Airway mucus in pulmonary diseases: Muco-adhesive and muco-penetrating particles to overcome the airway mucus barriers

Abstract

Airway mucus is a complex viscoelastic gel that provides a defensive physical barrier and shields the airway epithelium by trapping inhaled foreign pathogens and facilitating their removal via mucociliary clearance (MCC). In patients with respiratory diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), non-CF bronchiectasis, and asthma, an increase in crosslinking and physical entanglement of mucin polymers as well as mucus dehydration often alters and typically reduces mucus mesh network pore size, which reduces neutrophil migration, decreases pathogen capture, sustains bacterial infection, and accelerates lung function decline. Conventional aerosol particles containing hydrophobic drugs are rapidly captured and removed by MCC. Therefore, it is critical to design aerosol delivery systems with the appropriate size and surface chemistry that can improve drug retention and absorption with the goal of increased efficacy. Biodegradable muco-adhesive particles (MAPs) and muco-penetrating particles (MPPs) have been engineered to achieve effective pulmonary delivery and extend drug residence time in the lungs. MAPs can be used to target mucus as they get trapped in airway mucus by steric obstruction and/or adhesion. MPPs avoid muco-adhesion and are designed to have a particle size smaller than the mucus network, enhancing lung retention of particles as well as transport to the respiratory epithelial layer and drug absorption. In this review, we aim to provide insight into the composition of airway mucus, rheological characteristics of airway mucus in healthy and diseased subjects, the most recent techniques to study the flow dynamics and particle diffusion in airway mucus (in particular, multiple particle tracking, MPT), and the advancements in engineering MPPs that have contributed to improved airway mucus penetration, lung distribution, and retention.

Keywords: Aerosol; Cystic fibrosis; Microrheology; Mucociliary clearance; Multiple particle tracking; Pulmonary drug delivery; Rheology.

Figure 1

(A) BALF total mucin concentration from CF patients and non-CF controls; (B) & (C) represents IHC of MUC5B (green) and MUC5AC (red) in a cytospin from non-CF and CF BALF, respectively. *p<0.05 after multivariate analysis. Reproduced with permission from (Esther Jr et al., 2019).

Figure 2

SEM of airway mucus that shows a mesh-like architecture with the pore size ranging up to hundreds of nanometers in diameter (scale bar 500 nm). Reproduced with permission from (Benjamin S. Schuster et al., 2013).

Figure 3

Diffusion of MIPs (1 μm) in mucus from primary HBE cells. (A) Representative particle trajectories of 1 μm MIPs in mucus from normal control, healthy smoker, and COPD patients. Scale bar, 5 μm. (B) Ensemble-averaged geometric mean square displacements () as a function of time scale. (C) Effective viscosity of mucus from normal control, healthy smoker, and COPD patients. (D) Comparative effective viscosity of each mucus samples at 0.6 Hz. (E) Mucus percent solids content by weight in each mucus samples. (F) Plot between mucus solid content and effective viscosity for mucus from each group. Reproduced with permission from (Lin et al., 2020)

Figure 4

Schematic illustration of the essential steps of NET formation. Reproduced with permission (Block and Zarbock, 2021).

Figure 5

Schematic on the role of mucus barrier. (A) As shown in figure, airway mucus entraps hazardous (red spiked structures) and therapeutic (green structures) inhaled particles. (B) Depending on the size and surface charge, the inhaled particles either penetrate the mucus barrier or (C) interacts with mucin backbone. Reproduced with permission from (Huck et al., 2022).

Figure 6

Diffusion of gene carriers in CF sputum. (A) TEM image of CK₃₀PEG_10k DNA-nanoparticles with hydrodynamic diameter of 60 nm which presented a rod-shape structure. (B) Representative trajectories of CK₃₀PEG_10k DNA-nanoparticles which are immobilized in CF sputum, and muco-inert PS-PEG_2K nanoparticles with larger particle size. (C) TEM image of conventionally coated PEI/DNA NP (PEI-CCP) which had a loose spherical shape. (D) TEM image of PEI-MPP presented a more compacted spherical structure. (E) Representative trajectories of PEI-CCP nanoparticles, un-PEGylated PEI-nanoparticles (PEI-UCP) and PEI-MPP. PEI-CCP and PEI-UCP nanoparticles were restrained in CF sputum, while PEI-MPP can penetrate through CF sputum. Reproduced with permission from (Boylan et al., 2012) and (Suk et al., 2014).

Figure 7

Diffusion experiment using MIP suspension or MIP-containing EEG dry powder in CF sputum. (A) Ensemble-averaged geometric mean square displacements () as a function of time scale for PS suspension, PS-PEG suspension, PS aerosol, and PS-PEG aerosol in the CF mucus. (B) Representative particles trajectories of PS suspension, PS-PEG suspension, PS aerosol, and PS-PEG aerosol in the CF mucus in CF mucus. Scale bar, 1 μm. (C) The diffusion rate distribution of PS suspension, PS-PEG suspension, PS aerosol, and PS-PEG aerosol in the CF mucus. Reproduced with permission from (Chai et al., 2020).