Apatinib-loaded lipid nanobubbles combined with ultrasound-targeted nanobubble destruction for synergistic treatment of HepG2 cells in vitro

摘要

Purpose: Apatinib, an oral small-molecule antiangiogenetic medicine, is used to treat patients with advanced hepatocellular carcinoma. However, its systemic toxic side effects cannot be ignored. The ultrasound (US)-targeted nanobubble destruction technology can minimize systemic drug exposure and maximize therapeutic efficacy. The aim of this study was to develop novel GPC3-targeted and drug-loaded nanobubbles (NBs) and further assess the associated therapeutic effects on hepatocellular carcinoma cells in vitro. Materials and methods: Apatinib-loaded NBs were prepared by a mechanical vibration method. GPC3, a liver tumor homing peptide, was coated onto the surface of apatinib-loaded NBs through biotin–avidin interactions to target liver cancer HepG2 cells. The effects of different treatment groups on cell proliferation, cell cycle, and apoptosis of HepG2 cells were tested. Results: The NBs could achieve 68% of optimal drug encapsulation. In addition, ligand binding assays demonstrated that attachment of targeted NBs to human HepG2 liver cancer cells was highly efficient. Furthermore, cell proliferation assays indicated that the antiproliferative activities of GPC3-targeted and apatinib-loaded NBs in combination with US (1 MHz, 1 W/cm2, 30 s) were, respectively, 44.11%±2.84%, 57.09%±6.38%, and 67.51%±2.89% after 24, 48, and 72 h of treatment. Treatment with GPC3-targeted and apatinib-loaded NBs also resulted in a higher proportion of cells in the G1 phase compared with other treatment groups such as apatinib only and nontargeted apatinib-loaded NBs when US was utilized. Conclusion: US-targeted and drug-loaded nanobubble destruction successfully achieved selective growth inhibition and apoptosis in HepG2 cells in vitro. Therefore, GPC3-targeted and apatinib-loaded NBs can be considered a novel chemotherapeutic approach for treating liver cancer in combination with US.