The Role of Airway Mucus as a Barrier to Nanoparticles: Implications for Pulmonary Drug Delivery

Abstract

A layer of mucus covers the surface of the pulmonary airways. Mucus is a hydrogel mainly composed of water, mucins (glycoproteins), DNA, proteins, lipids, and cell debris, which conditions the inhaled air and protects us from airborne threats. The natural protective role of mucus is nowadays acknowledged as a major barrier to be overcome in non-invasive drug delivery. The heterogeneity of mucus components offers a wide range of potential chemical interaction sites for macromolecules, while the mesh-like architecture given to mucus by the intermolecular cross- linking of mucin molecules results in a dense network that physically, and in a size-dependent manner, hinders the diffusion of macromolecules and nanoparticles through mucus. In this thesis, native airway mucus samples of porcine and human origin have been exhaustively characterized utilizing techniques that allow its investigation while preserving its original viscoelastic properties. The rheological properties and the penetration of differently sized nanoparticles either mechanically mixed with mucus or deposited as an aerosol onto mucus layers have been investigated. Additionally, a significant research effort has been spent in the development of in vitro models aimed at mimicking the bronchial region under diverse physiological conditions, including bacterial infection. These models have been proved suitable for investigating the translocation of nanoparticle-based drug delivery systems through the airways as well as for testing the efficacy of antibiotics in the context of cystic fibrosis.