9B-6 Inhibition of Smooth Muscle Proliferation by Ultrasound-Triggered Release of Rapamycin from Microbubbles

Vascular smooth muscle cell (SMC) proliferation plays a critical role in blood vessel narrowing associated with stent implantation, i.e. in-stent restenosis. Microbubble contrast agents can be modified to carry therapeutic reagents and modulate cell membrane permeability to drugs in the presence of ultrasound. A focused 1 MHz transducer was used to insonate cultured SMC cells. Nine minute application of 35% -6dB BW ultrasound pulses (PRF=1.0 kHz) at 1 MHz, 600 kPa, triggered delivery of rapamycin from a microbubble carrier to smooth muscle cells. Proliferation was decreased by 65% compared to treatment with control (Dil) bubbles. Two minute application of the same ultrasound pulses (except, PRF=5 kHz), within 6 minutes of presence of rapamycin microbubbles resulted in a decrease in proliferation of 72% compared to cells which received neither ultrasound nor microbubbles. Focusing of the drug delivery effect was achieved by narrowing the beam width of the applied ultrasound field which was controlled by axial distance of the transducer with respect to cells. For -6dB beam widths of 11.0, 3.0, and 2.5 mm, a >50% decrease in proliferation was induced in regions of 14, 8, and 6 mm respectively. Results suggest that ultrasound-triggered release of rapamycin from microbubble carriers may ultimately prove to be an effective way to localize treatment and prevention of SMC proliferation.