Show simple item record

dc.contributor.authorde Groot, Anne Mariten
dc.contributor.authorThanki, Kaushiken
dc.contributor.authorGangloff, Moniqueen
dc.contributor.authorFalkenberg, Emilyen
dc.contributor.authorZeng, Xianghuien
dc.contributor.authorvan Bijnen, Djai CJen
dc.contributor.authorvan Eden, Willemen
dc.contributor.authorFranzyk, Henriken
dc.contributor.authorNielsen, Hanne Men
dc.contributor.authorBroere, Femkeen
dc.contributor.authorGay, Nicholasen
dc.contributor.authorFoged, Camillaen
dc.contributor.authorSijts, Alice JAMen
dc.date.accessioned2018-06-04T11:59:45Z
dc.date.available2018-06-04T11:59:45Z
dc.date.issued2018-06en
dc.identifier.issn2162-2531
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/276527
dc.description.abstractTherapeutics based on small interfering RNA (siRNA) have promising potential as antiviral and anti-inflammatory agents. To deliver siRNA across cell membranes to reach the RNAi pathway in the cytosol of target cells, non-viral nanoparticulate delivery approaches are explored. Recently, we showed that encapsulation of siRNA in lipid-polymer hybrid nanoparticles (LPNs), based on poly(DL-lactic-co-glycolic acid) (PLGA) and cationic lipid-like materials (lipidoids), remarkably enhances intracellular delivery of siRNA as compared to siRNA delivery with LPNs modified with dioleoyltrimethylammoniumpropane (DOTAP) as the lipid component. However, the potential immune modulation by these cationic lipids remains unexplored. By testing lipidoids and DOTAP for innate immune-receptoractivating properties in vitro, we found that neither lipidoids nor DOTAP activate human Toll-like receptor (TLR) 2, 3, 7, and 9. However, in contrast to DOTAP, lipidoids are strong agonists for TLR4 and activate murine antigen-presenting cells in vitro. This agonistic effect was further confirmed in silico using a prediction model based on crystal structures. Also, lipidoids formulated as lipoplexes or as stable nucleic acid lipid particles, which was the reference formulation for siRNA delivery, proved to activate TLR4. However, by combining lipidoids with PLGA into LPNs, TLR4 activation was abrogated. Thus, lipidoid-mediated TLR4 activation during siRNA delivery may be modulated via optimization of the formulation design.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherNature Publishing Group
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.titleImmunogenicity Testing of Lipidoids In Vitro and In Silico: Modulating Lipidoid-Mediated TLR4 Activation by Nanoparticle Design.en
dc.typeArticle
prism.endingPage169
prism.publicationDate2018en
prism.publicationNameMolecular therapy. Nucleic acidsen
prism.startingPage159
prism.volume11en
dc.identifier.doi10.17863/CAM.23825
dcterms.dateAccepted2018-02-06en
rioxxterms.versionofrecord10.1016/j.omtn.2018.02.003en
rioxxterms.versionVoR*
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2018-06en
dc.contributor.orcidThanki, Kaushik [0000-0003-0823-7160]
dc.contributor.orcidGangloff, Monique [0000-0001-6131-0115]
dc.contributor.orcidZeng, Xianghui [0000-0001-7586-1751]
dc.contributor.orcidvan Eden, Willem [0000-0003-1272-704X]
dc.contributor.orcidFranzyk, Henrik [0000-0002-2822-1927]
dc.contributor.orcidGay, Nicholas [0000-0002-2782-7169]
dc.contributor.orcidFoged, Camilla [0000-0003-2812-5588]
dc.contributor.orcidSijts, Alice JAM [0000-0003-3815-4788]
dc.identifier.eissn2162-2531
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (100321/Z/12/Z)
pubs.funder-project-idMRC (MR/P02260X/1)


Files in this item

Thumbnail
Thumbnail

This item appears in the following Collection(s)

Show simple item record

Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International