Glutathione and bicarbonate nanoparticles improve mucociliary transport in cystic fibrosis epithelia

Abstract

IntroductionCystic fibrosis (CF) airway disease is characterized by thick mucus and impaired mucociliary transport (MCT). Loss of functional cystic fibrosis transmembrane receptor (CFTR) leads to acidification and oxidation of airway surface mucus. Replacing bicarbonate (HCO3−) topically fails due to rapid reabsorption and neutralization, while the scavenging antioxidant, glutathione sulfhydryl (GSH), is also rapidly degraded. The objective of this study is to investigate GSH/NaHCO3 nanoparticles as novel strategy for CF airway disease.MethodsGSH/NaHCO3 poly (lactic‐co‐glycolic acid) nanoparticles were tested on primary CF (F508del/F508del) epithelial cultures to evaluate dose‐release curves, surface pH, toxicity, and MCT indices using micro‐optical coherence tomography. In vivo tests were performed in three rabbits to assess safety and toxicity. After 1 week of daily injections, histopathology, computed tomography (CT), and blood chemistries were performed and compared to three controls. Fluorescent nanoparticles were injected into a rabbit with maxillary sinusitis and explants visualized with confocal microscopy.ResultsSustained release of GSH and HCO3− with no cellular toxicity was observed over 2 weeks. Apical surface pH gradually increased from 6.54 ± 0.13 (baseline) to 7.07 ± 0.10 (24 h) (p < 0.001) and 6.87 ± 0.05 at 14 days (p < 0.001). MCT, ciliary beat frequency, and periciliary liquid were significantly increased. When injected into the maxillary sinuses of rabbits, there were no changes to histology, CT, or blood chemistries. Nanoparticles penetrated rabbit sinusitis mucus on confocal microscopy.ConclusionFindings suggest that GSH/NaHCO3− nanoparticles are a promising treatment option for viscous mucus in CF and other respiratory diseases of mucus obstruction such as chronic rhinosinusitis.

Safety and Pharmacokinetics of a Ciprofloxacin and Azithromycin Stent for Chronic Rhinosinusitis

“…[33][34][35][36][37][38] Because ivacaftor is under patent and expensive, we sought other hydrophobic candidate compounds that are either stimulated CFTR (i.e., flavonoids) or inexpensive antibiotics that are used for sinus infections. [39][40][41][42][43][44][45][46][47] Since azithromycin is a hydrophobic antibiotic, our subsequent studies used an outer layer of azithromycin to control the release of ciprofloxacin. 48,49 The ciprofloxacin-azithromycin sinus stent (CASS) provided sustained release of ciprofloxacin over 28 days.…”