Effects of ultrasound combinations of different pulse lengths and pulse repetition frequencies to stimulate microbubble cavitation on tumor perfusion and drug delivery in mice

Abstract

Objective To determine the effects of ultrasound stimulated microbubble (USMB) by different ultrasound combinations of pulse length (PL) and pulse repetition frequency (PRF) under fixed mechanical index and duty cycle on tumor perfusion and drug delivery in C57BL/6 mice. Methods Twenty-four female C57BL/6 mice (6~8 weeks old, average body weight 17.74±0.43 g) were randomly divided into 3 groups (n=8): control group (group A), DOX+PL3.0+PRF2000 group (group B) and DOX+PL30.5+PRF200 group (group C) after being carried with MC38 xenograft tumor. Contrast-enhanced ultrasound (CEUS) was performed before and after USMB treatment to compare the peak intensity (PI), area under the curve (AUC) and tumor perfusion percentage. Doxorubicin (DOX) was injected slowly after USMB treatment, and then the concentration of DOX in the tumor was detected with high-performance liquid chromatography (HPLC). Microstructure of the tumor was observed pathologically. Results The values of PI and AUC after treatment had no significant differences when compared with those before treatment in group A (P>0.05), the values were increased by 19.3% and 18.0%, respectively in group B (P0.05), and the area increased by 21.0% in group B (P0.05). The pathological results showed that the tumor microvessels in group A and B were slightly and moderately dilated, while those in group C were ruptured and bleeding. Conclusion Under the fixed mechanical index and duty cycle, USMB with higher PRF and lower PL can enhance tumor blood perfusion and promote drug delivery. However, higher PL and lower PRF can block tumor blood perfusion.

Keywords

• ultrasound stimulated microbubble
• pulse length
• pulse repetition frequency
• tumor perfusion
• doxorubicin