Development of an inhalable antiviral powder formulation against respiratory syncytial virus
Respiratory viruses including the respiratory syncytial virus (RSV) aggravate the global burden of virus-inflicted morbidity and mortality. Entry inhibitors are a promising class of antiviral drugs for combating these viruses, as they can prevent infection at the site of viral entry, i.e., the respi...
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Veröffentlicht in: | Journal of controlled release 2023-05, Vol.357, p.264-273 |
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creator | Heida, Rick Akkerman, Renate Jacob Silva, Paulo H. Lakerveld, Anke J. Ortiz, Daniel Bigogno, Chiara Gasbarri, Matteo van Kasteren, Puck B. Stellacci, Francesco Frijlink, Henderik W. Huckriede, Anke L.W. Hinrichs, Wouter L.J. |
description | Respiratory viruses including the respiratory syncytial virus (RSV) aggravate the global burden of virus-inflicted morbidity and mortality. Entry inhibitors are a promising class of antiviral drugs for combating these viruses, as they can prevent infection at the site of viral entry, i.e., the respiratory tract. Here we used a broad-spectrum entry inhibitor, composed of a β-cyclodextrin backbone, functionalized with 11-mercapto-1-undecanesulfonate (CD-MUS) that is capable of neutralizing a variety of viruses that employ heparan sulfate proteoglycans (HSPG) to infect host cells. CD-MUS inactivates viral particles irreversibly by binding to viral attachment proteins through a multivalent binding mechanism. In the present study, we show that CD-MUS is well tolerated when administered to the respiratory tract of mice. Based on this, we developed an inhalable spray-dried powder formulation that fits the size requirements for lung deposition and disperses well upon use with the Cyclops dry powder inhaler (DPI). Using an in vitro dose-response assay, we show that the compound retained its activity against RSV after the spray drying process. Our study sets the stage for further in vivo studies, exploring the efficacy of pulmonary administered CD-MUS in animal models of RSV infection.
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•The novel antiviral entry inhibitor CD-MUS is well-tolerated in vivo.•CD-MUS shows suitable pharmacokinetic behavior after pulmonary administration.•CD-MUS can successfully be formulated into an inhalable dry powder formulation.•CD-MUS retains its activity against respiratory syncytial virus after spray drying.•CD-MUS is well dispersed from the Cyclops dry powder inhaler. |
doi_str_mv | 10.1016/j.jconrel.2023.03.059 |
format | Article |
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[Display omitted]
•The novel antiviral entry inhibitor CD-MUS is well-tolerated in vivo.•CD-MUS shows suitable pharmacokinetic behavior after pulmonary administration.•CD-MUS can successfully be formulated into an inhalable dry powder formulation.•CD-MUS retains its activity against respiratory syncytial virus after spray drying.•CD-MUS is well dispersed from the Cyclops dry powder inhaler.</description><identifier>ISSN: 0168-3659</identifier><identifier>EISSN: 1873-4995</identifier><identifier>DOI: 10.1016/j.jconrel.2023.03.059</identifier><identifier>PMID: 37015293</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Administration, Inhalation ; Animals ; Antiviral Agents - pharmacology ; Antiviral Agents - therapeutic use ; Broad-spectrum ; class ; dose response ; Dry powder inhalation ; Dry Powder Inhalers ; Entry inhibitor ; heparan sulfate ; lungs ; mortality ; Powders - therapeutic use ; proteoglycans ; Pulmonary drug delivery ; Respiratory syncytial virus ; Respiratory Syncytial Virus Infections - drug therapy ; Respiratory Syncytial Viruses - metabolism ; Spray drying ; Viral Proteins - metabolism</subject><ispartof>Journal of controlled release, 2023-05, Vol.357, p.264-273</ispartof><rights>2023 The Authors</rights><rights>Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c445t-e8e310971088c1acc55dd799dd023d5e36833c290dee3d0070e5c9189cd5e9323</citedby><cites>FETCH-LOGICAL-c445t-e8e310971088c1acc55dd799dd023d5e36833c290dee3d0070e5c9189cd5e9323</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S016836592300250X$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37015293$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Heida, Rick</creatorcontrib><creatorcontrib>Akkerman, Renate</creatorcontrib><creatorcontrib>Jacob Silva, Paulo H.</creatorcontrib><creatorcontrib>Lakerveld, Anke J.</creatorcontrib><creatorcontrib>Ortiz, Daniel</creatorcontrib><creatorcontrib>Bigogno, Chiara</creatorcontrib><creatorcontrib>Gasbarri, Matteo</creatorcontrib><creatorcontrib>van Kasteren, Puck B.</creatorcontrib><creatorcontrib>Stellacci, Francesco</creatorcontrib><creatorcontrib>Frijlink, Henderik W.</creatorcontrib><creatorcontrib>Huckriede, Anke L.W.</creatorcontrib><creatorcontrib>Hinrichs, Wouter L.J.</creatorcontrib><title>Development of an inhalable antiviral powder formulation against respiratory syncytial virus</title><title>Journal of controlled release</title><addtitle>J Control Release</addtitle><description>Respiratory viruses including the respiratory syncytial virus (RSV) aggravate the global burden of virus-inflicted morbidity and mortality. Entry inhibitors are a promising class of antiviral drugs for combating these viruses, as they can prevent infection at the site of viral entry, i.e., the respiratory tract. Here we used a broad-spectrum entry inhibitor, composed of a β-cyclodextrin backbone, functionalized with 11-mercapto-1-undecanesulfonate (CD-MUS) that is capable of neutralizing a variety of viruses that employ heparan sulfate proteoglycans (HSPG) to infect host cells. CD-MUS inactivates viral particles irreversibly by binding to viral attachment proteins through a multivalent binding mechanism. In the present study, we show that CD-MUS is well tolerated when administered to the respiratory tract of mice. Based on this, we developed an inhalable spray-dried powder formulation that fits the size requirements for lung deposition and disperses well upon use with the Cyclops dry powder inhaler (DPI). Using an in vitro dose-response assay, we show that the compound retained its activity against RSV after the spray drying process. Our study sets the stage for further in vivo studies, exploring the efficacy of pulmonary administered CD-MUS in animal models of RSV infection.
