Improved delivery of doxorubicin by altering the tumor microenvironment using ultrasound combined with microbubbles and chemotherapy.

PURPOSE: To determine whether low-intensity pulsed ultrasound (US) using microbubbles (MB) can temporarily promote regional blood flow in the tumor and increase the delivery of doxorubicin (ad). METHODS: We randomly divided 66 tumor-bearing rabbits into 6 groups (n=11/group). The 6 groups were as follows: doxorubicin and ultrasound combined with microbubble treatment group (Ad-US-MB treatment group), US-MB treatment group, US treatment group, MB treatment group, doxorubicin treatment group (Ad-treatment group), and control group. The animals were intravenously injected with doxorubicin hydrochloride; next, the tumors in the Ad-US-MB treatment group were subjected to low-intensity ultrasound with microbubbles for 10 min. Contrast-enhanced ultrasound (CEUS) imaging of tumor tissues was performed before and after the intervention. Next, we randomly selected 8 rabbits/group, which were euthanized immediately after treatment. The remaining rabbits were reared and underwent the intervention every 7 days. RESULTS: Tumor perfusion increased immediately in the Ad-US-MB treatment group (p<0.01). Unlike the Ad treatment group, the Ad-US-MB treatment group showed high levels of doxorubicin in the tumor samples (p<0.05). Immunofluorescent staining showed high levels of doxorubicin mainly around the blood vessels; in addition, doxorubicin was observed in other areas in the Ad-US-MB treatment group. Inhibition of tumor growth was observed in the Ad-US-MB treatment group. CONCLUSIONS: Low-intensity ultrasound combined with microbubbles and chemotherapy can alter the tumor microenvironment and temporarily increase the regional blood flow to the tumor.

Ultrasound Combined With Microbubbles Increase the Delivery of Doxorubicin by Reducing the Interstitial Fluid Pressure.

The aims of this study were to determine the change of interstitial fluid pressure (IFP) after therapy using pulsed low-frequency ultrasound combined with microbubbles and to determine the change of doxorubicin penetration in VX2 tumor. In this study, all 48 tumor-bearing rabbits were divided randomly into 6 groups (n = 8 per group). These 6 groups include doxorubicin therapy together with ultrasound combined with microbubble treatment group (Ad-US-MB treatment group), US-MB treatment group, US treatment group, MB treatment group, doxorubicin treatment group (Ad treatment group), and blank control group. The animals were intravenously injected with doxorubicin hydrochloride, and then the tumors of the animals were disposed by low-intensity ultrasound and mirobubbles for 10 minutes. The IFP of tumor tissues in rabbits was detected before and after intervention. Rabbits in each group were sacrificed immediately after treatment. The concentration and the distribution of doxorubicin were detected. The tumor IFP was significantly lower than that before treatment in the Ad-US-MB treatment and US-MB treatment groups (P = 0.01, P = 0.013). Ultrasound combined with microbubble increased the concentration of doxorubicin in the sample of the Ad-US-MB treatment group compared with the Ad treatment group (P < 0.05). In immunofluorescent staining section, high concentrations of doxorubicin were observed mainly around the blood vessels, and some were even discovered at a farther area in the Ad-US-MB treatment group. The pulsed low-frequency ultrasound combined with the microbubbles enhances the vascular clearance of particles into the tumor interstitium by reducing IFP.