Poly(sebacic acid) microparticles loaded with azithromycin as potential pulmonary drug delivery system: antimicrobial activity, macrophage response, and S. aureus - lung epithelial cell coculture tests.

Lower respiratory tract infections caused by Staphylococcus aureus present a significant clinical challenge in patients with cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) due to biofilm formation, intracellular persistence, and the limited efficacy of conventional antibiotic therapies. Azithromycin (AZ) has broad-spectrum antibacterial activity and immunomodulatory effects, making it an attractive candidate for advanced drug delivery strategies. An interesting approach to the administration of antibiotics to the lungs is through inhalation therapy, which bypasses the gastrointestinal tract and allows for the use of lower drug dosages while achieving the same therapeutic outcomes. Here, we present AZ-loaded poly(sebacic acid) microparticles (PSA_AZ MPs) in the form of a dry powder formulation. PSA_AZ MPs displayed a fine particles fraction reaching 66.4 ± 1.6% and median mass aerodynamic diameter of 3.76 ± 0.17 μm, promising for pulmonary delivery. Studies in A549 lung epithelial cells and RAW264.7 macrophages revealed that PSA_AZ MPs are safe up to 100 μg/mL concentration, significantly less phagocytized by RAW264.7 cells compared to unloaded PSA MPs, and do not stimulate reactive oxygen species (ROS) production. PSA_AZ MPs significantly inhibited S. aureus biofilm formation with a 4-log reduction in effectiveness. In coculture conditions of A549 and S. aureus cells, PSA_AZ MPs exhibited a 3-log reduction in bacterial viability while preserving A549 cells viability. Thus, PSA_AZ MPs represent a formulation that combines antibacterial activity with the ability to influence host-pathogen interactions.