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    Location of a single histidine within peptide carriers increases mRNA delivery

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    Author
    He, J.
    Xu, S.
    Leng, Q.
    Mixson, A.J.
    Date
    2020-11-10
    Journal
    Journal of Gene Medicine
    Publisher
    Blackwell Publishing Inc.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1002/jgm.3295
    Abstract
    Background: Previously, we determined that four-branched histidine-lysine (HK) peptides were effective carriers of plasmids and small interfering RNA. In the present study, we compared several branched HK carriers and, in particular, two closely-related H3K4b and H3K(+H)4b peptides for their ability as carriers of mRNA. The H3K(+H)4b peptide differed from its parent analogue, H3K4b, by only a single histidine in each branch. Methods: A series of four-branched HK peptides with varied sequences was synthesized on a solid-phase peptide synthesizer. The ability of these peptides to carry mRNA expressing luciferase to MDA-MB-231 cells was investigated. With gel retardation and heparin displacement assays, the stability of HK polyplexes was examined. We determined the intracellular uptake of HK polyplexes by flow cytometry and fluorescence microscopy. The size and polydispersity index of the polyplexes in several media were measured by dynamic light scattering. Results: MDA-MB-231 cells transfected by H3K(+H)4b-mRNA polyplexes expressed 10-fold greater levels of luciferase than H3K4b polyplexes. With gel retardation and heparin displacement assays, the H3K(+H)4b polyplexes showed greater stability than H3K4b. Intracellular uptake and co-localization of H3K(+H)4b polyplexes within acidic endosomes were also significantly increased compared to H3K4b. Similar to H3K(+H)4b, several HK analogues with an additional histidine in the second domain of their branches were effective carriers of mRNA. When combined with DOTAP liposomes, H3K(+H)4b was synergistic in delivery of mRNA. Conclusions: H3K(+H)4b was a more effective carrier of mRNA than H3K4b. Mechanistic studies suggest that H3K(+H)4b polyplexes were more stable than H3K4b polyplexes. Lipopolyplexes formed with H3K(+H)4b markedly increased mRNA transfection. Copyright 2020 The Authors. The Journal of Gene Medicine published by John Wiley & Sons Ltd.
    Sponsors
    This work was supported by grants from Sirnaomics, Inc. and from the National Institutes of Health (R01-EB028534).
    Keyword
    Non-viral vector
    peptide synthesis
    RNA transfer
    transfection
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/14599
    ae974a485f413a2113503eed53cd6c53
    10.1002/jgm.3295
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