Abstract
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.
Highlights
Previous work showed that the inhibition of the Ca2+ activated Cl− channel TMEM16A inhibits excessive mucus production in inflammatory airway diseases such as asthma and cystic fibrosis
The effects induced by intratracheal application in vivo could be reproduced in vitro. Along with these additional results, which indicate the inhibition of TMEM16A by suppression of intracellular Ca2+ signals, we propose niclosamide encapsulated in polyethylene glycol (PEG)-microspheres/nanospheres as an effective topical treatment of inflammatory airway disease
We further examined whether Ca2+ activated TMEM16A currents present in Calu-3 human airway submucosal cells are inhibited by encapsulated niclosamide
Summary
Previous work showed that the inhibition of the Ca2+ activated Cl− channel TMEM16A inhibits excessive mucus production in inflammatory airway diseases such as asthma and cystic fibrosis (reviewed in [1]). TMEM16 proteins are highly relevant therapeutic targets in asthma, cystic fibrosis, and viral lung infections caused by SARS-CoV-2, respiratory syncytial virus, or influenza [10,12]. These predominantly airway-located diseases are of very different origin, involving distinct cytokines and patho-mechanisms, they have a participation of one (TMEM16A) or two (TMEM16A and TMEM16F) members of the TMEM16-family of proteins in common. The effects induced by intratracheal application in vivo could be reproduced in vitro Along with these additional results, which indicate the inhibition of TMEM16A by suppression of intracellular Ca2+ signals, we propose niclosamide encapsulated in PEG-microspheres/nanospheres as an effective topical treatment of inflammatory airway disease
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