A multifunctional nanoparticle system combines sonodynamic therapy and chemotherapy to treat hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common and deadly malignancies worldwide. To date, the survival of patients with HCC has not improved because of the insensitivity of HCC to conventional treatments. Sonodynamic therapy (SDT) is a promising new approach that shows remarkable potential in the treatment of HCC. Here, we designed a simple, biocompatible, and multifunctional nanosystem that combines SDT and chemotherapy to treat HCC. This nanosystem, called HPDF nanoparticles, had a core–shell structure in which hematoporphyrin (HP) was complexed with doxorubicin (DOX) to form the hydrophobic core and the surface was coated with Pluronic F68 to form the hydrophilic shell. In HCC cells, HPDF nanoparticles in combination with ultrasonic irradiation (1.0 MHz, 1.5 W/cm2, 30 s) exhibited potent cytotoxicity, resulting from the synergistic effects of a large amount of reactive oxygen species generated from HP and DOX-induced DNA damage. Notably, HPDF nanoparticles in combination with ultrasonic irradiation significantly reversed drug resistance in Nanog-positive cancer stem cells (CSCs) in HCC. In nude mice bearing HCC tumors, HPDF nanoparticles efficiently accumulated in the tumors and reached the maximum levels within 6‒8 h, post intravenous injection. HPDF nanoparticles, in combination with ultrasonic irradiation (1.0 MHz, 3 W/cm2, 5 min), suppressed tumor growth, angiogenesis, and collagen deposition, considerably. In summary, our results show that HPDF nanoparticles can effectively combine SDT and chemotherapy to inhibit HCC growth and progression through multiple mechanisms in both cellular and animal models.