Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.
School of Pharmacy, The University of Sydney, NSW 2006, Australia.
Int J Pharm. 2019 Oct 5;569:118616. doi: 10.1016/j.ijpharm.2019.118616. Epub 2019 Aug 12.
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.
呼吸道感染由多药耐药革兰氏阴性菌引起是严重的负担对公众来说。我们之前的研究结果表明，与单药治疗相比，通过脂质体共同装载多粘菌素和环丙沙星可提高对多药耐药铜绿假单胞菌的体外抗菌活性。本研究旨在通过体外 Calu-3 细胞单层（一种在气界面条件下培养的肺上皮模型）研究多粘菌素和环丙沙星在脂质体中的转运行为。细胞活力结果表明，在浓度≤500μg/mL 时，暴露于单药或联合药物的细胞没有明显的毒性。与多粘菌素相比，环丙沙星更容易进入细胞，很快达到平台期。多粘菌素在黏液中滞留较少，或黏附在顶端细胞膜上，穿过细胞单层的转运也少于环丙沙星。环丙沙星在顶端的沉积随时间增加（从 1 小时到 4 小时）。当它们以溶液形式一起给药时，在跨细胞单层转运过程中没有观察到药物-药物相互作用。当多粘菌素和环丙沙星负载在脂质体中时，穿过细胞单层的药物量减少。当两种药物都在脂质体中时，它们在黏液中滞留更多，或更黏附在顶端细胞膜上。本研究表明，在单个脂质体中共同递送多粘菌素和环丙沙星可以降低两种药物穿过肺上皮细胞单层的转运能力，并增强药物在肺上皮表面的保留；因此，这是一种治疗多药耐药铜绿假单胞菌引起的呼吸道感染的有前途的方法。
