A columnar phase of dendritic lipid-based cationic liposome-DNA complexes for gene delivery: Hexagonally ordered cylindrical micelles embedded in a DNA honeycomb lattice

Kai K. Ewert, Heather M. Evans, Alexandra Zidovska, Nathan F. Bouxsein, Ayesha Ahmad, Cyrus R. Safinya

    Research output: Contribution to journalArticle

    Abstract

    Gene therapy holds great promise as a future approach to fighting disease and is explored in worldwide clinical trials. Cationic liposome (CL)-DNA complexes are a prevalent nonviral delivery vector, but their efficiency requires improvement and the understanding of their mechanism of action is incomplete. As part of our effort to investigate the structure-transfection efficiency relationships of self-assembled CL-DNA vectors, we have synthesized a new, highly charged (16+) multivalent cationic lipid, MVLBG2, with a dendritic headgroup. Our synthetic scheme allows facile variation of the headgroup charge and the spacer connecting hydrophobic and headgroup moieties as well as gram-scale synthesis. Complexes of DNA with mixtures of MVLBG2 and neutral 1,2-dioleoyl-sn-glycerophosphatidylcholine (DOPC) exhibit the well-known lamellar phase at 90 mol % DOPC. Starting at 20 mol % dendritic lipid, however, two novel nonlamellar phases are observed by synchrotron X-ray diffraction. The structure of one of these phases, present in a narrow range of composition around 25 mol % MVLBG2, has been solved. In this novel dual lattice structure, termed HI C, hexagonally arranged tubular lipid micelles are surrounded by DNA rods forming a three-dimensionally continuous substructure with honeycomb symmetry. Complexes in the HI C phase efficiently transfect mouse and human cells in culture. Their transfection efficiency, as well as that of the lamellar complexes containing only 10 mol % dendritic lipid, reaches and surpasses that of commercially available, optimized DOTAP-based complexes. In particular, complexes containing MVLBG2 are significantly more transfectant over the entire composition range in mouse embryonic fibroblasts, a cell line empirically known to be hard to transfect.

    Original languageEnglish (US)
    Pages (from-to)3998-4006
    Number of pages9
    JournalJournal of the American Chemical Society
    Volume128
    Issue number12
    DOIs
    StatePublished - Mar 29 2006

    Fingerprint

    Liposomes
    Micelles
    Lipids
    DNA
    Genes
    Transfection
    Cells
    Gene therapy
    Synchrotrons
    Fibroblasts
    Chemical analysis
    Cell culture
    X-Ray Diffraction
    Genetic Therapy
    Cell Culture Techniques
    Clinical Trials
    Cell Line
    X ray diffraction
    1,2-oleoylphosphatidylcholine

    ASJC Scopus subject areas

    • Chemistry(all)

    Cite this

    A columnar phase of dendritic lipid-based cationic liposome-DNA complexes for gene delivery : Hexagonally ordered cylindrical micelles embedded in a DNA honeycomb lattice. / Ewert, Kai K.; Evans, Heather M.; Zidovska, Alexandra; Bouxsein, Nathan F.; Ahmad, Ayesha; Safinya, Cyrus R.

    In: Journal of the American Chemical Society, Vol. 128, No. 12, 29.03.2006, p. 3998-4006.

    Research output: Contribution to journalArticle

    Ewert, Kai K. ; Evans, Heather M. ; Zidovska, Alexandra ; Bouxsein, Nathan F. ; Ahmad, Ayesha ; Safinya, Cyrus R. / A columnar phase of dendritic lipid-based cationic liposome-DNA complexes for gene delivery : Hexagonally ordered cylindrical micelles embedded in a DNA honeycomb lattice. In: Journal of the American Chemical Society. 2006 ; Vol. 128, No. 12. pp. 3998-4006.
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    abstract = "Gene therapy holds great promise as a future approach to fighting disease and is explored in worldwide clinical trials. Cationic liposome (CL)-DNA complexes are a prevalent nonviral delivery vector, but their efficiency requires improvement and the understanding of their mechanism of action is incomplete. As part of our effort to investigate the structure-transfection efficiency relationships of self-assembled CL-DNA vectors, we have synthesized a new, highly charged (16+) multivalent cationic lipid, MVLBG2, with a dendritic headgroup. Our synthetic scheme allows facile variation of the headgroup charge and the spacer connecting hydrophobic and headgroup moieties as well as gram-scale synthesis. Complexes of DNA with mixtures of MVLBG2 and neutral 1,2-dioleoyl-sn-glycerophosphatidylcholine (DOPC) exhibit the well-known lamellar phase at 90 mol {\%} DOPC. Starting at 20 mol {\%} dendritic lipid, however, two novel nonlamellar phases are observed by synchrotron X-ray diffraction. The structure of one of these phases, present in a narrow range of composition around 25 mol {\%} MVLBG2, has been solved. In this novel dual lattice structure, termed HI C, hexagonally arranged tubular lipid micelles are surrounded by DNA rods forming a three-dimensionally continuous substructure with honeycomb symmetry. Complexes in the HI C phase efficiently transfect mouse and human cells in culture. Their transfection efficiency, as well as that of the lamellar complexes containing only 10 mol {\%} dendritic lipid, reaches and surpasses that of commercially available, optimized DOTAP-based complexes. In particular, complexes containing MVLBG2 are significantly more transfectant over the entire composition range in mouse embryonic fibroblasts, a cell line empirically known to be hard to transfect.",
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