Dual-frequency ultrasound-mediated delivery of rapamycin from microbubbles decreases drug dose needed to reduce neointima formation in vivo

Ultrasound-mediated drug delivery from microbubbles has been investigated as an alternative therapy for hyper-proliferation of cells connected to the process of restenosis (re-occlusion of blood vessels). In this study, rats underwent arterial balloon injury to induce neointima formation - a hyper-proliferation of smooth muscle cells. High (109) or low (108) doses of microbubbles carrying rapamycin (anti-proliferative drug) were injected via the jugular vein. Acoustic radiation force (1.2 MHz, 65kPa, 100% duty cycle) and contrast-destruction pulses (5MHz, 1.5 MPa, 0.5% duty cycle) were applied focally to enhance drug delivery to the arteries. The addition of acoustic radiation force enhanced drug-mimicking DiI delivery by 90% compared to burst ultrasound alone. Applying both modes of ultrasound using a low dose of microbubbles resulted in a 35.9% reduction in neointima formation, compared to a 34.9% reduction from a high dose of microbubbles without ultrasound. These results validate the ability of ultrasound to provide equivalent drug delivery at 10% of the original dose, and thereby enhancing the “therapeutic window” of targeted drug therapy.