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Delivery of siRNA Complexed with Palmitoylated alpha-Peptide/beta-Peptoid Cell-Penetrating Peptidomimetics: Membrane Interaction and Structural Characterization of a Lipid-Based Nanocarrier System
Univ Copenhagen, Dept Pharm, Fac Hlth & Med Sci, Univ Pk 2, DK-2100 Copenhagen O, Denmark..
Univ Copenhagen, Dept Pharm, Fac Hlth & Med Sci, Univ Pk 2, DK-2100 Copenhagen O, Denmark..
Univ Copenhagen, Dept Pharm, Fac Hlth & Med Sci, Univ Pk 2, DK-2100 Copenhagen O, Denmark..
Univ Copenhagen, Dept Pharm, Fac Hlth & Med Sci, Univ Pk 2, DK-2100 Copenhagen O, Denmark..
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2016 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 13, no 6, 1739-1749 p.Article in journal (Refereed) PublishedText
Abstract [en]

Proteolytically stable alpha-peptide/beta-peptoid peptidomimetics constitute promising cell-penetrating carrier candidates exhibiting superior cellular uptake as compared to commonly used cell-penetrating peptides (CPPs). The aim of the present study was to explore the potential of these peptidomimetics for delivery of small interfering RNA (siRNA) to the cytosol by incorporation of a palmitoylated peptidomimetic construct into a cationic lipid-based nanocarrier system. The optimal construct was selected on the basis of the effect of palmitoylation and the influence of the length of the peptidomimetic on the interaction with model membranes and the cellular uptake. Palmitoylation enhanced the peptidomimetic adsorption to supported lipid bilayers as studied by ellipsometry. However, both palmitoylation and increased peptidomimetic chain length were found to be beneficial in the cellular uptake studies using fluorophore-labeled analogues. Thus, the longer palmitoylated peptidomimetic was chosen for further formulation of siRNA in a dioleoylphosphatidylethanolamine/cholesteryl hemisuccinate (DOPE/CHEMS) nanocarrier system, and the resulting nanoparticles were found to mediate efficient gene silencing in vitro. Cryo-transmission electron microscopy (cryo-TEM) revealed multilamellar, onion-like spherical vesicles, and small-angle X-ray scattering (SAXS) analysis confirmed that the majority of the lipids in the nanocarriers were organized in lamellar structures, yet coexisted with a hexagonal phase, which is important for efficient nanocarrier-mediated endosomal escape of siRNA ensuring cytosolic delivery. The present work is a proof-of-concept for the use of alpha-peptides/beta-peptoid peptidomimetics in an efficient delivery system that may be more generally exploited for the intracellular delivery of biomacromolecular drugs.

Place, publisher, year, edition, pages
2016. Vol. 13, no 6, 1739-1749 p.
Keyword [en]
siRNA delivery, cell-penetrating peptide, peptidomimetic, palmitoylation, nanocarrier, oyo-TEM, SAXS, drug delivery, nanomedicine
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-299065DOI: 10.1021/acs.molpharmaceut.5b00309ISI: 000377424600001PubMedID: 26654841OAI: oai:DiVA.org:uu-299065DiVA: diva2:948764
Swedish Research CouncilEU, European Research Council, 026668, 226716
Available from: 2016-07-13 Created: 2016-07-13 Last updated: 2016-07-13Bibliographically approved

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Malmsten, Martin
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