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Article

Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway Disease

1
Physiological Institute, University of Regensburg, University Street 31, 93040 Regensburg, Germany
2
Department of Pharmaceutical Technology, University of Regensburg, 93040 Regensburg, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Massimo Conese
Int. J. Mol. Sci. 2022, 23(3), 1085; https://doi.org/10.3390/ijms23031085
Received: 30 November 2021 / Revised: 3 January 2022 / Accepted: 17 January 2022 / Published: 19 January 2022
Repurposing of the anthelminthic drug niclosamide was proposed as an effective treatment for inflammatory airway diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Niclosamide may also be effective for the treatment of viral respiratory infections, such as SARS-CoV-2, respiratory syncytial virus, and influenza. While systemic application of niclosamide may lead to unwanted side effects, local administration via aerosol may circumvent these problems, particularly when the drug is encapsulated into small polyethylene glycol (PEG) hydrospheres. In the present study, we examined whether PEG-encapsulated niclosamide inhibits the production of mucus and affects the pro-inflammatory mediator CLCA1 in mouse airways in vivo, while effects on mucociliary clearance were assessed in excised mouse tracheas. The potential of encapsulated niclosamide to inhibit TMEM16A whole-cell Cl currents and intracellular Ca2+ signalling was assessed in airway epithelial cells in vitro. We achieved encapsulation of niclosamide in PEG-microspheres and PEG-nanospheres (Niclo-spheres). When applied to asthmatic mice via intratracheal instillation, Niclo-spheres strongly attenuated overproduction of mucus, inhibited secretion of the major proinflammatory mediator CLCA1, and improved mucociliary clearance in tracheas ex vivo. These effects were comparable for niclosamide encapsulated in PEG-nanospheres and PEG-microspheres. Niclo-spheres inhibited the Ca2+ activated Cl channel TMEM16A and attenuated mucus production in CFBE and Calu-3 human airway epithelial cells. Both inhibitory effects were explained by a pronounced inhibition of intracellular Ca2+ signals. The data indicate that poorly dissolvable compounds such as niclosamide can be encapsulated in PEG-microspheres/nanospheres and deposited locally on the airway epithelium as encapsulated drugs, which may be advantageous over systemic application. View Full-Text
Keywords: TMEM16A; TMEM16F; asthma; inflammatory airway disease; COVID-19; hydrospheres; nanospheres; niclosamide TMEM16A; TMEM16F; asthma; inflammatory airway disease; COVID-19; hydrospheres; nanospheres; niclosamide
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MDPI and ACS Style

Ousingsawat, J.; Centeio, R.; Cabrita, I.; Talbi, K.; Zimmer, O.; Graf, M.; Göpferich, A.; Schreiber, R.; Kunzelmann, K. Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway Disease. Int. J. Mol. Sci. 2022, 23, 1085. https://doi.org/10.3390/ijms23031085

AMA Style

Ousingsawat J, Centeio R, Cabrita I, Talbi K, Zimmer O, Graf M, Göpferich A, Schreiber R, Kunzelmann K. Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway Disease. International Journal of Molecular Sciences. 2022; 23(3):1085. https://doi.org/10.3390/ijms23031085

Chicago/Turabian Style

Ousingsawat, Jiraporn, Raquel Centeio, Inês Cabrita, Khaoula Talbi, Oliver Zimmer, Moritz Graf, Achim Göpferich, Rainer Schreiber, and Karl Kunzelmann. 2022. "Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway Disease" International Journal of Molecular Sciences 23, no. 3: 1085. https://doi.org/10.3390/ijms23031085

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