UCLA

Nanomaterials have been used in the treatment of cancer to increase the solubility of insoluble payloads, increase the plasma half-lives of payloads, avoiding rapid renal clearance, and diminish off-target effects by controlling the biodistribution and the non-specific uptake of the nanocarrier. Perfluorocarbon (PFC) nanoemulsions, droplets of fluorous solvent, stabilized by a surfactant dispersed in water, can solubilize and protect payloads, release payloads upon introduction of stimuli, and deliver oxygen simultaneously with the payload. Perfluorocarbons are biocompatible, with several garnering FDA approval for use in 19F-MRI, and the inherent hydrophobicity of PFCs provide orthogonality from both hydrophilic and hydrophobic environments found within the body. By solubilizing payloads in the perfluorocarbon phase, we form orthogonal droplets that do not significantly leach payload, increasing the utility of these nanoemulsions for drug delivery. Chapter One is a perspective on cancer nanomedicine and the role of PFC nanoemulsions within this vast field. Chapter Two describes a systematic study of the polymer surfactant necessary for PFC nanoemulsion stabilization. Through this systematic study we put forward a series of design principles for PFC nanoemulsions. Chapters Three and Four describe various payloads that can be solubilized within and delivered by PFC nanoemulsions. Chapter Three focuses on photodynamic therapy (PDT), a treatment modality that uses light, oxygen, and a photosensitizer to produce cytotoxic reactive oxygen species. PFC nanoemulsions were perfect for this application as photosensitizer and oxygen could be delivered simultaneously, increasing the photodynamic efficacy compared to other nanomaterial systems. This chapter also contains a perspective on the current state of fluorinated nanomaterials for PDT focusing on three architectures: lipid stabilized PFC nanoemulsions, macromolecule stabilized PFC nanoemulsions, and micelles. Chapter Four describes the design of a fluorous soluble, redox responsive, small molecule fluorophore as well as the first report of plasmid DNA (pDNA) solubilization within perfluorocarbon solvents. Upon delivery of redox responsive nanomaterials containing pDNA to the cytosol, the plasmid was released and transcribed into the fluorescent protein eGFP. Chapter Five details two methods to visualize endosomal rupture: lysosome size and genetically engineered cells. Hopefully, these assays can be used to further understand the endosomal uptake of PFC nanoemulsions, with the goal of designing materials that can efficiently escape the endosomal / lysosomal pathway, avoiding degradation. Chapter Six describes efforts toward targeting PFC nanoemulsions to diseased tissues using the well characterized RGD peptide. Through cyclization of the RGD peptide with bromomaleimide chemistry, we were able to cyclize and functionalize the peptide simultaneously. Unfortunately, the first iteration of this project was unsuccessful, and is currently being modified to increase avidity by appending the cyclic peptides directly to the PFC nanoemulsion.