Ceramide-Fabricated Co-Loaded Liposomes for the Synergistic Treatment of Hepatocellular Carcinoma
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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.
KEY WORDShepatocellular carcinoma co-delivery sorafenib ceramide liposomes
We are very thankful for Dr. Livesey David Olerile (School of Pharmaceutical Sciences, Shandong University) for modifying the English language of this manuscript.
This work was partially funded by the National Natural Science Foundation of China (no. 81573368) and the Science and Technology Development Project of Shandong Province (2014GGE27121).
Compliance with Ethical Standards
All of the animal experiments were performed with the approval of Institutional Animal Care and Use Committee of Shandong University and in compliance with the Animal Management Rules of Ministry of Health of the People's Republic of China (document number 55, 2001).
The authors declare that they have no conflicts of interest in this work.
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