Hepatocellular carcinoma (HCC) is the 5th most common cancer type and the worldwide’s third cause of cancer-related deaths. Conventional chemotherapy is the only available therapeutic option for non-resectable or metastatic tumors, but it is challenged by high off-target cytotoxicity and the emergence of multidrug resistance by cancer cells. In the current study, we used RNA interference gene therapy (RNAi) by small interfering RNA (siRNA) to knockdown Midkine gene (MK), an overexpressed gene in HCC, which is responsible for anti-apoptotic and chemoresistant functions. We proposed that using such approach in combination with the cytotoxic drug, sorafenib (SOR), would act synergistically to maximize the anticancer activity and reduce the therapeutic dose of the drug.

We designed a novel lipid-based nanocarrier for the co-delivery of SOR and MK-siRNA to HCC cells based on YSK05, a novel pH-responsive lipid synthesized in our laboratory. Nanoparticles were modified with a novel targeting peptide to ensure highly-specific delivery of the payload. The performance of the delivery system and the cargo was evaluated by cytotoxicity and gene knockdown studies. Furthermore, optimization of the different formulation variables maximized the efficiency of the combination and the biotolerability of the nanocarrier. We showed the first proof that MK-siRNA increases the sensitivity of HCC cells to SOR. In addition, our system showed amazing selectivity to HCC cells compared to other cancerous and normal cells.

Our selective and efficient co-delivery system, encapsulating the novel anticancer combination, holds promise as a novel strategy for HCC treatment. We are currently optimizing it for the in vivo application.