Polymer-coated pH-responsive high-density lipoproteins

J Control Release. 2016 Apr 28;228:132-140. doi: 10.1016/j.jconrel.2016.03.005. Epub 2016 Mar 6.


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.

Keywords: Anticancer drug delivery; Endosomal escape; Internalization; Membranolytic polymer; Mildly acidic pH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Curcumin / administration & dosage
  • Curcumin / pharmacokinetics
  • Curcumin / pharmacology
  • Delayed-Action Preparations / chemistry*
  • Doxorubicin / administration & dosage
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / pharmacology
  • Endosomes / metabolism
  • Fatty Acids, Monounsaturated / chemistry*
  • Humans
  • Hydrogen-Ion Concentration
  • Lipoproteins, HDL / chemistry*
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Polyethylene Glycols / chemistry
  • Polymethacrylic Acids / chemistry*
  • Quaternary Ammonium Compounds / chemistry*
  • Recombinant Fusion Proteins / chemistry


  • Antineoplastic Agents
  • Delayed-Action Preparations
  • Fatty Acids, Monounsaturated
  • Lipoproteins, HDL
  • Polymethacrylic Acids
  • Quaternary Ammonium Compounds
  • Recombinant Fusion Proteins
  • Polyethylene Glycols
  • Doxorubicin
  • Curcumin
  • 1,2-dioleoyloxy-3-(trimethylammonium)propane