Development of ultrasound-responsive biogenic gas vesicles as multifunctional theranostic carriers for enhanced cancer therapy

Abstract

Nanobubbles, as a kind of special nanoparticles, have been investigated as theranostic particles in cancer nanomedicine. Despite the huge potential of nanobubbles for ultrasonic molecular imaging as well as nanocarrier for gas and drug delivery for tumor therapy, stabilization is still a big limitation of nanobubbles that could affect their function. Gas vesicles (GVs), as a novel kind of nanoparticle, which are naturally occurring gas-filled microcavities, have been demonstrated as the first biomolecular acoustic reporters with gene editability and inherent stability. Here, the theranostic potential of GVs for cancer treatment is investigated in this study. First, we explored the potential of GVs for tumor imaging. However, this ability is limited by the quick clearance of GVs by the reticuloendothelial system (RES) in vivo. Thus, we developed PEGylated HA-GVs (PH-GVs) for in-tumor molecular ultrasound imaging by integrating polyethylene glycol (PEG) and hyaluronic acid (HA) in GV shells. PH-GVs were demonstrated to be able to escape the clearance from the RES and to penetrate tumor vasculature. Further, PH-GVs produced strong ultrasound contrast in the tumor site in vivo, with no obvious side-effects detected following intravenous injection. Thus, we demonstrate the potential of PH-GVs as novel, nanosized and targeted UCAs for efficient and specific molecular tumor imaging. Next, the application of PH-GVs on sonodynamic therapy was further investigated. Sonodynamic therapy (SDT) is a promising alternative treatment method for cancer. Nanometer-sized GVs have the potential to be a kind of nanosized agent for enhanced cavitation during SDT. Here, the existence of GVs could enhance the production of ROS in the solution, was demonstrated. Besides, GVs were confirmed to be able to enhance SDT both in vitro and in vivo. Thus, we demonstrated that GVs could function as a kind of targeted nanosized agent for enhanced SDT against cancer. GVs, as natural gas-filled bubbles, have the potential to be oxygen carriers for tumor therapy. Tumor hypoxia is believed to be a factor limiting successful outcomes of oxygen-consuming cancer therapy, thereby reducing patient survival. In this study, we also explored the potential of biogenic GVs as a new kind of oxygen carrier to alleviate tumor hypoxia. GVs were modified on the surface of their protein shells by a layer of liposome. A substantial improvement of oxygen concentration was observed in subcutaneous tumors when lipid-GVs(O2) were tail-injected. Significant enhancement of tumor cell apoptosis and necrosis was also observed during photodynamic therapy (PDT) in the presence of lipid-GVs(O2) both in vitro and in vivo. In conclusion, lipid-GVs exhibited promising performance for intravenous gas delivery, enhanced PDT efficacy and low toxicity, a quality that may be applied to alleviate hypoxia in cancers, as well as hypoxia-related clinical treatments. In all, we demonstrate the potential of GVs as novel, nanosized agents for efficient and specific molecular tumor imaging, enhanced SDT as well as oxygen carrier for enhanced PDT, paving the way for the application of GVs in precise and personalized medicine.