Perfluorohexane-Loaded Polymeric Nanovesicles with Oxygen Supply for Enhanced Sonodynamic Therapy

Sonodynamic therapy (SDT), as a new method of non-invasive tumor treatment developed from photodynamic therapy (PDT), can overcome the disadvantage of poor laser penetration while retaining the function of PDT. However, the lack of efficient sonosensitizer accumulation and the hypoxic environment in tumor sites limited the therapeutic efficacy of SDT. Here, we constructed a highly efficient liquid fluorocarbon-encapsulated polymeric nanovesicle for enhanced sonodynamic efficacy as well as tumor hypoxia relief. This multifunctional nanovesicle was constructed by fluorinated cationic polymer C₉F₁₇-PAsp(DET) with PEG-conjugated protoporphyrin IX (PEG-PpIX) modification, which could yield the simultaneous loading of perfluorohexane (PFH) and oxygen. We found that the PAsp(DET)-PpIX-PEG@PFH nanovesicles could not only generate the reactive oxygen species (ROS) under ultrasound irradiation after intravenous (i.v.) injection but also could generate and prolong the ROS under nanovesicle preparation by ultrasonication in vitro, so-called the ″exogenous ROS", which might result in enhanced cytotoxicity in tumor tissue. Furthermore, oxygen-loaded PAsp(DET)-PpIX-PEG nanovesicles could not only reduce therapeutic resistance by relieving tumor hypoxia but also increase ROS production for enhanced sonodynamic therapy. An in vivo study revealed that the nanovesicles could accumulate in the tumor site after i.v. injection and achieved remarkable tumor growth inhibition in both with and without preloaded oxygen groups, which indicated that the nanovesicle system could efficiently achieve oxygen loading during in vivo circulation and provide a better solution for SDT application.