Dual-ligand-modified cantharidin nanoparticles for the treatment of hepatocellular carcinoma via the inhibition of EphB4

In this study, we aimed to construct novel dual-ligand-modified cantharidin (CTD)-loaded solid lipid nanoparticles (GA-FA-CSLNs) for the targeted therapy of hepatocellular carcinoma. This design leverages the hepatocyte-targeting property of 18-GA-Suc (GA) and the long-circulation characteristic of FA-PEG3500-DSPE (FA). Nanoparticles were prepared via the emulsification-ultrasonic method and characterized. GA-FA-CSLNs not only exhibited excellent tumor-targeting ability but also markedly enhanced CTD’s inhibitory effect on Huh-7 cells and promoted Huh-7 cell apoptosis. In vivo experiments showed that GA-FA-CSLNs significantly inhibited tumor growth, downregulated the expression of EphB4 and Bcl-2 proteins, and upregulated the expression of caspase 3 and Bax proteins—thus suppressing tumor cell proliferation and inducing tumor cell apoptosis—with favorable in vivo safety. Pharmacokinetic studies revealed that GA-FA-CSLNs exhibited prolonged in vivo circulation time and improved bioavailability. Collectively, GA-FA-CSLNs emerge as a promising actively targeted nanocarrier system that enhances the specificity and efficacy of CTD while reducing its adverse effects, providing a potential strategy for the targeted therapy of HCC.