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Updated: Nov 20, 2025
An Air-liquid Interface Bronchial Epithelial Model for Realistic, Repeated Inhalation Exposure to Airborne Particles for Toxicity Testing
Published on: May 13, 2020
In vitro evaluation of drug delivery behavior for inhalable amorphous nanoparticle formulations in a human lung
Jianting Chen1, Maizbha U Ahmed2, Chune Zhu3
1Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA; Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
Abstract:
Respiratory tract infections caused by multidrug-resistant (MDR) Gram-negative bacteria such as Pseudomonas aeruginosa are serious burdens to public health, especially in cystic fibrosis patients. The combination of colistin, a cationic polypeptide antibiotic, and ivacaftor, a cystic fibrosis transmembrane regulator (CFTR) protein modulator, displays a synergistic antibacterial effect against P. aeruginosa. The primary aim of the present study is to investigate the transport, accumulation and toxicity of a novel nanoparticle formulation containing colistin and ivacaftor in lung epithelial Calu-3 cells. The cell viability results demonstrated that ivacaftor alone or in combination with colistin in the physical mixture showed significant toxicity at an ivacaftor concentration of 10 μg/mL or higher. However, the cellular toxicity was significantly reduced in the nanoparticle formulation. Ivacaftor transport into the cells reached a plateau rapidly as compared to colistin. Colistin transport across the Calu-3 cell monolayer was less than ivacaftor. A substantial amount (46-83%) of ivacaftor, independent of dose, was accumulated in the cell monolayer following transport from the apical into the basal chamber, whereas the intracellular accumulation of colistin was relatively low (2-15%). The nanoparticle formulation significantly reduced the toxicity of colistin and ivacaftor to Calu-3 cells by reducing the accumulation of both drugs in the cell and potential protective effects by bovine serum albumin (BSA), which could be a promising safer option for the treatment of respiratory infections caused by MDR P. aeruginosa.
Insights
A novel nanoparticle formulation of colistin and ivacaftor significantly reduced toxicity in lung cells compared to a physical mixture. This nanoparticle delivery system offers a safer treatment option for multidrug-resistant Pseudomonas aeruginosa infections.
Area of Science:
- Pharmacology
- Nanotechnology
- Infectious Diseases
Background:
- Multidrug-resistant (MDR) Gram-negative bacteria, like Pseudomonas aeruginosa, pose significant public health threats, particularly for cystic fibrosis patients.
- Colistin and ivacaftor exhibit synergistic antibacterial effects against P. aeruginosa.
- Developing safer drug delivery systems is crucial for managing MDR infections.
Purpose of the Study:
- To evaluate the transport, accumulation, and toxicity of a novel nanoparticle formulation containing colistin and ivacaftor.
- To compare the nanoparticle formulation with a physical mixture of the drugs in lung epithelial Calu-3 cells.
- To assess the potential of this formulation as a safer therapeutic option.
Main Methods:
- Investigated drug transport and accumulation across Calu-3 cell monolayers.
- Assessed cell viability to determine drug toxicity.
- Utilized a novel nanoparticle formulation for colistin and ivacaftor delivery.
- Compared nanoparticle formulation with physical drug mixtures.
Main Results:
- The nanoparticle formulation significantly reduced cellular toxicity compared to physical mixtures of colistin and ivacaftor.
- Ivacaftor showed rapid cellular uptake and high accumulation (46-83%), while colistin accumulation was low (2-15%).
- The nanoparticle formulation decreased drug accumulation in cells, potentially due to protective effects from bovine serum albumin (BSA).
Conclusions:
- The novel nanoparticle formulation of colistin and ivacaftor demonstrates reduced toxicity in lung epithelial cells.
- This formulation may offer a safer and more effective treatment strategy for respiratory tract infections caused by MDR P. aeruginosa.
- Further research into nanoparticle drug delivery systems is warranted for managing challenging bacterial infections.
