Magnetic targeting of oxygen loaded microbubbles for sonodynamic therapy

Previous work has demonstrated that the efficacy of sonodynamic therapy (SDT) can be significantly enhanced by conjugating SDT drugs to oxygen filled microbubbles. For eventual clinical use however, achieving adequate microbubble stability and targeting represents a considerable challenge. This study investigated whether functionalizing microbubbles with magnetic nanoparticles could both improve their longevity and enable localization of the microbubbles to a target site. Phospholipid coated microbubbles containing oxygen and 50 nm spherical magnetite particles were produced by sonication and conjugated to the SDT drug Rose Bengal via an Avidin-Biotin linker. The addition of the nanoparticles was found to substantially enhance the stability of the microbubbles to changes in size and concentration. Orthotopic tumors were induced in BALB/c SCID mice using the BxPc-3 human pancreatic cell line and exposed to ultrasound for 3.5 min (3.5 Wcm-2 at 1 MHz center frequency, 100 Hz pulse repetition frequency, and 30% duty cycle) following intravenous injection of the microbubbles with or without application of a 0.1 T magnetic field. 38 days postimplantation the tumors treated with both ultrasound and the magnet were 50% smaller than the control tumors and exhibited a threefold increase in active caspase as a marker of apoptosis. There was no statistically significant effect of ultrasound alone.