Synergistic effect of Linggui Zhugan Decoction combined with matrix metalloproteinases enzyme-responsive doxorubicin stepwise targeting liposomes on primary liver cancer
KONG Liang
CAO Hui-min
GUO Rui-bo
ZHANG Lu
LI Xue-tao
JIA Lian-qun
Abstract：Objective:To investigate the synergistic effect of Linggui Zhugan Decoction combined with matrix metalloproteinases(MMP)and doxorubicin(DOX)targeting liposomes on primary liver cancer.Methods:HepG2 cells were used to build cell model in vitro.Synergistic index of Linggui Zhugan Decoction combined with MMP enzyme-responsive DOX targeting liposomes was analyzed by SynergyFinder software.Fifty 3-week-old SPF C57BL/6 mice were randomly divided into 2 groups:blank control group(n=10)and modeling group(n=40).A mouse model of primary liver cancer was established by intraperitoneal injection of diethylnitrosamine(DEN)combined with a high-fat diet.Subsequently,the mice were divided into model group,Linggui Zhugan group(LGZGT),liposomes group(Lip)and combined treatment group(LGZGT+Lip).Mice in each treatment group were given LGZGT by gavage,Lip by intraperitoneal injection,and the mice in the other groups were given equal amount of normal saline for 8 weeks.The body weight and liver index of mice were recorded.The levels of alpha-fetoprotein(AFP)and carcinoembryonic antigen(CEA),the activities of aspartate aminotransferase(AST),alanine aminotransferase(ALT),γ-glutamyl transferase(γ-GT),and alkaline phosphatase(AKP),the pathological changes of liver were observed by HE staining and Masson staining.The proliferation and apoptosis of tumor cells were observed by immunohistochemical staining and TUNEL staining.Results:The results of synergistic index showed that the ZIP value of the two drugs combined intervention was 2.697,indicating synergistic effect.In vivo pharmacodynamic results showed that LGZGT,Lip and LGZGT+Lip intervention can reduce liver index,expression levels of AFP and CEA,activities of ALT,AKP,AST,and γ-GT,ameliorate liver pathological injury and liver fibrosis,inhibit the proliferation of liver cancer cells and promote apoptosis of liver cancer cells.It turns out that LGZGT+Lip has the strongest intervention ability.Conclusion:Linggui Zhugan Decoction combined with MMP-responsive DOX stepwise targeting liposomes in the treatment of primary liver cancer has a synergistic effect,providing a new idea for the clinical treatment of primary liver cancer.
Keywords：Linggui Zhugan Decoctionmatrix metalloproteinasesdoxorubicinstepwise targeting liposomesprimary liver cancersynergistic effect
Publication Date：2024-06-15
Online Publishing Date：2026-08-14(First online date of this platform, not the publication date of the document)
Pages：9( 1155-1163 )