Ultrasound cavitation enhanced chemotherapy: In vivo research and clinical application

Abstract

Ultrasound and microbubbles can induce apoptosis of tumor cells. However, the effects of ultrasound and microbubbles (USMB) combined with chemotherapy on in vivo tumors have rarely been studied. This research is to evaluate the efficacy of targeted USMB and chemotherapeutic drugs on apoptosis and inhibition of hepatic carcinoma cells in nude mice. We also summarize case reports of its clinical application. It was divided into three parts: First, the subcutaneous hepatic tumors of nude mice were irradiated with ultrasound (20 kHz, 2 W/cm2, 40% duty cycle) and SonoVue microbubbles injected to the tail vein of the mice followed by chemotherapy comprising cisplatin, mitomycin, and 5-fluorouracil. The apoptosis of hepatoma cells was examined by TUNEL staining, and the expression of the Bax and Bcl-2 proteins in the tumor tissues was detected by immunohistochemistry. The microvasculature of the tumor tissues was observed by transmission electron microscope. Second, orthotopic hepatic tumors in nude mice were irradiated by USMB and chemotherapy. The therapeutic effects were evaluated by magnetic resonance imaging. Third, the malignant tumors in three patients were treated with USMB and chemotherapy. Our results showed that microbubbles focused by low-frequency US ruptured microvessel walls, through which more chemotherapy drugs entered into the carcinoma cells, thus enhancing cell apoptosis, increasing Bax protein expression, and decreasing Bcl-2 expression. The survival period of the nude mice in the USMB and chemotherapy group was the longest, compared with the control, USMB, and chemotherapy (χ2=29.37, P < 0.0001). Magnetic resonance imaging examinations revealed the tumor volumes in nude mice decreased after USMB and chemotherapy (t = 3.91, P = 0.0173). In clinical cases, after USMB and chemotherapy, the diameters of tumors decreased and the symptoms of the patients were relieved. Targeted low-frequency ultrasound combined with chemotherapy can promote tumor cell apoptosis, inhibit tumor growth, and relieve clinical symptoms of patients. Impact statement The novelty of this research is that we used ultrasound cavitation to enhance the effects of chemotherapy in the subcutaneous and orthotopic hepatic carcinomas in nude mice. Case reports of the effects of the targeting ultrasound cavitation and chemotherapy on malignant tumors in clinical patients were also examined. We found that low-frequency ultrasound cavitation combined with chemotherapy is effective in the inhibition of tumor growth to some extent.

Involvement of Ceramide Signalling in Radiation-Induced Tumour Vascular Effects and Vascular-Targeted Therapy

“…These holes generate a cellular response to reseal them, and if the damage induced by the ultrasound-stimulated microbubbles (USMB) is sufficiently large, the cells will die as a result of their microbubble-induced injuries [ 58 , 59 ]. The effects of USMB on tumour vasculature have been shown to facilitate an enhanced sensitivity towards chemotherapy [ 60 , 61 , 62 ] and radiation therapy (XRT) [ 63 , 64 , 65 ]. The safety of using USMB in clinical settings has already been established for the treatment of several diseases; however, the idea of utilizing USMB as a therapeutic agent for cancer has only recently been looked into.…”

Optimal treatment occasion for ultrasound stimulated microbubbles in promoting gemcitabine delivery to VX2 tumors

“…Ultrasound targeted microbubble destruction (UTMD) or USMB has been widely used in promoting chemotherapy of various experimental solid tumors (Todorova et al, 2013 ; Kotopoulis et al, 2014 ; Ingram et al, 2020 ; Shen et al, 2020 ; Xia et al, 2021 ). For these studies, local drug concentration and tumor growth inhibition were the primary concerns because they are directly related to major therapeutic effects in a clinical context (Kurdziel et al, 2011 ).…”

Combination therapy with low-frequency ultrasound irradiation and radiofrequency ablation as a synergistic treatment for pancreatic cancer

“…Low-intensity ultrasound, as a safe and noninvasive treatment, has been widely used in cancer treatment [ 14 , 15 ]. As one of the important effects of ultrasound biology, ultrasound cavitation significantly inhibits tumor cell proliferation and formation mainly through the mechanical effects and cavitation effects produced by ultrasound [ 14 , 16 ]. Studies have shown that ultrasound microbubble contrast agents can significantly enhance the cavitation effect produced by low-frequency and reduce the cavitation threshold, indicating that low-frequency ultrasound-stimulated microbubbles (USMB) has a significant inhibitory effect on tumor cell growth [ 17 ].…”