Investigating the effects of pulsed low intensity ultrasound and microbubbles in mouse tumors

We previously demonstrated that it was feasible to induce both transient and sustained blood flow reductions in mouse tumors using microbubbles and low intensity ultrasound. In the present study this phenomenon is investigated further, by assessing the signals emitted from bubbles subjected to treatment pulses, and by examining the potential for inducing therapeutic effects in tumors. Subcutaneous xenograft tumors were situated in the hind limbs of mice and exposed to 1 MHz (740 kPa) pulsed ultrasound following a bolus injection of Definity¿ microbubbles. Bubble emissions were monitored with a 750 kHz detection transducer co-localized with the transmit transducer beam within the tumors. The results showed the presence of distinct sub- and ultraharmonic peaks, along with substantial levels of broadband emissions, consistent with the occurence of inertial cavitation. The ability to induce these signals diminished with time, but they continued to be produced up to 45 minutes after injection, well after bubbles were undetectable with imaging. Therapeutic effects were evaluated by comparing growth curves of control and treated tumors. With a therapy scheme involving weekly treatment exposures, a significant growth delay was observed in treated relative to control tumors, suggesting the potential of this approach for therapeutic applications. Both short and long term flow modifications may have implications for US potentiated local drug enhancement.