Optimization of low-frequency low-intensity ultrasound-mediated microvessel disruption on prostate cancer xenografts in nude mice using an orthogonal experimental design

Abstract

Abstract. The present study aimed to provide a complete exploration of the effect of sound intensity, frequency, duty cycle, microbubble volume and irradiation time on low-frequency low-intensity ultrasound (US)-mediated microvessel disruption, and to identify an optimal combination of the five factors that maximize the blockage effect. An orthogonal experimental design approach was used. Enhanced US imaging and acoustic quantification were performed to assess tumor blood perfusion. In the confirmatory test, in addition to acoustic quantification, the specimens of the tumor were stained with hematoxylin and eosin and observed using light microscopy. The results revealed that sound intensity, frequency, duty cycle, microbubble volume and irradiation time had a significant effect on the average peak intensity (API). The extent of the impact of the variables on the API was in the following order: Sound intensity; frequency; duty cycle; microbubble volume; and irradiation time. The optimum conditions were found to be as follows: Sound intensity, 1.00 W/cm 2 ; frequency, 20 Hz; duty cycle, 40%; microbubble volume, 0.20 ml; and irradiation time, 3 min. In the confirmatory test, the API was 19.97±2.66 immediately subsequent to treatment, and histological examination revealed signs of tumor blood vessel injury in the optimum parameter combination group. In conclusion, the Taguchi L 18 (3) 6 orthogonal array design was successfully applied for determining the optimal parameter combination of API following treatment. Under the optimum orthogonal design condition, a minimum API of 19.97±2.66 subsequent to low-frequency and low-intensity mediated blood perfusion blockage was obtained.

Enhanced analgesic effects of nefopam in combination with acetaminophen in rodents

“…The orthogonal array method was used to optimize the proportions of nefopam and acetaminophen (18)(19)(20). In brief, the L9 ( 3 2 ) factorial design, a factorial arrangement with two factors at three levels, was used to indicate the optimal proportions of nefopam and acetaminophen in combination (Table I).…”

Low-frequency ultrasound-mediated microvessel disruption combined with docetaxel to treat prostate carcinoma xenografts in nude mice: A novel type of chemoembolization

“…The diameter of the therapeutic US transducer was 20 mm, which covered the entire tumor. The therapeutic parameters were determined by our previous orthogonal experimental design as follows: Frequency, 20 kHz; acoustic intensity, 1 W/cm 2 ; duty cycle, 40% (2 sec on, 3 sec off); and irradiation time, 3 min (14). The intermittent working mode allowed microbubbles to refill after every microbubble was destroyed.…”

Advances in low-frequency ultrasound combined with microbubbles in targeted tumor therapy

“…Intravenous microbubbles can be used to enhance the cavitation effect of low-frequency ultrasound, which can, in a targeted manner, destroy the neovascularization of a tumor. Microbubbles can reduce the threshold of the ultrasonic cavitation effect, enhance the cavitation effect, damage the vascular wall, activate endogenous or exogenous coagulation, induce large areas of capillary embolism, and block the nutritional supply of tumor cells, leading to tumor cell death (Yang et al, 2015b). Shock waves produced by the cavitation effect not only increase the permeability of the cell membrane, but also rupture the microvessel and widen the gap between endothelial cells.…”