociation) stability. These data suggest that the placement of fluorocarbons, not just their presence, is important in triphilic design. The ability of linear and dibranched triphiles to encapsulate paclitaxel (a model hydrophobic drug) was also shown to increase with the presence of and increasing size of fluorinated substituents.;Nanoemulsions are non-equilibrium drug delivery systems that can suffer from poor rapid particle size growth. The formulation of anesthetic nanoemulsions was studied to evaluate the effectiveness of triphilic surfactants in decreasing particle-size growth. A 30 vol% isoflurane formulation was developed, the highest concentration yet achieved in isoflurane emulsification; however, attempts to increase stability of this emulsion have so far proven unsuccessful. Triphilic surfactants proved successful at formulating highly stable, propofol nanoemulsions. Three propofol formulations were selected for in vivo evaluation in rat models, where efficacy similar to the clinically used DiprivanRTM formulation was observed.