Oxygen-sufficient lipid nanobubbles combined with UTMD for enhanced sonodynamic therapy of Hep-G2 cells.

Sonodynamic therapy (SDT) is an emerging noninvasive therapeutic approach, which could penetrate deep-seated tissues and activate sonosensitizer to produce cytotoxic reactive oxygen species (ROS). Nevertheless, the hypoxic tumor microenvironment significantly limits the efficiency of SDT due to its oxygen-consumption treatment principle. To break hypoxia-induced resistance and improve the efficacy of SDT, we developed shell-core structured oxygen-sufficient nanobubbles(NBs), which were designed with a lipid shell loaded the sonosensitizer IR780 and a gas core loaded with oxygen. With the aid of ultrasound-targeted microbubble destruction (UTMD), IR780@O NBs not only make sonosensitizers more effectively enriched at the tumor site in a controlled manner, but also directly mediate oxygen release and provide sufficient oxygen for producing more ROS to induce cell apoptosis. Thus, IR780@O NBs can efficiently inhibit the proliferation of Hep-G2 cells under ultrasound exposure. What is more, IR780@O NBs have a potential for contrast enhanced ultrasound (CEUS) imaging. We believe that our oxygen-sufficient NBs trigged by UTMD could be an ideal therapeutic and imaging system for hepatocellular carcinoma.