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 AdUS-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.