• Advancing human pulmonary disease models in preclinical research: opportunities for lung-on-chips..

      Artzy-Schnirman, Arbel; Lehr, Claus-Michael; Sznitman, Josué; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Taylor&Francis, 2020-03-11)
      [No abstracr available]
    • Human airway mucus alters susceptibility of Pseudomonas aeruginosa biofilms to tobramycin, but not colistin.

      Müller, Laura; Murgia, Xabier; Siebenbürger, Lorenz; Börger, Carsten; Schwarzkopf, Konrad; Sewald, Katherina; Häussler, Susanne; Braun, Armin; Lehr, Claus-Michael; Hittinger, Marius; et al.
      Objectives: In the context of cystic fibrosis, Pseudomonas aeruginosa biofilms often develop in the vicinity of airway mucus, which acts as a protective physical barrier to inhaled matter. However, mucus can also adsorb small drug molecules administered as aerosols, including antibiotics, thereby reducing their bioavailability. The efficacy of antibiotics is typically assessed by determining the MIC using in vitro assays. This widespread technique, however, does not consider either bacterial biofilm formation or the influence of mucus, both of which may act as diffusion barriers, potentially limiting antibiotic efficacy. Methods: We grew P. aeruginosa biofilms in the presence or absence of human tracheal mucus and tested their susceptibility to tobramycin and colistin. Results: A significant reduction of tobramycin efficacy was observed when P. aeruginosa biofilms were grown in the presence of mucus compared with those grown in the absence of mucus. Diffusion of tobramycin through mucus was reduced; however, this reduction was more pronounced in biofilm/mucus mixtures, suggesting that biofilms in the presence of mucus respond differently to antibiotic treatment. In contrast, the influence of mucus on colistin efficacy was almost negligible and no differences in mucus permeability were observed. Conclusions: These findings underline the important role of mucus in the efficacy of anti-infective drugs.
    • Polysaccharide Submicrocarrier for Improved Pulmonary Delivery of Poorly Soluble Anti-infective Ciprofloxacin: Preparation, Characterization, and Influence of Size on Cellular Uptake.

      Ho, Duy-Khiet; Costa, Ana; de Rossi, Chiara; de Souza Carvalho-Wodarz, Cristiane; Loretz, Brigitta; Lehr, Claus-Michael; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (American Chemical Society, 2018-02-21)
      The majority of the currently used and developed anti-infectives are poorly water-soluble molecules. The poor solubility might lead to limited bioavailability and pharmacological action of the drug. Novel pharmaceutical materials have thus been designed to solve those problems and improve drug delivery. In this study, we propose a facile method to produce submicrocarriers (sMCs) by electrostatic gelation of anionic ß-cyclodextrin (aß-CD) and chitosan. The average hydrodynamic size ranged from 400 to 900 nm by carefully adjusting polymer concentrations and N/C ratio. The distinct host-guest reaction of cyclodextrin derivative is considered as a good approach to enhance solubility, and prevent drug recrystallization, and thus was used to develop sMC to improve the controlled release profile of a poorly soluble and clinically relevant anti-infective ciprofloxacin. The optimal molar ratio of ciprofloxacin to aß-CD was found to be 1:1, which helped maximize encapsulation efficiency (∼90%) and loading capacity (∼9%) of ciprofloxacin loaded sMCs. Furthermore, to recommend the future application of the developed sMCs, the dependence of cell uptake on sMCs size (500, 700, and 900 nm) was investigated in vitro on dTHP-1 by both flow cytometry and confocal microscopy. The results demonstrate that, regardless of their size, an only comparatively small fraction of the sMCs were taken up by the macrophage-like cells, while most of the carriers were merely adsorbed to the cell surface after 2 h incubation. After continuing the incubation to reach 24 h, the majority of the sMCs were found intracellularly. However, the sMCs had been designed to release sufficient amount of drug within 24 h, and the subsequent phagocytosis of the carrier may be considered as an efficient pathway for its safe degradation and elimination. In summary, the developed sMC is a suitable system with promising perspectives recommended for pulmonary extracellular infection therapeutics.
    • Vibrational spectroscopic imaging and live cell video microscopy for studying differentiation of primary human alveolar epithelial cells.

      Vukosavljevic, Branko; Hittinger, Marius; Hachmeister, Henning; Pilger, Christian; Murgia, Xabier; Gepp, Michael M; Gentile, Luca; Huwer, Hanno; Schneider-Daum, Nicole; Huser, Thomas; et al. (Wiley-VCH, 2019-02-20)