pH-Responsive Hyaluronic Acid-Based Mixed Micelles for the Hepatoma-Targeting Delivery of Doxorubicin

Int J Mol Sci. 2016 Mar 30;17(4):364. doi: 10.3390/ijms17040364.


The tumor targetability and stimulus responsivity of drug delivery systems are crucial in cancer diagnosis and treatment. In this study, hepatoma-targeting mixed micelles composed of a hyaluronic acid-glycyrrhetinic acid conjugate and a hyaluronic acid-l-histidine conjugate (HA-GA/HA-His) were prepared through ultrasonic dispersion. The formation and characterization of the mixed micelles were confirmed via ¹H-NMR, particle size, and ζ potential measurements. The in vitro cellular uptake of the micelles was evaluated using human liver carcinoma (HepG2) cells. The antitumor effect of doxorubicin (DOX)-loaded micelles was investigated in vitro and in vivo. Results indicated that the DOX-loaded HA-GA/HA-His micelles showed a pH-dependent controlled release and were remarkably absorbed by HepG2 cells. Compared with free DOX, the DOX-loaded HA-GA/HA-His micelles showed a higher cytotoxicity to HepG2 cells. Moreover, the micelles effectively inhibited tumor growth in H22 cell-bearing mice. These results suggest that the HA-GA/HA-His mixed micelles are a good candidate for drug delivery in the prevention and treatment of hepatocarcinoma.

Keywords: glycyrrhetinic acid; hepatoma-targeting; hyaluronic acid; micelle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / administration & dosage
  • Antibiotics, Antineoplastic / chemistry*
  • Antibiotics, Antineoplastic / pharmacology
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / pathology
  • Cell Survival / drug effects
  • Doxorubicin / administration & dosage
  • Doxorubicin / chemistry*
  • Doxorubicin / pharmacology
  • Drug Carriers / chemistry*
  • Female
  • Hep G2 Cells
  • Histidine / chemistry
  • Humans
  • Hyaluronic Acid / chemistry*
  • Hydrogen-Ion Concentration
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / pathology
  • Magnetic Resonance Spectroscopy
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Micelles*
  • Microscopy, Electron, Transmission
  • Particle Size
  • Transplantation, Heterologous


  • Antibiotics, Antineoplastic
  • Drug Carriers
  • Micelles
  • Histidine
  • Doxorubicin
  • Hyaluronic Acid