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

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. 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). 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. This study is the first report involving that liquid-to-gas transition based SDT has the potential to combat hypoxic tumors.