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

Luhua BAI; Tingting LUO; Jiawei TANG; Junhui TANG; Zheng LIU

doi:10.16016/j.2097-0927.202202130

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

Biomedical Engineering | 更新时间：2026-01-09

- Effects of ultrasound combinations of different pulse lengths and pulse repetition frequencies to stimulate microbubble cavitation on tumor perfusion and drug delivery in mice
- Journal of Army Medical University Vol. 44, Issue 9, Pages: 935-942(2022)
- 作者机构：
  
  400037 重庆，陆军军医大学第二附属医院超声科
- 作者简介：
- 基金信息：
  
  the Major Program of National Natural Science Foundation of China(82127804);the Chongqing Talents Program, Chongqing Chief Expert Program and National Key Research and Development Program of China(2017YFC0107300)
- DOI：10.16016/j.2097-0927.202202130
  CLC： R73-36; R445.9; R459.9; R453.9
- Received：23 February 2021，
  
  Revised：2021-03-24，
  
  Published：15 May 2022
- 稿件说明：
移动端阅览
Luhua BAI, Tingting LUO, Jiawei TANG, et al. Effects of ultrasound combinations of different pulse lengths and pulse repetition frequencies to stimulate microbubble cavitation on tumor perfusion and drug delivery in mice[J]. Journal of Army Medical University, 2022, 44(9): 935-942.
DOI：

Luhua BAI, Tingting LUO, Jiawei TANG, et al. Effects of ultrasound combinations of different pulse lengths and pulse repetition frequencies to stimulate microbubble cavitation on tumor perfusion and drug delivery in mice[J]. Journal of Army Medical University, 2022, 44(9): 935-942. DOI： 10.16016/j.2097-0927.202202130.

摘要

目的

机械指数(mechanical index，MI)和占空比固定时，探讨超声不同脉冲宽度(pulse length，PL)和脉冲重复频率(pulse repetition frequency，PRF)组合激励微泡空化(ultrasound stimulated microbubble，USMB)对C57BL/6小鼠肿瘤组织血流灌注和化疗药物释放的影响。

方法

健康6~8周龄雌性C57BL/6荷瘤小鼠24只，体质量(17.74±0.43)g，随机分为3组(

=8)：对照组(A组，超声假照)，PL3.0+PRF2000+DOX组(B组，较高PRF较低PL超声辐照)，PL34.5+PRF200+DOX(C组，较高PL较低PRF超声辐照)。USMB治疗前后分别进行超声造影(contrast-enhanced ultrasound，CEUS)，比较各组肿瘤峰值强度(peak intensity，PI)、曲线下面积(area under curve，AUC)和肿瘤血流灌注面积百分比。治疗后缓慢推注阿霉素(doxorubicin，DOX)，检测肿瘤组织中DOX药物浓度；病理切片观察小鼠肿瘤组织微结构。

结果

治疗后，A组的PI、AUC值与治疗前相比无显著差别(

0.05)；B组的PI、AUC值较治疗前分别增加19.3%、18.0%(

0.05)；C组的PI、AUC值较治疗前分别减少16.0%、15.8%(

0.05)。治疗后，A组的肿瘤灌注面积较治疗前无显著差别(

0.05)；B组的肿瘤灌注面积较治疗前增加21.0%(

0.05)；C组的肿瘤灌注面积较治疗前减少8.2%(

0.05)。高效液相分析发现B组DOX药物浓度分别是A组的5.0倍和C组的4.8倍(

0.05)；A组和C

组DOX药物浓度无显著差别(

0.05)。病理结果发现A组和B组肿瘤组织微血管呈轻度和中度扩张，而C组肿瘤微血管破裂出血。

结论

在相同的MI和相似占空比条件下，较低脉冲宽度和较高脉冲重复频率超声组合激励微泡空化可增强肿瘤血供、促进化疗药物释放；较高脉冲宽度和较低脉冲重复频率超声组合可阻断肿瘤血供。

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 (

=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 (

0.05)

the values were increased by 19.3% and 18.0%

respectively in group B (

0.05)

and decreased by 16.0% and 15.8% in group C (

0.05). Compared with the tumor perfusion area before treatment

there was no significant difference in the area in group A (

0.05)

and the area increased by 21.0% in group B (

0.05)

and decreased by 8.2% in group C after treatment (

0.05). The results of HPLC showed that the concentration of Dox in gro

up B was 5.0 times higher than that of group A

and 4.8 times higher than that in group C (

0.05). No statistical difference was seen in the DOX concentration between group A and group C (

0.05). 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.

关键词

Keywords

references

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