Silibinin-ConjugatedGalactose Dendrimers for TargetedTreatment of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains one of the most prevalent and lethal forms of liver cancer, contributing significantly to global cancer-related mortality. Conventional treatments, including surgical resection, liver transplantation, and systemic therapies such as multikinase inhibitors and immune checkpoint inhibitors, often face limitations such as systemic toxicity and drug resistance, emphasizing the urgent need for more effective therapeutic strategies. In this study, we developed a galactose-functionalized dendrimer (Gal24) conjugated with a natural flavonoid, silibinin, (Gal24-Sil), for HCC therapy. In our previous study, we developed a Gal24 dendrimer to target hepatocytes <i>in vivo</i>. Here, we further demonstrated that the conjugation of silibinin to Gal24 dendrimer platform significantly enhanced its solubility and efficacy. <i>In vitro</i> studies demonstrated that Gal24-Sil conjugates significantly improved the anticancer efficacy of silibinin in HepG2 and Hep3B liver cancer cells. The conjugate induced an inflammatory response and reactive oxygen species (ROS) generation, triggering cellular apoptosis and necrosis. Furthermore, Gal24-Sil effectively reduced cell proliferation by promoting mitochondrial membrane potential (MMP) depolarization and inducing DNA damage. Our findings demonstrate the potential of Gal24-Sil as a promising nanoplatform for HCC therapy, offering enhanced therapeutic efficacy over free Silibinin. This study highlights the broader applicability of the Gal24 dendrimer platform for addressing various liver diseases.