Effect Of A Novel Drug Delivery System Made Of Oleanolic Acid Formulated Into Multivesicular Liposomes On Hepatocellular Carcinoma In Vitro And In Vivo

Objective: To develop a novel dosage form of multivesicular liposomes for oleanolic acid(OA)to overcome its poor solubility,prolong therapeutic drug levels in the blood,and preliminary demonstrate the inhibition to the L-02,HepG2 and SMMC-7721 cells.The aim of the present study was to explore whether OA-MVLs could inhibit the migration and invasion of HCC cells,suppress the growth of tumor and reduce the toxicity effects.Methods: In this study,we utilized the obtained optimized formulation to prepare OA-MVLs.Subsequently,the human HCC cell lines SMMC-7721 and HepG2 were treated with different doses of OA-MVLs and OA,respectively.Cellular survival,adhesion,migration and invasion in vitro were investigated.Then,chronic toxicity study of OA-MVLs in the sprague dawley rats was evaluated.Finally,the effects of tumor inhibition and survival prolongation of OA-MVLs were investigated in H22 tumor bearing mice.Results: We found that the optimized OA-MVLs significantly decreased the ability of HCC cells to proliferate,adhere,migrate and invade in vitro.Furthermore,OA-MVLs significantly inhibited the survival of HCC cells at 160 μmol/L,but showed no obviousinhibition effect on the cell vitality of normal liver cells.The in vivo toxicity study indicated that medium-dose OA-MVLs showed no toxic effect on the hosts.In addition,OA-MVLs suppressed the growth of murine H22 hepatoma and prolonged the survival of tumor-bearing mice.Conclusions: Our findings indicate that OA-MVLs did inhibit the cell survival,adhesion,invasion and metastasis of HCC cells in vitro,and the growth of tumor in vivo;the medium-dose OA-MVLs is more suitable for cancer therapy.