Ceramide-Fabricated Co-Loaded Liposomes for the Synergistic Treatment of Hepatocellular Carcinoma.

Combination therapy is one of the important methods to improve therapeutic effect on the treatment of hepatocellular carcinoma (HCC). Sorafenib (SF) is a canonical US Food and Drug Administration-approved multikinase molecule inhibitor against HCC. However, therapeutic benefit with Sorafenib alone was usually unsatisfactory. Ceramide (CE) is an endogenous bioactive sphingolipid, which has a strong potential to suppress various tumors. The combination of SF and CE was hoping to exert maximum synergistic antitumor effect through different tumor-suppressible mechanisms. In this respect, SF and CE co-loaded liposomes (SF/CE-liposomes) were developed to verify synergistic antitumor efficacy. The optimal molar ratio of SF and CE was determined through combination index. SF/CE-liposomes were prepared by thin-film hydration method, which exhibited spherical or ellipsoidal shape. Particle size of SF/CE-liposomes was 174 ± 4 nm with homogeneous distribution. Release profile of SF demonstrated that addition of CE imposed no significant impact on the release of SF. SF/CE-liposomes exhibited acceptable stability in different media and desirable storage stability over 30 days at 4°C. In vitro cellular uptake confirmed that SF/CE-liposomes could be efficiently internalized into HepG2 cells. In vitro cytotoxicity evaluation indicated that SF/CE-liposomes exhibited higher cytotoxicity on HepG2 cells. IC50 value of SF/CE-liposomes was 11.5 ± 0.44 μM, which was significantly lower than that of SF-liposomes (**p < 0.01). Evaluation of in vivo synergistic effect on H22-bearing mice verified that SF/CE-liposomes achieved robust antitumor activity in preventing tumor growth. All results suggested that SF/CE-liposomes might be served as an efficient co-delivery system for improving therapeutic efficacy of HCC.