A 3D Model of the Human Lung Airway for Evaluating Permeability of Inhaled Drugs

Current in vitro cell-based methods, relying on single
cell types,
have structural and functional limitations in determining lung drug
permeability, which is a contributing factor affecting both local
and systemic drug levels. To address this issue, we investigated a
3D human lung airway model generated using a cell culture insert,
wherein primary human lung epithelial and endothelial cells were cocultured
at an air–liquid interface (ALI). To ensure that the cell culture
mimics the physiological and functional characteristics of airway
tissue, the model was characterized by evaluating several parameters
such as cellular confluency, ciliation, tight junctions, mucus-layer
formation, transepithelial electrical resistance, and barrier function
through assaying fluorescein isothiocyanate-dextran permeability.
To understand how the characterized ALI quality attributes influenced
the absorption of inhaled drugs through the epithelial-endothelial
barrier, we measured the permeability and epithelial intracellular
concentrations of albuterol sulfate (AL), formoterol fumarate (FO),
and fluticasone furoate (FL). The presented characterization results
overall demonstrate that this culture platform mimicked the airway-specific
structure and barrier function. An apparent permeability (Papp) of 5.7 × 10–6 cm/s
and an intracellular concentration below 1% were quantified for AL
over 3 h. The Papp of FO was 8.5 ×
10–6 cm/s, with an intracellular concentration of
3.8%. Due to its high lipophilicity, FL showed a higher intracellular
concentration (17.4%) compared to AL and FO, but also a 73.1% loss
of the compound over 3 h due to nonspecific binding, with a Papp as low as 1.3 × 10–7 cm/s. While the model exhibited physiologically relevant properties,
its utility in estimating the permeability of inhaled drugs may be
drug-specific, warranting further optimization and study.