The Disruption of Murine Tumor Neovasculature by Low-intensity Ultrasound—Comparison Between 1- and 3-MHz Sonication Frequencies

Abstract

The goal was to determine whether the tumor vascular disrupting actions of low-intensity ultrasound were frequency dependent. The effect of the frequency (1 MHz at 2.2 W/cm2 or 3 MHz at 2.4 W/cm2) of low-intensity ultrasound as a neovascular disrupting modality was investigated in 15 murine melanomas (K1735(22)) insonated for 3 minutes after the intravenous injection of a microbubble contrast agent (Definity). In contrast-enhanced power Doppler observations of each tumor (before and after treatment), measurements were made of the size of the area of the tumor that was perfused with blood containing the ultrasound contrast agent (percentage area of flow [PAF]), and the volume of contrast agent flowing through the unit volume of the tumor (color-weighted fractional area [CWFA]). During insonation of the tumor, the temperature was measured with a fine wire thermocouple in an additional eight mice. The antivascular action of low-intensity ultrasound was significantly enhanced (PAF by 64%; CWFA by 106%) when the tumor was treated with 3-MHz ultrasound rather than 1 MHz (analysis of variance: PAF, P=.02; CWFA, P=.04). The average rate of tumor temperature increase was 2.6+/-1.3 degrees C/min for 1 MHz and 5.0+/-1.7 degrees C/min for 3 MHz; these increases were significantly different (P=.04). Insonation of the tumor at a higher frequency amplified the heating of the neoplasm and led to greater disruption of the tumor vasculature; 3-MHz ultrasound was more efficacious than 1 MHz for antivascular cancer therapy.