An evaluation of the use of superparamagnetic iron oxide nanoparticles to overcome extracellular barriers to lung disease for drug delivery

Primary barriers to drug delivery include mucus and biofilms, which can hinder drug and gene delivery by several orders of magnitude, preventing effective therapeutic effects. By understanding the physical and chemical properties of these ubiquitous barriers, one may employ drug delivery approaches, such as design of nanoparticle and microparticle systems, to attempt to overcome the transport barriers. Nanoparticles are a growing interest in drug delivery, specifically as drug carriers, though most will become entrapped within these extracellular barriers further limiting their desired affects. Previous studies have generally manipulated the surface chemistries or size of these nanoparticles to allow for nearly a 2-fold increase in passive diffusion through barriers. To expand the current ideas of overcoming these barriers, studies in presented in this dissertation were performed using a type of active nanoparticle, superparamagnetic iron oxide nanoparticles. It was first investigated whether these particles would disrupt extracellular barriers under an oscillating magnetic field, which resulted in a 2-fold increased diffusion of particles upon biopolymer breakage. Secondly, influences of an external static magnetic field on diffusion of these nanoparticles through model barriers were determined. Both of these methods resulted in higher fold increases, reaching up to 28-fold compared to 2-fold as described in the literature. Next an examination of drug permeation enhancement in models of extracellular barriers by nanoparticle interactions was performed, using a passive mechanism as found in the literature. With a range of different nanoparticles including diesel particulate matter, barrier function was disrupted resulting in a 5-fold increase in drug permeation. To further manipulate drug diffusion an assisted delivery systems was observed, where magnetic nanoparticles could influence un-associated drug diffusion, resulting in 4-fold increase in drug diffusion. Finally formulations of nanosuspensions were created for aerosol delivery and their performance evaluated in vitro. A dry powder formulation containing drug and nanoparticles was formulated using a spray-drying technique. Upon barrier deposition studies using the dry powder formulation, permeation rates were determined resulting in a 2-fold increase for nanoparticle permeation. When drug diffusion was determined up to a 54-fold increase in drug was seen when co-delivered with nanoparticles, compared to controls containing only drug.