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To assess the difference in the fate of the antibiotic colistin (COLI) after its pulmonary delivery as a powder or a solution, we developed a COLI powder and evaluated the COLI pharmacokinetic properties in rats after pulmonary administration of the powder or the solution. The amorphous COLI powder prepared by spray drying was characterized by a mass median aerodynamic diameter and fine particle fraction of 2.68 ± 0.07 µm and 59.5 ± 5.4%, respectively, when emitted from a Handihaler®. After intratracheal administration, the average pulmonary epithelial lining fluid (ELF): plasma area under the concentration versus time curves (AUC) ratios were 570 and 95 for the COLI solution and powder, respectively. However, the same COLI plasma concentration profiles were obtained with the two formulations. According to our pharmacokinetic model, this difference in ELF COLI concentration could be due to faster systemic absorption of COLI after the powder inhalation than for the solution. In addition, the COLI apparent permeability (Papp) across a Calu-3 epithelium model increased 10-fold when its concentration changed from 100 to 4000 mg/L. Based on this last result, we propose that the difference observed in vivo between the COLI solution and powder could be due to a high local ELF COLI concentration being obtained at the site where the dry particles impact the lung. This high local COLI concentration can lead to a local increase in COLI Papp, which is associated with a high concentration gradient and could produce a high local transfer of COLI across the epithelium and a consequent increase in the overall absorption rate of COLI.

Recently, various types of cultured cells have been used to research the mechanisms of transport and metabolism of drugs. Although many studies using cultured cell systems have been published, a comparison of different cultured cell systems has never been reported. In this study, Caco-2, Calu-3, Madin–Darby canine kidney (MDCK), EpiAirway and MucilAir were used as popular in vitro cell culture systems, and the permeability of model compounds across these cell systems was evaluated to compare barrier characteristics and to clarify their usefulness as an estimation system for nasal drug absorption in rats. MDCK unexpectedly showed the best correlation (r = 0.949) with the fractional absorption (Fn) in rats. Secondly, a high correlation was observed in Calu-3 (r = 0.898). Also, Caco-2 (r = 0.787) and MucilAir (r = 0.750) showed a relatively good correlation with Fn. The correlation between Fn and permeability to EpiAirway was the poorest (r = 0.550). Because EpiAirway forms leakier tight junctions than other cell culture systems, the paracellular permeability was likely overestimated with this system. On the other hand, because MDCK formed such tight cellular junctions that compounds of paracellular model were less likely permeated, the paracellular permeability could be underestimated. Calu-3, Caco-2 and MucilAir form suitable cellular junctions and barriers, indicating that those cell systems enable the precise estimation of nasal drug absorption.

The RPMI 2650 and Calu-3 cell lines have been previously evaluated as models of the nasal and airway epithelial barrier, and they have demonstrated the potential to be used in drug permeation studies. However, limited data exist on the utilization of these two cell models for the assessment of nasal formulations. In our study, we tested these cell lines for the evaluation of in vitro permeation of intranasally administered drugs having a local and systemic effect from different solution- and suspension-based formulations to observe how the effects of formulations reflect on the measured in vitro drug permeability. Both models were shown to be sufficiently discriminative and able to reveal the effect of formulation compositions on drug permeability, as they demonstrated differences in the in vitro drug permeation comparable to the in vivo bioavailability. Good correlation with the available bioavailability data was also established for a limited number of drugs formulated as intranasal solutions. The investigated cell lines can be applied to the evaluation of in vitro permeation of intranasally administered drugs with a local and systemic effect from solution- and suspension-based formulations.

