Improving the Therapeutic Effect of Ultrasound Combined With Microbubbles on Muscular Tumor Xenografts With Appropriate Acoustic Pressure

Abstract

Ultrasound combined with microbubbles (USMB) is a promising antitumor therapy because of its capability to selectively disrupt tumor perfusion. However, the antitumor effects of repeated USMB treatments have yet to be clarified. In this study, we established a VX2 muscular tumor xenograft model in rabbits, and performed USMB treatments at five different peak negative acoustic pressure levels (1.0, 2.0, 3.0, 4.0, or 5.0 MPa) to determine the appropriate acoustic pressure. To investigate whether repeated USMB treatments could improve the antitumor effects, a group of tumor-bearing rabbits was subjected to one USMB treatment per day for three consecutive days for comparison with the single-treatment group. Contrast-enhanced ultrasonic imaging and histological analyses showed that at an acoustic pressure of 4.0 MPa, USMB treatment contributed to substantial cessation of tumor perfusion, resulting in severe damage to the tumor cells and microvessels without causing significant effects on the normal tissue. Further, the percentages of damaged area and apoptotic cells in the tumor were significantly higher, and the tumor growth inhibition effect was more obvious in the multiple-treatment group than in the single USMB treatment group. These findings indicate that with an appropriate acoustic pressure, the USMB treatment can selectively destroy tumor vessels in muscular tumor xenograft models. Moreover, the repeated treatments strategy can significantly improve the antitumor effect. Therefore, our results provide a foundation for the clinical application of USMB to treat solid tumors using a novel therapeutic strategy.

Ultrasound and Microbubbles for the Treatment of Ocular Diseases: From Preclinical Research towards Clinical Application

“…In line with this study, Hwang et al observed a positive correlation between inertial cavitation (1-9 MPa PNP) and blood vascular damage in vivo [45]. This microbubble-driven blood vessel narrowing might explain the significant decrease in blood perfusion previously observed in numerous preclinical studies [46][47][48][49][50][51]. On the other hand, some studies have shown that USMB can induce blood vessel dilation and local increase in blood perfusion [50,52,53].…”

Microbubble-assisted ultrasound for retinal drug delivery

“…In line with this study, Hwang et al observed a positive correlation between inertial cavitation (1-9 MPa P neg ) and blood vascular damage in vivo [45]. This microbubbledriven blood vessel narrowing might explain the significant decrease in blood perfusion previously observed in numerous preclinical studies [46,47,48,49,50,51]. On the other hand, some studies have shown that USMB can induce blood vessel dilation and local increase in blood perfusion [50,52,53].…”

“…Detachment of HUVEC after exposure to USMB was previously reported at similar ultrasound pressures [37]. In conclusion, cell detachment in combination with insufficient barrier tightness [51] make HUVEC not an ideal endothelial barrier model for investigating the effect of USMB on molecular permeability. In future studies, co-culture of HUVEC with other supportive cells, such as pericytes, could improve the tightness of the barrier and provide a more suitable model for permeability studies [52,53].…”

Radiation combined with ultrasound and microbubbles: A potential novel strategy for cancer treatment

“…Additionally, greater tumor cell death and vessel damage were reported at a higher pressure of 4.0, and 5.0 MPa. They found the optimal acoustic pressure to be 4.0 MPa, at which a significant anti-tumor effect was observed, with no damage seen around the surrounding tissue [61] . Several other studies have also looked at the effect of different ultrasound pressure [62] , [63] , [64] , [65] , [66] .…”

“…Several studies, primarily in vitro , have recently been conducted in investigating the effect of USMB and radiation on various tumor cell types including metastatic follicular thyroid carcinoma cells (FTC-238), non-small cell lung carcinoma cells (NCI-H727) with kV and MV energies [75] , esophageal squamous cell carcinoma cell lines (KYSE-410, KYSE-1140, KYSE-510) [60] , [61] , [87] , and ovarian cancer [88] . In these studies, a significant increase in tumor cell death was observed with the combination of USMB treatments alongside XRT compared to either modality alone.…”