Ultrasound Trigger Ultrasmall Multifunction Nanobubbles for Thrombus Visual Treatment

CeO₂/MnO_X@UK@PFP, an ultrasmall nanobubble is presented for integration of imaging and therapy by ultrasound trigger, which achieved the visual delivery of thrombolytic drugs and ROS scavenging agents to adjust thrombus microenvironment. Under LIPUS irradiation, CeO₂/MnO_X@UK@PFP is visually delivered to the thrombus site. Compared with other groups, the thrombolysis rate is significantly increased and the ROS at the thrombus site are remarkably reduced.

Abstract

Intravenous injection of thrombolytic drugs is the prevailing strategy for the treatment of thrombotic disease. However, its applications are limited due to hemorrhagic risk and thrombus microenvironment. In pursuit of visualized thrombolysis and inspired by the excessive reactive oxygen species (ROS) and inflammatory factors within the thrombus site, an ultrasmall nanobubble (CeO₂/MnO_X@UK@PFP) for integration of imaging and therapy by low intensity pulse ultrasound (LIPUS) trigger is designed, which achieved the visual delivery of Urokinas (UK) and ROS scavenging agents to adjust thrombus microenvironment. In this study, CeO₂/MnO_X with ROS scavenging activity are prepared and wrapped with UK and perfluoropentane (PFP) by lipid layer, forming a CeO₂/MnO_X@UK@PFP. Under LIPUS, PFP undergoes phase transition from liquid to gas for real-time imaging, meanwhile, CeO₂/MnO_X@UK@PFP is burst to release UK and CeO₂/MnO_X. UK is delivered to the side of the clot avoiding hemorrhagic risk. CeO₂/MnO_X@UK@PFP not only can detect the progression of thrombolytic treatment through ultrasound imaging (US) in real-time but also play an important role in the elimination of excessive ROS at the thrombus microenvironment for protecting endangium. Taken together, the in vitro and in vivo experiments illustrated that CeO₂/MnO_X@UK@PFP displayed excellent efficiency in thrombolysis visual, anti-inflammation, and ROS scavenging.