Estimating the dissolution behavior of a solid in the nasal mucus is challenging for solid dosage forms designed for the nasal application as the solid dissolves into nasal mucus and permeates through the mucosa. In the current study, the dissolution behavior of powders in the artificial nasal fluid was investigated using a 3D-printed chamber system to establish in vitro evaluation system for the dissolution of solid formulations that can simulate the intranasal environment in vivo. The dissolution rates of the five model drugs correlated with their solubility (r2 = 0.956, p < 0.01). The permeation rate of drugs across the Calu-3 cell layers after powder application depends on the membrane permeability of the drug. An analysis of membrane permeability considering the dissolution of powders showed the possibility of characterizing whether the drug in the powder was dissolution-limited or permeation-limited. This suggests that critical information can be obtained to understand which mechanism is more effective for the improvement of drug absorption from powders. This study indicates that the elucidation of drug dissolution behavior into nasal mucus is an important factor for the formulation of nasal powders and that the in vitro system developed could be a useful tool.

Purpose CriticalSorb™, with the principal component Solutol® HS15, is a novel mucosal drug delivery system demonstrated to improve the bioavailability of selected biotherapeutics. The intention of this study is to elucidate mechanism(s) responsible for the enhancement of trans-mucosal absorption of biological drugs by Solutol® HS15. Methods Micelle size and CMC of Solutol® HS15 were determined in biologically relevant media. Polarised airway Calu-3 cell layers were used to measure the permeability of a panel of biological drugs, and to assess changes in TEER, tight junction and F-actin morphology. The rate of cell endocytosis was measured in vitro in the presence of Solutol® HS15 using a membrane probe, FM 2–10. Results This work initially confirms surfactant-like behaviour of Solutol® HS15 in aqueous media, while subsequent experiments demonstrate that the effect of Solutol® HS15 on epithelial tight junctions is different from a ‘classical’ tight junction opening agent and illustrate the effect of Solutol® HS15 on the cell membrane (endocytosis rate) and F-actin cytoskeleton. Conclusion Solutol® HS15 is the principle component of CriticalSorb™ that has shown an enhancement in permeability of medium sized biological drugs across epithelia. This study suggests that its mechanism of action arises primarily from effects on the cell membrane and consequent impacts on the cell cytoskeleton in terms of actin organisation and tight junction opening.

Pollen allergy is rated as a major public health problem, causing significant morbidity and adversely affecting the quality of people’s lives. The airway epithelium serves as the first line of defense in the respiratory system, playing a crucial role in orchestrating immune responses to allergens. In this work, we studied the important transport steps in the major alder pollen allergen Aln g 1 through the human airway epithelium in comparison with those of the birch pollen allergen Bet v 1. Using fluorescence spectroscopy, we showed that both allergens can destroy liposomes with a composition modeling the adult human pulmonary surfactant. Using a polarized Calu-3 monolayer, we showed similar efficiencies of Aln g 1 and Bet v 1 transport through the artificial epithelial barrier. Using qPCR, we showed that Aln g 1 upregulates the expression of IL-33, TSLP, IL-1β, CXCL8 in epithelial cells, playing an important role in the sensitization process. The obtained results may improve our understanding of the primary sensitization mechanisms with the involvement of the PR-10 family of lipid-binding allergens.

Purpose To evaluate the ability of human airway epithelial cell layers and a simple rat isolated perfused lung (IPL) model to predict pulmonary drug absorption in rats in vivo . Method The permeability of seven compounds selected to possess a range of lipophilicity was measured in two airway cell lines (Calu-3 and 16HBE14o-), in normal human bronchial epithelial (NHBE) cells and using a simple isolated perfused lungs (IPL) technique. Data from the cell layers and ex vivo lungs were compared to published absorption rates from rat lungs measured in vivo . Results A strong relationship was observed between the logarithm of the in vivo absorption half-life and the absorption half-life in the IPL ( r  = 0.97; excluding formoterol). Good log-linear relationships were also found between the apparent first-order absorption rate in vivo and cell layer permeability with correlation coefficients of 0.92, 0.93, 0.91 in Calu-3, 16HBE14o- and NHBE cells, respectively. Conclusion The simple IPL technique provided a good prediction of drug absorption from the lungs, making it a useful method for empirical screening of drug absorption in the lungs. Permeability measurements were similar in all the respiratory epithelial cell models evaluated, with Calu-3 having the advantage for routine permeability screening purposes of being readily availability, robust and easy to culture.

