Respiratory tract infections caused by multidrug-resistant Gram-negative bacteria are serious burdens to the public. Our previous findings indicated that co-loading of colistin and ciprofloxacin via liposomes improved in vitro antimicrobial activities against multidrug resistant Pseudomonas aeruginosa as compared to the monotherapies. The current study aims to investigate the transport behavior of colistin and ciprofloxacin in liposomes using the in vitro Calu-3 cell monolayer, which is a lung epithelial model cultured under the air-interfaced condition. The cell viability results demonstrated that there was no obvious toxicity of cells exposed to single or co-administered drugs at the concentration ≤500 μg/mL. Transport of ciprofloxacin into the cells was easier than that of colistin, which reached a plateau rapidly. Colistin was less trapped in the mucus or adhered to the apical cell membrane, and less transported across the cell monolayer than ciprofloxacin. The deposition of ciprofloxacin on the apical side increased over time (from 1 to 4 h). There was no drug-drug interaction observed during the transport of ciprofloxacin and colistin across the cell monolayer, when they were dosed together in the solution form. The amount of drug transported across the cell monolayer was decreased in both agents when loaded in liposomes. Both drugs were more trapped in the mucus or more adhered to the apical side cell membrane of the cell monolayer when they were in liposomes. This study demonstrated that co-delivery of colistin and ciprofloxacin in a single liposome can reduce transport capacity of both drugs across the lung epithelial cell monolayer and enhance drug retention on the lung epithelial surfaces; therefore, it is a promising approach to treat the respiratory infections caused by multidrug resistant Pseudomonas aeruginosa.
Keywords: Calu-3 cell monolayer; Ciprofloxacin; Co-delivery; Colistin; Drug transport; Liposomes.
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