UCLA

Effective drug delivery requires exquisite chemical control in the complex environment of the body. To enable a general approach to drug delivery, a modular scaffold that relies on chemistry orthogonal to that found in nature is required. This dissertation focuses on exploiting the unique properties of the perfluorocarbon (PFC) phase to create a versatile drug delivery system, accomplished by developing new polymeric amphiphiles to kinetically stabilize droplets of PFC in water, known as PFC nanoemulsions. PFC nanoemulsions are non-toxic, dynamic nanomaterials that have been previously employed as oxygen carriers and contrast agents. However, their use has been limited by nonfunctional poloxamer surfactants that result in size heterogeneity, instability, and multi-dose toxicity. The development of a biocompatible, functionalizable surfactant would expand the versatility and utility of PFC emulsions, enabling responsive and targeted nanomaterials. This dissertation reports the use of multifunctional poly(2-oxazoline) (POx) surfactants to control the size, charge, surface chemistry, cellular uptake, and the controlled disassembly of these nanomaterials. Chapter One is a perspective on the historical development of drug delivery carriers, the challenges that underlie them, and how PFC emulsions can be viewed as a solution to these limitations. Similarly, it discusses previous surfactants employed in PFC emulsion formation and explains the motivation behind the choice of POx as a modular surfactant platform. Chapter Two outlines our early efforts in developing POx surfactants that can both form and stabilize PFC nanoemulsions (<300 nm) over time and discusses the structure-property relationships that underlie these amphiphiles in the context of nanomedicine. Chapter Three reports selectively modifying surface properties of PFC nanoemulsions by leveraging functionalizable POx surfactants. Post-emulsion surface charge modifications are shown to affect cytotoxicity and the magnitude of cellular uptake in macrophage and non-macrophage cells. Chapter Four illustrates the development of redox-cleavable POx block copolymers that allow for the formation of glutathione-responsive PFC nanoemulsions. These nanoemulsions can selectively degrade in response to intracellular triggers. These advances are leveraged alongside a noncovalent fluorous tagging strategy that allows one to solubilize a GFP plasmid within the fluorous phase, whereafter protein expression is achieved selectively when employing stimuli-responsive surfactants. This work contributes a methodology for non-viral gene delivery and represents a general approach to nanoemulsions that respond to endogenous stimuli. Chapter Five establishes a new intracellular stimulus–macromolecular crowding–as a trigger for responsive nanomaterials. Transition temperatures of thermoresponsive POx are shown to vary with changes in crowding, and this dependence can be tuned such that the system is stable to low extracellular concentrations of protein but destabilizes at high intracellular concentrations. Ultimately, we demonstrate that the cytosol is an effective stimulus for nanoemulsions, with droplet fusion occurring upon injection into cells of zebrafish embryos. With this report, we set the stage for the wide-ranging class of thermoresponsive materials to respond to macromolecule concentration rather than conventional temperature changes. Chapter Six is a compilation of collaborative highlights, preliminary work and future directions for this platform. It discusses internal collaborations with Professor Chong Liu and Professor Jeffrey Zink’s lab, including manuscripts that are either accepted, in revision, or in preparation. Additionally, it discusses preliminary findings in host-guest mediated emulsion fusion, laying the groundwork for in situ prodrug synthesis in living systems using the fluorous phase.