Effect And Mechanism Of Multi-Targeted Self-Microemulsion Preparation RGO On The Growth Of Hepatocellular Carcinoma

Background: Currently,the treatment for advanced hepatocellular carcinoma(HCC)is extremely limited,urgent need a new liver cancer treatment strategy.Ginsenoside Rg3,ganoderma lucidum polysaccharide,and Oridonin have shown great potential in anti-tumor therapy in previous studies,but low bioavailability and poor solubility seriously hinder their clinical application.How to improve the bioavailability of hydrophobic compounds has become an important focus of drug development.Methods: Cell viability,cell proliferation,cell migration,colony formation,tubule formation,sphere formation,and flow cytometry assay were used to assess the effect of a new drug,RGO-SMEDDS,(self-microemulsifying drug delivery system comprising of Rg3,ganoderma lucidum polysaccharide,and Oridonin)on HCC.Specific anti-tumor mechanisms of RGO-SMEDDS were investigated by western blot,q RT-PCR,and immunohistochemistry.Staining with hematoxylin and eosin were used to assess the effects of RGO-SMEDDS on tumorigenesis and drug toxicity in vivo.Results: We developed a self-microemulsifying drug delivery system(RGO-SMEDDS)for these three plant monomers.Treatment with RGO-SMEDDS resulted in induction of G2/M phase arrest and apoptosis,inhibition of migration and invasion,and suppression of cell proliferation,both in vitro and in vivo.Furthermore,RGO-SMEDDS reshaped immune microenvironments by suppressing the production of immunosuppressive cytokine and M2-polarized macrophages,reduced angiogenesis by down-regulation of vascular endothelial growth factor and its receptor,and attenuated stemness of HCC by inhibiting EGFR/AKT/GSK-3 signaling pathways.In addition to excellent anti-tumor effects,RGO-SMEDDS showed certain safety in acute toxicity tests.Conclusion: RGO-SMEDDS exerted significant anti-tumor effects by reducing angiogenesis,remodeling immune microenvironments,and promoting apoptosis,without obvious toxicities.With these attributes RGO-SMEDDS is a promising therapy for the treatment of hepatocellular carcinoma.