Heparin-azithromycin microparticles show anti-inflammatory effects and inhibit SARS-CoV-2 and bacterial pathogens associated to lung infections

• Published in: Carbohydrate polymers 2025-01, Vol.348 (Pt B), p.122930, Article 122930
• Main Authors: Anaya, Brayan J., D'Angelo, Davide, Bettini, Ruggero, Molina, Gracia, Sanz-Perez, Amadeo, Dea-Ayuela, María Auxiliadora, Galiana, Carolina, Rodríguez, Carmina, Tirado, Diego F., Lalatsa, Aikaterini, González-Burgos, Elena, Serrano, Dolores R.
• Format: Article
• Language: English
• Subjects: aerodynamics; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; antibacterial properties; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; antiviral properties; azithromycin; Azithromycin - chemistry; Azithromycin - pharmacology; blood; Cell Line; COVID-19 - virology; COVID-19 Drug Treatment; COVID-19 infection; cytotoxicity; Dry powder inhaler; Dry Powder Inhalers; Enoxaparin; epithelium; Heparin; Heparin - chemistry; Heparin - pharmacology; Humans; inhibitory concentration 50; Lung - drug effects; Lung - microbiology; Lung - pathology; Lung - virology; Lung delivery; lungs; mammals; microparticles; mortality; oral administration; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pulmonary infectious diseases; SARS-CoV-2; SARS-CoV-2 - drug effects; Severe acute respiratory syndrome coronavirus 2; Streptococcus pneumoniae; Streptococcus pneumoniae - drug effects
• ISSN: 0144-8617; 1879-1344; 1879-1344
• DOI: 10.1016/j.carbpol.2024.122930

Pulmonary infections are a leading cause of morbidity and mortality worldwide, a situation exacerbated by the COVID-19. Azithromycin (AZM) is used orally to treat pulmonary infections due to its ability to accumulate in lung tissues and immune cells after oral administration. Sulfated polysaccharides, such as heparin, are known to inhibit SARS-CoV-2 entry. This study presents a novel approach focused on developing a dry powder inhaler of AZM-loaded microparticles composed of either heparin or its derivatives. The microparticle formulations exhibited potent antiviral activity against SARS-CoV-2 (IC50 ≤ 95 nM) while retaining superior antibacterial efficacy against Streptococcus pneumoniae and Pseudomonas aeruginosa compared to free AZM (MIC ≤15 μg/mL). Importantly, at bactericidal concentrations, no cytotoxic effects were observed on mammalian cells, including Calu-3 cells and red blood cells. The formulations demonstrated effective alveolar aerodynamic deposition (MMAD ranging from 1 μm to 3 μm) with a Fine Particle Fraction below 5 μm close to 50 %. Adopting a conservative estimate of 20 mL for the pulmonary epithelial lining fluid volume in healthy adults, efficacious local concentrations of sulfated polysaccharides and AZM would be delivered to the lung using this multifaceted strategy which holds promise for the treatment of bacterial pulmonary infections associated with COVID-19. [Display omitted]