Comparison of the synergistic effect of lipid nanobubbles and SonoVue microbubbles for high intensity focused ultrasound thermal ablation of tumors

Yuanzhi Yao,Ke Yang,Zhigang Wang,Xuan Zhou,Dong Wang,Jinshun Xu,Yang Cao,Jianxin Liu,Qi Wang

doi:10.7717/peerj.1716

Abstract

Microbubbles (MBs) are considered as an important enhancer for high intensity focused ultrasound (HIFU) treatment of benign or malignant tumors. Recently, different sizes of gas-filled bubbles have been investigated to improve the therapeutic efficiency of HIFU thermal ablation and reduce side effects associated with ultrasound power and irradiation time. However, nanobubbles (NBs) as an ultrasound contrast agent for synergistic therapy of HIFU thermal ablation remain controversial due to their small nano-size in diameter. In this study, phospholipid-shell and gas-core NBs with a narrow size range of 500–600 nm were developed. The synergistic effect of NBs for HIFU thermal ablation was carefully studied both in excised bovine livers and in breast tumor models of rabbits, and made a critical comparison with that of commercial SonoVue microbubbles (SonoVue MBs). In addition, the pathological changes of the targeted area in tumor tissue after HIFU ablation were further investigated. Phosphate buffer saline (PBS) was used as the control. Under the same HIFU parameters, the quantitative echo intensity of B-mode ultrasound image and the volume of coagulative necrosis in lipid NBs groups were significantly higher and larger than that in PBS groups, but could not be demonstrated a difference to that in SonoVue MBs groups both ex vivo and in vivo. These results showed that the synergistic effect of lipid NBs for HIFU thermal ablation were similar with that of SonoVue MBs, and further indicate that lipid NBs could potentially become an enhancer for HIFU thermal ablation of tumors.

Highlights

High intensity focused ultrasound (HIFU) has been gained widespread attention in research and application of tumor treatment (Hassanuddin et al, 2014; Peek et al, 2015; Zhang et al, 2011)
We further introduced lipid NBs and SonoVue MBs into rabbit breast VX2 tumor models to evaluate the synergistic effect of lipid NBs for HIFU thermal ablation compared with SonoVue MBs
By carefully comparing the echo intensity of B-mode ultrasound images, the coagulative necrosis volume, and the pathological change after HIFU ablation in the presence of lipid NBs and SonoVue MBs both in ex vivo and in vivo experiments, these results showed that lipid NBs had the same effect as SonoVue MBs for synergistic HIFU thermal ablation

Summary

Introduction

High intensity focused ultrasound (HIFU) has been gained widespread attention in research and application of tumor treatment (Hassanuddin et al, 2014; Peek et al, 2015; Zhang et al, 2011). In order to overcome its intrinsic limitations, one strategy is to improve the therapeutic transducer based on multiple elements transducer using fast electronicsteering phased array transducer, which belongs to the HIFU engineering field (Ellens et al, 2015). Another strategy to accelerate the therapeutic efficiency of HIFU is to introduce the enhancer into the targeted region during HIFU exposure (Moyer et al, 2015; Sun et al, 2012; Hamano et al, 2014; Ma et al, 2014)

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