The Synergistic Effects of Multidrug‐Loaded Nanocarriers Improve Tumor Microenvironment Responsive Chemo‐Sonodynamic Therapy of Hepatocellular Carcinoma

Abstract Chemotherapy works synergistically with sonodynamic therapy in a multi‐functional system and is employed to improve the therapeutic outcomes of hepatocellular carcinoma. In this study, ultrasound‐responsive multi‐functional nanoparticles (USFNPs) are loaded with dual drugs, doxorubicin, and a composite ultrasound‐sensitive agent, curcumin‐gold. The USFNPs are modified with an acid‐hydrolyzable polyethylene glycol outermost layer, making it stable in blood and normal tissues while peeling off in the acidic tumor microenvironment. The USFNPs have high specificity to liver tumor cells (Hepa 1–6 cells); can escape from lysosomes following endocytosis, and exhibit better biocompatibility. Moreover, the carriers enhance the nuclear delivery of the drugs and inhibit p‐glycoprotein (P‐gp) expression of Hepa 1–6 cells. In cancer cells, carriers convert hydrogen peroxide into oxygen, improving the hypoxic microenvironment and generating abundant superoxide anion and hydroxyl radicals. Confocal laser scanning microscopy, 1 H nuclear magnetic resonance, flow cytometry, cytotoxicity, acute toxicity assays, and Western blot analysis are used to demonstrate the results. The findings suggest USFNPs as novel and potential antitumor agents for treating hepatocellular carcinoma.