An in-vivo investigation of the therapeutic effect of pulsed focused ultrasound on tumor growth.

C.‐M Ma,Dusica Cvetkovic,Xiaoming Chen,Lili Chen

doi:10.1118/1.4901352

Abstract

High-intensity focused ultrasound (HIFU) has been investigated for ablative therapy and drug enhancement for gene therapy and chemotherapy. The aim of this work is to explore the feasibility of pulsed focused ultrasound (pFUS) for cancer therapy using an in vivo animal model. A clinical HIFU system (InSightec ExAblate 2000) integrated with a 1.5 T GE MR scanner was used in this study. Suitable ultrasound parameters were investigated to perform nonthermal sonications, keeping the temperature elevation below 4 °C as measured in real time by MR thermometry. LNCaP cells (10(6)) were injected into the prostates of male mice (n = 20). When tumors reached a diameter of about 5 mm in 3D as measured on magnetic resonance imaging (MRI), the tumor-bearing mice (n = 8) were treated with pFUS (1 MHz frequency; 25 W acoustic power; 0.1 duty cycle; 60 s duration). A total of 4-6 sonications were used to cover the entire tumor volume under MR image guidance. The animals were allowed to survive for 4 weeks after the treatment. The tumor growth was monitored on high-resolution (0.2 mm) MRI weekly post treatment and was compared with that of the control group (n = 12). Significant tumor growth delay was observed in the tumor-bearing mice treated with pFUS. The mean tumor volume for the pFUS treated mice remained the same 1 week after the treatment while the mean tumor volume of the control mice grew 42% over the same time. Two weeks after the pFUS treatment, the control group had a mean tumor volume 40% greater than that of the treated group. There was a greater variation in tumor volume at 4 weeks post treatment for both treated and control mice and a slightly faster tumor growth for the pFUS treated mice. The authors' results demonstrated that pFUS may have a great potential for cancer therapy. Further experiments are warranted to understand the predominantly nonthermal cell killing mechanisms of pFUS and to derive optimal ultrasound parameters and fractionation schemes to maximize the therapeutic effect of pFUS.

Highlights

IntroductionHigh-intensity focused ultrasound (HIFU) has a great potential for cancer therapy because of its qualities of noninvasiveness, high spatial precision, and certain penetration in tissues HIFU has been used clinically for thermal tissue ablation in the treatment of uterine fibroids and various solid tumors. Recent in vivo animal studies have suggested that pulsed focused ultrasound (pFUS) exposures may temporarily alter the tissue properties such as the vascular or cell membrane permeability to enhance drug delivery for chemo- and gene therapy. Enhancement of drug delivery to the tumor target by pFUS exposures and its effect on tumor growth inhibition in vivo have been reported by several investigators.11,14–18Over the past decades, there have been encouraging findings from in vitro studies on the predominantly nonthermal (
122901-5 Ma et al.: The therapeutic effect of pulsed FUS. This was to ensure a temperature of
We have used an acoustic power of 25 W and a 10% duty cycle for the pFUS sonication, which kept the temperature elevation below 5 ◦C in our phantom measurements and in targeted tumor tissues in mice as measured by MR thermometry (Fig. 3). These results were consistent with our previous measurements using an acoustic power of 5 W and a 50% duty cycle for pFUS drug delivery studies,14,16 which delivered the same acoustic energy for the same sonication duration, leading to an identical temperature elevation

Summary

Introduction

High-intensity focused ultrasound (HIFU) has a great potential for cancer therapy because of its qualities of noninvasiveness, high spatial precision, and certain penetration in tissues HIFU has been used clinically for thermal tissue ablation in the treatment of uterine fibroids and various solid tumors. Recent in vivo animal studies have suggested that pulsed focused ultrasound (pFUS) exposures may temporarily alter the tissue properties such as the vascular or cell membrane permeability to enhance drug delivery for chemo- and gene therapy. Enhancement of drug delivery to the tumor target by pFUS exposures and its effect on tumor growth inhibition in vivo have been reported by several investigators.11,14–18Over the past decades, there have been encouraging findings from in vitro studies on the predominantly nonthermal (

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