Enhanced Apoptosis in Hepatocellular Carcinoma via Nanoscale Liposomal Codelivery of Ginsenoside CK and Sorafenib

Hepatocellular carcinoma (HCC) cells have low absorption efficiency of sorafenib and are prone to developing drug resistance, resulting in poor treatment efficacy. This study developed an oral liposomal codelivery system (Lipo-CK-SOR) that can simultaneously encapsulate both CK and sorafenib, enhancing the bioavailability and synergistic antitumor efficacy of sorafenib. Transmission electron microscopy analysis shows that well-dispersed spherical liposomes have a smooth surface with an average diameter of 88.99 nm and a ζ potential of −25.9 mV. These favorable nanoscale characteristics contribute not only to the colloidal stability of the formulation but also to its efficient utilization of the enhanced permeability and retention effect, thereby promoting selective accumulation in tumor tissues. After optimization, the encapsulation efficiencies could reach 87% for CK and 83% for SOR, respectively. The additional deoxycholic acid shell coating enabled a sustained control release of both drugs in simulated gastrointestinal fluids. The release amounts of CK and sorafenib in 48 h were 91 and 92%, respectively, effectively preventing premature drug leakage caused by the rupture of ordinary liposomes under acidic conditions. Fluorescence imaging confirmed that Lipo-CK-SOR can be successfully taken up by HepG2 cells. Moreover, compared to free CK, sorafenib, and their physical mixture, Lipo-CK-SOR not only enhanced cellular drug uptake but also significantly strengthened its inhibitory effect on HepG2 cell proliferation and invasion, while promoting cell apoptosis, indicating that liposome encapsulation significantly improved the synergistic antitumor effect of the two drugs, which is mechanistically supported by CK-mediated precise inhibition of the sorafenib-induced compensatory PI3K/Akt pathway activation revealed in Western blot experiments. This study presents a promising oral strategy to overcome sorafenib resistance and enhance therapeutic synergy in HCC, and contribute to the advancement of nanomedicine and oncology.