Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway Disease
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-...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/3/1085 |
| _version_ | 1797487662649573376 |
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| author | Jiraporn Ousingsawat Raquel Centeio Inês Cabrita Khaoula Talbi Oliver Zimmer Moritz Graf Achim Göpferich Rainer Schreiber Karl Kunzelmann |
| author_facet | Jiraporn Ousingsawat Raquel Centeio Inês Cabrita Khaoula Talbi Oliver Zimmer Moritz Graf Achim Göpferich Rainer Schreiber Karl Kunzelmann |
| author_sort | Jiraporn Ousingsawat |
| collection | DOAJ |
| description | 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<sup>−</sup> currents and intracellular Ca<sup>2+</sup> 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 Ca<sup>2+</sup> activated Cl<sup>−</sup> 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 Ca<sup>2+</sup> 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. |
| first_indexed | 2024-03-09T23:50:56Z |
| format | Article |
| id | doaj.art-aed0ab4c2caa4ffba7172cf1eaf2cc07 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:50:56Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-aed0ab4c2caa4ffba7172cf1eaf2cc072023-11-23T16:34:44ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-01-01233108510.3390/ijms23031085Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway DiseaseJiraporn Ousingsawat0Raquel Centeio1Inês Cabrita2Khaoula Talbi3Oliver Zimmer4Moritz Graf5Achim Göpferich6Rainer Schreiber7Karl Kunzelmann8Physiological Institute, University of Regensburg, University Street 31, 93040 Regensburg, GermanyPhysiological Institute, University of Regensburg, University Street 31, 93040 Regensburg, GermanyPhysiological Institute, University of Regensburg, University Street 31, 93040 Regensburg, GermanyPhysiological Institute, University of Regensburg, University Street 31, 93040 Regensburg, GermanyDepartment of Pharmaceutical Technology, University of Regensburg, 93040 Regensburg, GermanyDepartment of Pharmaceutical Technology, University of Regensburg, 93040 Regensburg, GermanyDepartment of Pharmaceutical Technology, University of Regensburg, 93040 Regensburg, GermanyPhysiological Institute, University of Regensburg, University Street 31, 93040 Regensburg, GermanyPhysiological Institute, University of Regensburg, University Street 31, 93040 Regensburg, GermanyRepurposing 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<sup>−</sup> currents and intracellular Ca<sup>2+</sup> 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 Ca<sup>2+</sup> activated Cl<sup>−</sup> 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 Ca<sup>2+</sup> 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.https://www.mdpi.com/1422-0067/23/3/1085TMEM16ATMEM16Fasthmainflammatory airway diseaseCOVID-19hydrospheres |
| spellingShingle | Jiraporn Ousingsawat Raquel Centeio Inês Cabrita Khaoula Talbi Oliver Zimmer Moritz Graf Achim Göpferich Rainer Schreiber Karl Kunzelmann Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway Disease International Journal of Molecular Sciences TMEM16A TMEM16F asthma inflammatory airway disease COVID-19 hydrospheres |
| title | Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway Disease |
| title_full | Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway Disease |
| title_fullStr | Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway Disease |
| title_full_unstemmed | Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway Disease |
| title_short | Airway Delivery of Hydrogel-Encapsulated Niclosamide for the Treatment of Inflammatory Airway Disease |
| title_sort | airway delivery of hydrogel encapsulated niclosamide for the treatment of inflammatory airway disease |
| topic | TMEM16A TMEM16F asthma inflammatory airway disease COVID-19 hydrospheres |
| url | https://www.mdpi.com/1422-0067/23/3/1085 |
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