This study aimed to prepare mucus-penetrating inhalable microparticles for dry powder inhalers and to evaluate their applicability in an asthma-induced rat model. Microparticles were prepared from water solutions containing tiotropium bromide, L-leucine, and sodium glycocholate (NaGc) as permeation enhancers using the spray drying method. Four formulations (SDL1, SDL2, SDL3, and SDL4) were used, depending on the various NaGc concentrations. Tiotropium microparticles were characterized by standard methods. Additionally, an asthma-induced rat model was used to confirm the effects of the formulations on lung function. Tiotropium microparticles with NaGc resulted in formulations with a more corrugated morphology and smaller particle size distribution than those without NaGc. SDL 1 had a rough surface with irregular morphology, and SDL 2, 3, and 4 had a corrugated morphology. All SDL formulations had an aerodynamic size of <3 µm. The microparticles with a corrugated morphology aerosolized better than SDL1 microparticles. The apparent permeability coefficient (Papp) values of SDL3 and SDL4 were significantly higher than those for raw tiotropium. In an in vivo study using an asthma-induced rat model, the specific airway resistance (Sraw), airway wall thickness, and mean alveolus size recovered to those of the negative control group in the SDL4 formulation.

models are very important in medicine and biology, because they provide an insight into cells' and microorganisms' behavior. Since these cells and microorganisms are isolated from their natural environment, these models may not completely or precisely predict the effects on the entire organism. Improvement in this area is secured by organ-on-a-chip development. The organ-on-a-chip assumes cells cultured in a microfluidic chip. The chip simulates bioactivities, mechanics and physiological behavior of organs or organ systems, generating artificial organs in that way. There are several cell lines used so far for each tested artificial organ. For lungs, mostly used cell lines are 16HBE, A549, Calu-3, NHBE, while mostly used cell lines for liver are HepG2, Hep 3B, TPH1, etc. In this paper, state of the art for lung and liver organ-on-a-chip is presented, together with the established testing on lung and liver cell lines, with the emphasis on Calu-3 (for lung cell lines) and Hep-G2 (for liver cell lines). Primary focus in this review is to discuss different researches on the topics of lung and liver cell line models, approaches in determining fate and transport, cell partitioning, cell growth and division, as well as cell dynamics, meaning toxicity and effects. The review is finalized with current research gaps and problems, stating potential future developments in the field.

Due to the continuing high impact of lung diseases on society and the emergence of new respiratory viruses, such as SARS-CoV-2, there is a great need for in vitro lung models that more accurately recapitulate the in vivo situation than current models based on lung epithelial cell cultures on stiff membranes. Therefore, we developed an in vitro airway epithelial–endothelial cell culture model based on Calu-3 human lung epithelial cells and human lung microvascular endothelial cells (LMVECs), cultured on opposite sides of flexible porous poly(trimethylene carbonate) (PTMC) membranes. Calu-3 cells, cultured for two weeks at an air–liquid interface (ALI), showed good expression of the tight junction (TJ) protein Zonula Occludens 1 (ZO-1). LMVECs cultured submerged for three weeks were CD31-positive, but the expression was diffuse and not localized at the cell membrane. Barrier functions of the Calu-3 cell cultures and the co-cultures with LMVECs were good, as determined by electrical resistance measurements and fluorescein isothiocyanate-dextran (FITC-dextran) permeability assays. Importantly, the Calu-3/LMVEC co-cultures showed better cell viability and barrier function than mono-cultures. Moreover, there was no evidence for epithelial- and endothelial-to-mesenchymal transition (EMT and EndoMT, respectively) based on staining for the mesenchymal markers vimentin and α-SMA, respectively. These results indicate the potential of this new airway epithelial–endothelial model for lung research. In addition, since the PTMC membrane is flexible, the model can be expanded by introducing cyclic stretch for enabling mechanical stimulation of the cells. Furthermore, the model can form the basis for biomimetic airway epithelial–endothelial and alveolar–endothelial models with primary lung epithelial cells.