Preparation of Glutathione-Regulated Sorafenib Targeted Nanodrug Delivery System and Its Antihepatocellular Carcinoma Activity

To enhance the therapeutic effect of sorafenib (SOR) on liver cancer, we have developed a targeted nanodrug delivery system with glutathione (GSH) downregulation functionality. The preparation process comprises the synthesis of amino-functionalized mesoporous silica nanoparticles (MSN-NH₂), surface modification with ethacrynic acid (EA), loading of SOR into the pores, and final surface coating with hyaluronic acid (HA) to obtain SOR@MSN-EA@HA (SMEH) nanoparticles. SMEH nanoparticles specifically enter tumor cells via CD₄₄ receptor-mediated endocytosis. EA binds to GSH to consume it, while SOR is slowly released from the pores to exert antitumor effects while inhibiting GSH production. This results in sustained oxidative stress in the cells, thus enhancing the antitumor efficacy. Both <i>in vitro</i> and <i>in vivo</i> antitumor experiments as well as hemolysis tests have demonstrated that SMEH nanoparticles can accurately target liver cancer cells, effectively downregulate GSH concentration, exhibit good antitumor effects, and possess excellent safety, showing great potential in tumor treatment.