Feasibility between Bifidobacteria Targeting and Changes in the Acoustic Environment of tumor Tissue for Synergistic HIFU

Die Xu,Binglei Jiang,Hai Qiao,Fujie Jiang,Yu Tang,Yaotai Wang,Jie Xiong,Huanan Li,Jianzhong Zou,Xuan Gao,Yong Luo,Chun Chen,Wenjuan Zou

doi:10.1038/s41598-020-64661-6

Die Xu, Binglei Jiang + Show 11 more

Open Access

https://doi.org/10.1038/s41598-020-64661-6

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Abstract

High intensity focused ultrasound (HIFU) has been recently shown as a rapidly developing new technique for non-invasive ablation of local tumors whose therapeutic efficiency can be significantly improved by changing the tissue acoustic environment (AET). Currently, the method of changing AET is mainly to introduce a medium with high acoustic impedance, but there are some disadvantages such as low retention of the introduced medium in the target area and a short residence time during the process. In our strategy, anaerobic bacterium Bifidobacterium longum (B. longum) which can colonize selectively in hypoxic regions of the animal body was successfully localized and shown to proliferate in the hypoxic zone of tumor tissue, overcoming the above disadvantages. This study aimed to explore the effects of Bifidobacteria on AET (including the structure and acoustic properties of tumor tissues) and HIFU ablation at different time. The results show that the injection of Bifidobacteria increased the collagen fibre number, elastic modulus and sound velocity and decreased neovascularization in tumor tissues. The number of collagen fibres and neovascularization decreased significantly over time. Under the same HIFU irradiation intensity, the B. longum injection increased the coagulative necrosis volume and decreased the energy efficiency factor (EEF). This study confirmed that Bifidobacteria can change the AET and increase the deposition of ultrasonic energy and thereby the efficiency of HIFU. In addition, the time that Bifidobacteria stay in the tumor area after injection is an important factor. This research provides a novel approach for synergistic biologically targeted HIFU therapy.

Highlights

Changing the tissue acoustic environment (AET) is one approach to maximize the benefits of High intensity focused ultrasound (HIFU) treatment and minimize the side effects
B. longum disappeared from normal tissues, and 2 weeks after the first injection, these bacteria homed to and proliferated only within the tumor, which is consistent with the results reported by Cronin[19,32]
Yong[33] proposed that Bifidobacteria enter tumors due to the rich nutrition, the complex and diverse immune microenvironment, and the local microvascular destruction found in tumor tissues, which are features that provide shelters that allow a small number of bacteria to escape the immune system[34,35]

Summary

Introduction

Changing the tissue acoustic environment (AET) is one approach to maximize the benefits of HIFU treatment and minimize the side effects. The currently available methods for changing the AET include increasing the acoustic impedance reflection interface[11,12], reducing blood perfusion[13,14], and enhancing the cavitation effects[15,16]. Each of these methods has certain disadvantages, such as a complicated operation and poor stability and controllability[17]. Bifidobacterium has not as a biological targeting material that is directly used to change the AET of tumors for synergistic HIFU, and no related studies have been performed at home or abroad. This study lays a foundation for the application of Bifidobacteria as a long-lasting HIFU synergist

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