Poly(sebacic acid) microparticles loaded with azithromycin as potential pulmonary drug delivery system: antimicrobial
Jonasz Czajkowski1, Rosa Calderon-Jacinto2, Konrad Kwiecień3
1Department of Biomaterials and Composites, Faculty of Materials Science and Ceramics, AGH University of Krakow, Al Mickiewicza 30, 30-059, Kraków, Poland; Łukasiewicz Research Network - Krakow Institute of Technology, ul. Zakopiańska 73, 30-418, Kraków, Poland.
Abstract:
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.
Insights
New azithromycin-loaded microparticles offer a promising inhaled therapy for lung infections like Staphylococcus aureus in cystic fibrosis and COPD patients. This formulation effectively reduces bacterial biofilms and improves host-pathogen interactions.
Area of Science:
- * Pharmaceutical Sciences
- * Microbiology
- * Respiratory Medicine
Background:
- * Lower respiratory tract infections caused by Staphylococcus aureus (S. aureus) pose significant challenges in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) due to biofilm formation and limited antibiotic efficacy.
- * Azithromycin (AZ) possesses broad-spectrum antibacterial and immunomodulatory properties, making it suitable for advanced drug delivery systems.
- * Inhalation therapy offers an effective route for delivering antibiotics directly to the lungs, potentially reducing dosage and systemic side effects.
Purpose of the Study:
- * To develop and characterize azithromycin-loaded poly(sebacic acid) microparticles (PSA_AZ MPs) for pulmonary delivery.
- * To evaluate the safety and efficacy of PSA_AZ MPs in combating S. aureus infections in vitro.
- * To assess the formulation's impact on host-pathogen interactions in lung epithelial cells and macrophages.
Main Methods:
- * Preparation and characterization of AZ-loaded poly(sebacic acid) microparticles (PSA_AZ MPs), including particle size and aerodynamic properties.
- * In vitro safety assessments using A549 lung epithelial cells and RAW264.7 macrophages, including cell viability and reactive oxygen species (ROS) production.
- * Evaluation of PSA_AZ MPs' efficacy against S. aureus biofilm formation and bacterial viability in co-culture models.
Main Results:
- * PSA_AZ MPs demonstrated suitable characteristics for pulmonary delivery, with a fine particle fraction of 66.4% and a mass median aerodynamic diameter of 3.76 μm.
- * The formulation was found to be safe for lung epithelial cells and macrophages at concentrations up to 100 μg/mL, with reduced phagocytosis and no ROS stimulation.
- * PSA_AZ MPs significantly inhibited S. aureus biofilm formation (4-log reduction) and reduced bacterial viability in co-cultures (3-log reduction) while preserving host cell viability.
Conclusions:
- * Azithromycin-loaded poly(sebacic acid) microparticles (PSA_AZ MPs) represent a viable dry powder formulation for inhaled antibiotic therapy.
- * The developed microparticles exhibit favorable safety profiles and potent antibacterial activity against S. aureus, including biofilm inhibition.
- * This formulation holds promise for managing challenging respiratory infections by combining direct antibacterial effects with modulation of host-pathogen interactions.
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