Molecular Sonosensitizer-Loaded Polymer Nanomicelle for Ultrasound-Based Cell Therapy via Singlet Oxygen Generation

Ultrasound-based sonodynamic therapy has great potential for the wireless treatment of human diseases that exploit sound-responsive materials such as microbubbles, piezoelectric nanoparticles, and molecular sonosensitizers. Although small molecule-based sonosensitizers are attractive, their performance needs significant improvement, and a clear understanding of the origin of the ultrasound-mediated reactive oxygen species (ROS) generation property is yet to be established. Here, we have investigated molecular sonosensitizer-loaded poly(ethylene glycol)–poly(lactide) (PEG–PLA) micelles to investigate their ROS generation performance in the presence of ultrasound. We found that molecular sonosensitizers produce singlet oxygen as the primary ROS component, and the ROS generation performance depends on the molecular structure and experimental conditions. We propose that sonoluminescence-induced molecular excitation is associated with such ROS generation. The nanocarrier-based cell delivery of a molecular sonosensitizer is shown to generate intracellular ROS under ultrasound exposure and has been used for cell therapy application. This work shows that singlet oxygen is primarily responsible for molecular sonosensitizer-based sonodynamic therapy, and a nanomicelle-based carrier can greatly improve this therapeutic performance.