Co-delivery of glycyrrhizin and doxorubicin by alginate nanogel particles attenuates the activation of macrophage and enhances the therapeutic efficacy for hepatocellular carcinoma

Theranostics. 2019 Aug 14;9(21):6239-6255. doi: 10.7150/thno.35972. eCollection 2019.


Nanocarrier drug delivery systems (NDDS) have been paid more attention over conventional drug delivery system for cancer therapy. However, the efficacy is hampered by the fast clearance of activated macrophage from the blood circulation system. In this study, glycyrrhizin (GL) was introduced into alginate (ALG) nanogel particles (NGPs) to construct multifunctional delivery vehicle to decrease the fast clearance of activated macrophage and enhance the anticancer efficacy with the combination therapy of GL and doxorubicin (DOX). Methods: We firstly synthesized the GL-ALG NGPs with intermolecular hydrogen bond and ionic bond as the multifunctional delivery vehicle. The immune response and phagocytosis of macrophage on GL-ALG NGPs were investigated on RAW 264.7 macrophages. The pharmacokinetic study of DOX loaded in GL-ALG NGPs was performed in rats. The active targeting effects of GL-ALG NGPs were further studied on hepatocellular carcinoma cell (HepG2) and H22 tumor-bearing mice. Moreover, the anticancer molecular mechanism of DOX/GL-ALG NGPs was investigated on HepG2 cells in vitro and tumor-bearing mice in vivo. Results: GL-ALG NGPs could not only avoid triggering the immuno-inflammatory responses of macrophages but also decreasing the phagocytosis of macrophage. The bioavailability of DOX was increased about 13.2 times by DOX/GL-ALG NGPs than free DOX in blood. The mice with normal immune functions used in constructing the tumor-bearing mice instead of the nude mouse also indicated the good biocompatibility of NGPs. GL-mediated ALG NGPs exhibited excellent hepatocellular carcinoma targeting effect in vitro and in vivo. The results suggested that the anticancer molecular mechanism of the combination therapy of glycyrrhizin and doxorubicin in ALG NGPs was performed via regulating apoptosis pathway of Bax/Bcl-2 ratio and caspase-3 activity, which was also verified in H22 tumor-bearing mice. Conclusion: DOX/GL-ALG NGPs could attenuate the activation of macrophage and enhance the therapeutic efficacy for hepatocellular carcinoma. Our results suggest that the combination therapy would provide a new strategy for liver cancer treatment.

Keywords: Alginate; Combination therapy; Glycyrrhizin; Macrophage; Nanogel particles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alginates / administration & dosage
  • Animals
  • Carcinoma, Hepatocellular / drug therapy*
  • Doxorubicin / administration & dosage*
  • Doxorubicin / chemistry
  • Doxorubicin / pharmacokinetics
  • Drug Delivery Systems*
  • Drug Therapy, Combination
  • Glycyrrhizic Acid / administration & dosage*
  • Glycyrrhizic Acid / chemistry
  • Glycyrrhizic Acid / pharmacokinetics
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / drug therapy*
  • Macrophages / drug effects
  • Male
  • Mice
  • Mice, Nude
  • Nanogels / administration & dosage*
  • RAW 264.7 Cells
  • Rats, Sprague-Dawley
  • Tissue Distribution


  • Alginates
  • Nanogels
  • Glycyrrhizic Acid
  • Doxorubicin