Engineering Particle Systems for Pulmonary Delivery

© 2020 Jiaying SongPulmonary delivery has proven to be a promising delivery route for either local lung targeting or systemic delivery. A variety of particle systems such as polymeric particles and lipid-based particle systems have been developed as therapeutic delivery carriers for pulmonary delivery. However, the majority of current inhaled particles have limited retention time and low bioavailability in the target lung region, leading to suboptimal efficacy of therapeutic delivery and needing increased drug dosage or dose frequency, which could cause severe side effects. This is mainly due to the clearance and metabolic degradation mechanisms in the lungs. The mucociliary clearance and the alveolar macrophage clearance defend the airway and deep lung region, respectively, and are responsible for the elimination of inhaled particles. Therefore, it is important to understand the interactions of particles with the complex lung physiological environment in order to design more effective drug delivery carriers that can overcome various biological barriers or exploit the defence mechanisms to achieve improved biological outcomes. This PhD thesis focuses on engineering particle systems for pulmonary drug delivery, with specific aims of studying the interactions between inhalable particles and complex biological systems in the lungs including particle–mucus interactions and the role of a pulmonary corona in the uptake or clearance of particles by alveolar macrophages. Poly (ethylene glycol) (PEG) as a low-fouling material commonly used for ‘stealth’ modification of particles to reduce immune clearance was first investigated. The use of PEG building blocks with various architectures resulted in PEG-based particles with different structures and mechanical properties, which further affected the interactions of particles with proteins and immune cells in a complex biological environment (e.g., human blood). The particle–mucus interactions were then studied in the second part of this PhD research by comparing different polymer particles with potentially mucoadhesive and mucus-penetrating properties, obtaining a basic understanding of mucociliary clearance of particles in the lungs. The role of the pulmonary protein corona in alveolar macrophage clearance of polymer particles was then studied. The presence of a protein corona on particles resulted in increased or reduced macrophage uptake depending on the particle properties. When particles were transferred from one biological environment into another (e.g., blood to lungs), the interplay of protein coronas formed in each environment determined the composition of the eventual mixed protein corona and the subsequent particle–cell interactions. Finally, drug (structurally nanoengineered antimicrobial peptide polymers) loading and intracellular delivery using promising polyphenol-based carriers were investigated as potential antimicrobial therapies against lung infections (e.g., tuberculosis)