(4dx) Design of Respiratory Nanoparticle Delivery Vehicle and Evaluation of Cellular Toxicity

The extracellular fluid lining the respiratory tract presents a significant barrier to the effective delivery of therapeutics to and through the respiratory system. However, the ability to bypass first pass metabolism and locally delivery therapeutics to the site of action for respiratory ailments is significant. The ability of the innate defenses of the respiratory tract to remove exogenous materials reduces the time available for the action of therapeutic agents. The residence time of the delivery vehicle will be defined by its ability to move through the extracellular fluid and interact with the underlying epithelium. In order to move through the extracellular fluids the particle must be small enough to pass through the mesh of the mucus gel layer and then avoid adhesive interactions with this network. My current research has been focused on developing a particle surface which allows the particle to overcome these extracellular fluid interactions while maintaining the ability to interact with the underlying epithelium layer. This has led to the development of particles with a polyethylene glycol (PEG) shell and the use of lipooligosaccharide (LOS) glycoforms naturally expressed on bacterial cell surface to facilitate particle-epithelial interactions. To determine the efficacy of these particles an in vitro model of the respiratory system was developed using the Calu-3 cell line, a human bronchial cancer line with secretory properties. The presence of mucus on the surface of these cells which made this a desirable system to study also caused difficulties in processing the cells for analysis. Therefore, several mucolytics were analyzed before settling on one which did not alter the properties of the cell monolayer. This model has been used to assess particle attachment and internalization to cells and cell viability after exposure to particles.