[Display omitted]
•The novel antiviral entry inhibitor CD-MUS is well-tolerated in vivo.•CD-MUS shows suitable pharmacokinetic behavior after pulmonary administration.•CD-MUS can successfully be formulated into an inhalable dry powder formulation.•CD-MUS retains its activity against respiratory syncytial virus after spray drying.•CD-MUS is well dispersed from the Cyclops dry powder inhaler.</description><subject>Administration, Inhalation</subject><subject>Animals</subject><subject>Antiviral Agents - pharmacology</subject><subject>Antiviral Agents - therapeutic use</subject><subject>Broad-spectrum</subject><subject>class</subject><subject>dose response</subject><subject>Dry powder inhalation</subject><subject>Dry Powder Inhalers</subject><subject>Entry inhibitor</subject><subject>heparan sulfate</subject><subject>lungs</subject><subject>mortality</subject><subject>Powders - therapeutic use</subject><subject>proteoglycans</subject><subject>Pulmonary drug delivery</subject><subject>Respiratory syncytial virus</subject><subject>Respiratory Syncytial Virus Infections - drug therapy</subject><subject>Respiratory Syncytial Viruses - metabolism</subject><subject>Spray drying</subject><subject>Viral Proteins - metabolism</subject><issn>0168-3659</issn><issn>1873-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1LAzEQhoMotn78BGWPXrYmm83u5iTiNwhe9CaENJlqSjZZk2yl_96UVq_CwDDM884w8yJ0RvCMYNJcLmdL5V0AO6twRWc4B-N7aEq6lpY152wfTTPXlbRhfIKOYlxijBmt20M0oS0mrOJ0it5vYQXWDz24VPhFIV1h3Ke0cm4hF8msTJC2GPy3hlAsfOhHK5PxrpAf0riYigBxyEzyYV3EtVPrZLIgy8Z4gg4W0kY43eVj9HZ_93rzWD6_PDzdXD-Xqq5ZKqEDSjBvCe46RaRSjGndcq51vkwzoE1Hqao41gBUY9xiYIqTjqvc5LSix-hiO3cI_muEmERvogJrpQM_RlF1tK6qmvH2f7TlDWkIqTco26Iq-BgDLMQQTC_DWhAsNh6Ipdh5IDYeCJyD8aw7360Y5z3oP9Xv0zNwtQUg_2RlIIioDDgF2gRQSWhv_lnxA4gCm_A</recordid><startdate>202305</startdate><enddate>202305</enddate><creator>Heida, Rick</creator><creator>Akkerman, Renate</creator><creator>Jacob Silva, Paulo H.</creator><creator>Lakerveld, Anke J.</creator><creator>Ortiz, Daniel</creator><creator>Bigogno, Chiara</creator><creator>Gasbarri, Matteo</creator><creator>van Kasteren, Puck B.</creator><creator>Stellacci, Francesco</creator><creator>Frijlink, Henderik W.</creator><creator>Huckriede, Anke L.W.</creator><creator>Hinrichs, Wouter L.J.</creator><general>Elsevier B.V</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope></search><sort><creationdate>202305</creationdate><title>Development of an inhalable antiviral powder formulation against respiratory syncytial virus</title><author>Heida, Rick ; Akkerman, Renate ; Jacob Silva, Paulo H. ; Lakerveld, Anke J. ; Ortiz, Daniel ; Bigogno, Chiara ; Gasbarri, Matteo ; van Kasteren, Puck B. ; Stellacci, Francesco ; Frijlink, Henderik W. ; Huckriede, Anke L.W. ; Hinrichs, Wouter L.J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c445t-e8e310971088c1acc55dd799dd023d5e36833c290dee3d0070e5c9189cd5e9323</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Administration, Inhalation</topic><topic>Animals</topic><topic>Antiviral Agents - pharmacology</topic><topic>Antiviral Agents - therapeutic use</topic><topic>Broad-spectrum</topic><topic>class</topic><topic>dose response</topic><topic>Dry powder inhalation</topic><topic>Dry Powder Inhalers</topic><topic>Entry inhibitor</topic><topic>heparan sulfate</topic><topic>lungs</topic><topic>mortality</topic><topic>Powders - therapeutic use</topic><topic>proteoglycans</topic><topic>Pulmonary drug delivery</topic><topic>Respiratory syncytial virus</topic><topic>Respiratory Syncytial Virus Infections - drug therapy</topic><topic>Respiratory Syncytial Viruses - metabolism</topic><topic>Spray drying</topic><topic>Viral Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Heida, Rick</creatorcontrib><creatorcontrib>Akkerman, Renate</creatorcontrib><creatorcontrib>Jacob Silva, Paulo H.