Low Intensity Focused Ultrasound Ignited “Deep-Penetration Nanobomb” (DPNB) for Tetramodal Imaging Guided Hypoxia-Tolerant Sonodynamic Therapy Against Hypoxic Tumors

Background: Sonodynamic therapy (SDT) has been regarded as a novel therapeutic modality for killing tumors. However, the hypoxic tumor microenvironment, especially deep-seated tumors distant from blood vessels, severely restricts therapeutic efficacy due to the oxygen-dependent manner of SDT. Methods: Herein, we report a novel ultrasonic cavitation effect-based therapeutic modality that is able to facilitate the hypoxia-tolerant SDT for inducing hypoxic tumor death. A tLyP-1 functionalized liposomes is fabricated, composed of hematoporphyrin monomethyl ether gadolinium as the sonosentizer and perfluoropentane (PFP) as the acoustic environment regulator. Moreover, the tLyP-1 functioned liposomes could achieve active tumor homing and effective deep-penetrating into hypoxic tumors. Upon low intensity focused ultrasound (LIFU) irradiation, the acoustic droplet vaporization effect of PFP induced fast liquid-to-gas transition and quick bubbles explosion to generate hydroxyl radicals, efficiently promoting cell death in both normoxic and hypoxic microenvironment (acting as deep-penetration nanobomb, DPNB). Results: The loading of PFP is proved to significantly enhance the therapeutic efficacy of hypoxic tumors. In particular, these DPNB can also act as ultrasound, photoacoustic, magnetic resonance, and near-infrared fluorescence tetramodal imaging agents for guiding the therapeutic process. Conclusion: This study is the first report involving that liquid-to-gas transition based SDT has the potential to combat hypoxic tumors.