Evaluation of pH-responsive liposomes containing amino acid-based zwitterionic lipids for improving intracellular drug delivery in vitro and in vivo

Yosuke Obata, Shoji Tajima, Shinji Takeoka

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    93 Citations (Scopus)

    Abstract

    We developed pH-responsive liposomes containing synthetic glutamic acid-based zwitterionic lipids and evaluated their properties both in vitro and in vivo with the aim of constructing an efficient liposome-based systemic drug delivery system. The glutamic acid-based lipids; 1,5-dihexadecyl N-glutamyl-. l-glutamate (L1) and 1,5-dihexadecyl N,. N-diglutamyl-lysyl-. l-glutamate (L2) were synthesized as a pH-responsive component of liposomes that respond to endosomal pH. The zeta potential of liposomes containing L1 or L2 was positive when the solution pH was below 4.6 or 5.6, respectively, but negative at higher pH values. The pH-responsive liposomes showed improved fusogenic potential to an endosome-mimicking anionic membrane at acidic pH, where the zeta potential of the liposomes was positive. We then prepared doxorubicin (DOX)-encapsulating liposomes containing L1 or L2, and clarified by confocal microscopic studies that the contents were rapidly transferred into both the cytoplasm and nucleus. Release of DOX from the endosomes mediated by the pH-responsive liposomes dramatically inhibited cancer cell growth. The L2-liposomes were slightly more effective than L1-liposomes as a drug delivery system. Intravenously injected L2-liposomes displayed blood persistence comparable to that of conventional phospholipid (PC)-based liposomes. Indeed, the antitumor efficacy of L2-liposomes was higher than that of PC-based liposomes against a xenograft breast cancer tumor in vivo. Thus, the high performance of L2-liposomes results from both efficient intracellular drug delivery and comparable blood persistence in comparison with the conventional PC-based liposomes in vitro and in vivo.

    Original languageEnglish
    Pages (from-to)267-276
    Number of pages10
    JournalJournal of Controlled Release
    Volume142
    Issue number2
    DOIs
    Publication statusPublished - 2010 Mar

    Fingerprint

    Liposomes
    Lipids
    Amino Acids
    Pharmaceutical Preparations
    Glutamic Acid
    In Vitro Techniques
    Endosomes
    Drug Delivery Systems
    Doxorubicin
    Breast Neoplasms
    Heterografts
    Phospholipids
    Cytoplasm

    Keywords

    • Amino lipid
    • Drug delivery
    • Liposomes
    • PH-responsive
    • Zwitterionic lipid

    ASJC Scopus subject areas

    • Pharmaceutical Science

    Cite this

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    abstract = "We developed pH-responsive liposomes containing synthetic glutamic acid-based zwitterionic lipids and evaluated their properties both in vitro and in vivo with the aim of constructing an efficient liposome-based systemic drug delivery system. The glutamic acid-based lipids; 1,5-dihexadecyl N-glutamyl-. l-glutamate (L1) and 1,5-dihexadecyl N,. N-diglutamyl-lysyl-. l-glutamate (L2) were synthesized as a pH-responsive component of liposomes that respond to endosomal pH. The zeta potential of liposomes containing L1 or L2 was positive when the solution pH was below 4.6 or 5.6, respectively, but negative at higher pH values. The pH-responsive liposomes showed improved fusogenic potential to an endosome-mimicking anionic membrane at acidic pH, where the zeta potential of the liposomes was positive. We then prepared doxorubicin (DOX)-encapsulating liposomes containing L1 or L2, and clarified by confocal microscopic studies that the contents were rapidly transferred into both the cytoplasm and nucleus. Release of DOX from the endosomes mediated by the pH-responsive liposomes dramatically inhibited cancer cell growth. The L2-liposomes were slightly more effective than L1-liposomes as a drug delivery system. Intravenously injected L2-liposomes displayed blood persistence comparable to that of conventional phospholipid (PC)-based liposomes. Indeed, the antitumor efficacy of L2-liposomes was higher than that of PC-based liposomes against a xenograft breast cancer tumor in vivo. Thus, the high performance of L2-liposomes results from both efficient intracellular drug delivery and comparable blood persistence in comparison with the conventional PC-based liposomes in vitro and in vivo.",
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    AU - Obata, Yosuke

    AU - Tajima, Shoji

    AU - Takeoka, Shinji

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    N2 - We developed pH-responsive liposomes containing synthetic glutamic acid-based zwitterionic lipids and evaluated their properties both in vitro and in vivo with the aim of constructing an efficient liposome-based systemic drug delivery system. The glutamic acid-based lipids; 1,5-dihexadecyl N-glutamyl-. l-glutamate (L1) and 1,5-dihexadecyl N,. N-diglutamyl-lysyl-. l-glutamate (L2) were synthesized as a pH-responsive component of liposomes that respond to endosomal pH. The zeta potential of liposomes containing L1 or L2 was positive when the solution pH was below 4.6 or 5.6, respectively, but negative at higher pH values. The pH-responsive liposomes showed improved fusogenic potential to an endosome-mimicking anionic membrane at acidic pH, where the zeta potential of the liposomes was positive. We then prepared doxorubicin (DOX)-encapsulating liposomes containing L1 or L2, and clarified by confocal microscopic studies that the contents were rapidly transferred into both the cytoplasm and nucleus. Release of DOX from the endosomes mediated by the pH-responsive liposomes dramatically inhibited cancer cell growth. The L2-liposomes were slightly more effective than L1-liposomes as a drug delivery system. Intravenously injected L2-liposomes displayed blood persistence comparable to that of conventional phospholipid (PC)-based liposomes. Indeed, the antitumor efficacy of L2-liposomes was higher than that of PC-based liposomes against a xenograft breast cancer tumor in vivo. Thus, the high performance of L2-liposomes results from both efficient intracellular drug delivery and comparable blood persistence in comparison with the conventional PC-based liposomes in vitro and in vivo.

    AB - We developed pH-responsive liposomes containing synthetic glutamic acid-based zwitterionic lipids and evaluated their properties both in vitro and in vivo with the aim of constructing an efficient liposome-based systemic drug delivery system. The glutamic acid-based lipids; 1,5-dihexadecyl N-glutamyl-. l-glutamate (L1) and 1,5-dihexadecyl N,. N-diglutamyl-lysyl-. l-glutamate (L2) were synthesized as a pH-responsive component of liposomes that respond to endosomal pH. The zeta potential of liposomes containing L1 or L2 was positive when the solution pH was below 4.6 or 5.6, respectively, but negative at higher pH values. The pH-responsive liposomes showed improved fusogenic potential to an endosome-mimicking anionic membrane at acidic pH, where the zeta potential of the liposomes was positive. We then prepared doxorubicin (DOX)-encapsulating liposomes containing L1 or L2, and clarified by confocal microscopic studies that the contents were rapidly transferred into both the cytoplasm and nucleus. Release of DOX from the endosomes mediated by the pH-responsive liposomes dramatically inhibited cancer cell growth. The L2-liposomes were slightly more effective than L1-liposomes as a drug delivery system. Intravenously injected L2-liposomes displayed blood persistence comparable to that of conventional phospholipid (PC)-based liposomes. Indeed, the antitumor efficacy of L2-liposomes was higher than that of PC-based liposomes against a xenograft breast cancer tumor in vivo. Thus, the high performance of L2-liposomes results from both efficient intracellular drug delivery and comparable blood persistence in comparison with the conventional PC-based liposomes in vitro and in vivo.

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    KW - Zwitterionic lipid

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