</creatorcontrib><creatorcontrib>Lakerveld, Anke J.</creatorcontrib><creatorcontrib>Ortiz, Daniel</creatorcontrib><creatorcontrib>Bigogno, Chiara</creatorcontrib><creatorcontrib>Gasbarri, Matteo</creatorcontrib><creatorcontrib>van Kasteren, Puck B.</creatorcontrib><creatorcontrib>Stellacci, Francesco</creatorcontrib><creatorcontrib>Frijlink, Henderik W.</creatorcontrib><creatorcontrib>Huckriede, Anke L.W.</creatorcontrib><creatorcontrib>Hinrichs, Wouter L.J.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><jtitle>Journal of controlled release</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Heida, Rick</au><au>Akkerman, Renate</au><au>Jacob Silva, Paulo H.</au><au>Lakerveld, Anke J.</au><au>Ortiz, Daniel</au><au>Bigogno, Chiara</au><au>Gasbarri, Matteo</au><au>van Kasteren, Puck B.</au><au>Stellacci, Francesco</au><au>Frijlink, Henderik W.</au><au>Huckriede, Anke L.W.</au><au>Hinrichs, Wouter L.J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development of an inhalable antiviral powder formulation against respiratory syncytial virus</atitle><jtitle>Journal of controlled release</jtitle><addtitle>J Control Release</addtitle><date>2023-05</date><risdate>2023</risdate><volume>357</volume><spage>264</spage><epage>273</epage><pages>264-273</pages><issn>0168-3659</issn><eissn>1873-4995</eissn><abstract>Respiratory viruses including the respiratory syncytial virus (RSV) aggravate the global burden of virus-inflicted morbidity and mortality. Entry inhibitors are a promising class of antiviral drugs for combating these viruses, as they can prevent infection at the site of viral entry, i.e., the respiratory tract. Here we used a broad-spectrum entry inhibitor, composed of a β-cyclodextrin backbone, functionalized with 11-mercapto-1-undecanesulfonate (CD-MUS) that is capable of neutralizing a variety of viruses that employ heparan sulfate proteoglycans (HSPG) to infect host cells. CD-MUS inactivates viral particles irreversibly by binding to viral attachment proteins through a multivalent binding mechanism. In the present study, we show that CD-MUS is well tolerated when administered to the respiratory tract of mice. Based on this, we developed an inhalable spray-dried powder formulation that fits the size requirements for lung deposition and disperses well upon use with the Cyclops dry powder inhaler (DPI). Using an in vitro dose-response assay, we show that the compound retained its activity against RSV after the spray drying process. Our study sets the stage for further in vivo studies, exploring the efficacy of pulmonary administered CD-MUS in animal models of RSV infection.
[Display omitted]
•The novel antiviral entry inhibitor CD-MUS is well-tolerated in vivo.•CD-MUS shows suitable pharmacokinetic behavior after pulmonary administration.•CD-MUS can successfully be formulated into an inhalable dry powder formulation.•CD-MUS retains its activity against respiratory syncytial virus after spray drying.•CD-MUS is well dispersed from the Cyclops dry powder inhaler.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>37015293</pmid><doi>10.1016/j.jconrel.2023.03.059</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Administration, Inhalation Animals Antiviral Agents - pharmacology Antiviral Agents - therapeutic use Broad-spectrum class dose response Dry powder inhalation Dry Powder Inhalers Entry inhibitor heparan sulfate lungs mortality Powders - therapeutic use proteoglycans Pulmonary drug delivery Respiratory syncytial virus Respiratory Syncytial Virus Infections - drug therapy Respiratory Syncytial Viruses - metabolism Spray drying Viral Proteins - metabolism |
title | Development of an inhalable antiviral powder formulation against respiratory syncytial virus |
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