Title: Nanostructured aerosols for pulmonary drug delivery
Description: The goal of this dissertation is to develop an aerosol drug delivery approach to improve the treatment of lung disease, particularly in the context of tuberculosis. The hypothesis of this approach is that the direct delivery of drug to the infected lung tissue results in relatively high local drug concentration, while maintaining systemic exposure to treat non-pulmonary disease. Targeting the site of action could possibly reduce the required body dose, the frequency of dosing and the overall treatment time. Furthermore, development of an aerosol incorporating drug-loaded polymeric nanoparticles could provide sustained drug release and the ability to target specific cells and organs--properties which could be affected by particle design. Tuberculosis antibiotics were formulated by spray drying into particles with nano-scale thin-wall structures. These dry powders contain high drug loads and characteristics suitable for efficient pulmonary drug delivery from a simple inhaler. Furthermore, drug was also incorporated into biodegradable poly(lactide- co -glycolide) (PLGA) nanoparticles, which were spray dried into micron-scale carrier particles. These 'porous nanoparticle-aggregate particles' (PNAPs) form a system wherein nanoparticles can be easily handled and delivered to the lungs, an otherwise difficult task owing to strong particle-particle interactions. Both particle delivery approaches were developed and tested in animals. The PNAP system was further explored to understand how particle design parameters may affect the release and fate of particles upon administration to the lungs.

The main results of this research are that tuberculosis antibiotics can be formulated into porous particles and PNAPs for aerosol delivery, and that these powder systems represent a promising method to treat tuberculosis. In vivo testing showed that pulmonary delivery of particles, at equal or lower doses as compared to oral delivery, resulted in comparable systemic levels and elevated lung levels (with apparent targeting to cells), and that reduced aerosol doses indicated efficacy in treating tuberculosis. The combination of systemic exposure upon dosing and elevated lung levels between dosing indicates the possibility of lowering the frequency of dosing. Nanoparticle release from PNAPs and fate in the lungs can also be affected by designing formulation properties, such as nanoparticle size and concentration of nanoparticles contained within the PNAPs.