Ultrasound induced phase-transition and invisible nanobomb for imaging-guided tumor sonodynamic therapy

Sonodynamic therapy (SDT) kills tumor cells by converting molecular oxygen (O2) into reactive oxygen species (ROS) using sonosensitizers and appropriate ultrasound (US) stimulation. However, pre-existing tumorous hypoxia severely limits SDT efficacy. Worse is that O2 consumption during SDT will aggravate local hypoxia. In this study, we developed an O2 self-supplied and lossless US-responsive detonation strategy to overcome the above limitation. This explores a perfluorohexane (PFH) bubbling-based “stealth camouflage” and a US-controlled on-demand system (RBC-HPBs/HMME/PFH) to realize US imaging-guided precise drug delivery and locally positioning tumor therapy. Compared with HPBs/HMME/PFH, the results showed that RBC encapsulation can promote cell phagocytosis. After US stimulation, the PFH phase change induced RBC instantaneous blasting. Simultaneous release of HMME and O2 resulted in plenty of ROS production and the intracellular redox system imbalance, significantly enhancing their cytotoxicity. Following US imaging guidance, the greatly improved local ROS level and the anti-tumor effect were proved in 4T1 tumor-bearing mice for HMME and the O2 synchronous co-transport system. Immunohistochemistry results proved that RBC-HPBs/HMME/PFH + US could significantly relieve tumorous hypoxia and reduce the microvessel density as an O2 reservoir, which would block nutritional sources to starve tumor cells and inhibit their metastasis, achieving a cancer multi-mechanism treatment.