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

Abstract

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.

CD44-targeted hyaluronic acid–curcumin reverses chemotherapeutics resistance by inhibiting P-gp and anti-apoptotic pathways

“…38,39 Combination therapy is increasingly used to treat cancer. 40 Recently, many studies have used nano-delivery systems to codeliver chemotherapeutics and chemosensitizers for tumor therapy. Wang et al revealed that the co-delivery of DOX and CUR polymeric micelles can improve anti-tumor efficacy.…”

Nanogel: A Versatile Nano-Delivery System for Biomedical Applications

“…Nanogels provide a platform for drug codelivery, which is attributed to their 3D network structure for incorporating with both hydrophilic and hydrophobic compounds. In a recent study, both glycyrrhizin (GL) and DOX were encapsulated into alginate (ALG) nanogel particles via the phase inversion temperature emulsification method; the obtained drug-loaded alginate nanogels (DOX/GL-ALG NGPs) exhibited not only the hepatocellular carcinoma targeting property by GL, but also the synergistic antitumor effects of GL and DOX ( Figure 9) [107]. In addition, ALG nanogels also presented favorable biocompatibility and low toxicity to hepatic tissues by controlled drug release [108].…”

Using Traditional Chinese Medicine to Treat Hepatocellular Carcinoma by Targeting Tumor Immunity

“…In HCC, TAM and Kupffer cells are characteristic immunosuppressive factors that mediate tumor evasion; the abundance of these cells is a negative biomarker for HCC prognosis. Wang et al [43] found that the intravenous administration of glycyrrhizin regulated the Bax/Bcl-2 ratio and caspase-3 activity, leading to Kupffer cell inactivation. Tumor immunity is consequently enhanced by the attenuation of the suppressive function of Kupffer cells and TAMs.…”