Hepatocellular carcinoma (HCC) is the fifth most common malignancy type around the world. The current study aimed at the design of a novel smart liposome for efficient and highly-specific co-delivery of the cytotoxic drug, Sorafenib (SOR), and a small interfering RNA against Midkine gene (MK-siRNA) to HCC cells. SOR is a multiple kinase inhibitor approved as the drug of choice for resistant HCC, but it is limited by its non-selective cytotoxicity and liability for the emergence of chemoresistance. Midkine is a growth cytokine overexpressed in HCC cells with several malignant functions including resistance to apoptosis.
YSK05, a novel smart pH-sensitive cationic lipid synthesized in our laboratory, was selected as the main lipid for the formulation of the co-delivery liposome and showed superior efficiency over other investigated lipids in terms of both chemotherapy and gene therapy. Optimization of various formulation variables improved the efficiency and biosafety of the liposome. Furthermore, the introduction of a novel targeting peptide, SP94, imparted high selectivity to hepatic cancer cells with a minimal effect on normal hepatocytes. Selectivity was confirmed in terms of cellular uptake, cytotoxicity and gene knockdown activities. Moreover, we showed the first evidence for synergism between SOR and MK-siRNA via the increase of HCC cell sensitivity to SOR by MK-siRNA. In addition, our liposome showed a pH-sensitive controlled release pattern of SOR which secures prolonged action and minimizes off-target cytotoxicity. It can be concluded that the SP94-modified smart liposome is a promising co-delivery system for the targeted combinational treatment of HCC.