title: Polymer-coated pH-responsive high-density lipoproteins.
abstract: Intracellular drug delivery by nanoparticles is often hampered by their endosomal entrapment followed by their degradation in the lysosomal compartment and/or exocytosis. Here, we show that internalization and endosomal escape of cargoes in a cationized natural nanocarrier, high-density lipoprotein (HDL), can be controlled in a pH-dependent manner through stable complexation with a membranolytic anionic block polymer. A genetically and chemically cationized form of HDL (catHDL) is prepared for the first time by both genetic fusion with YGRKKRRQRRR peptide and incorporation of 1,2-dioleoyloxy-3-(trimethylammonium)propane. Upon addition of poly(ethylene glycol)-block-poly(propyl methacrylate-co-methacrylic acid) (PA), catHDL yields inhibition of internalization at neutral pH and its subsequent recovery at mildly acidic pH. catHDL forms a stable discoidal-shape complex with PA (catHDL/PA) (ca. 50 nm in diameter), even in the presence of serum. Significant enhancement of endosomal escape of a catHDL component is observed after a 1-h treatment of human cancer cells with catHDL/PA. Doxorubicin and curcumin, fluorescent anti-cancer drugs, encapsulated into catHDL/PA are also translocated outside of endosomes, compared with that into catHDL, and their cytotoxicities are enhanced inside the cells. These data suggest that catHDL/PA may have a potential benefit to improve the cellular delivery and endosomal escape of therapeutics under mildly acidic conditions such as in tumor tissues.
authors.affiliation: Institute for Integrated Cell-Material Science (WPI-iCeMS), Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Hyungjin
authors.initials: H
authors.lastname: Kim
authors.affiliation: Institute for Integrated Cell-Material Science (WPI-iCeMS), Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Okamoto
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland.
authors.forename: Arnaud E
authors.initials: AE
authors.lastname: Felber
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Polomska
authors.affiliation: Institute for Integrated Cell-Material Science (WPI-iCeMS), Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Morone
authors.affiliation: Institute for Integrated Cell-Material Science (WPI-iCeMS), Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: John E
authors.initials: JE
authors.lastname: Heuser
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Leroux
authors.affiliation: Institute for Integrated Cell-Material Science (WPI-iCeMS), Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: murakami@icems.kyoto-u.ac.jp.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Murakami
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D003474:Curcumin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D011992:Endosomes / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008075:Lipoproteins, HDL / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D011109:Polymethacrylic Acids / Q000737:chemistry*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*; D011993:Recombinant Fusion Proteins / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D005229:Fatty Acids, Monounsaturated; D008075:Lipoproteins, HDL; D011109:Polymethacrylic Acids; D000644:Quaternary Ammonium Compounds; D011993:Recombinant Fusion Proteins; D011092:Polyethylene Glycols; D004317:Doxorubicin; D003474:Curcumin; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane
keywords: Anticancer drug delivery; Endosomal escape; Internalization; Membranolytic polymer; Mildly acidic pH