Breast Cancer Brain Metastasis Response to Radiation After Microbubble Oxygen Delivery in a Murine Model

Abstract

Objectives: Hypoxic cancer cells have been shown to be more resistant to radiation therapy than normoxic cells. Hence, this study investigated whether ultrasound (US)-induced rupture of oxygen-carrying microbubbles (MBs) would enhance the response of breast cancer metastases to radiation.

Methods: Nude mice (n = 15) received stereotactic injections of brain-seeking MDA-MB-231 breast cancer cells into the right hemisphere. Animals were randomly assigned into 1 of 5 treatment groups: no intervention, 10 Gy radiation using a small-animal radiation research platform, nitrogen-carrying MBs combined with US-mediated MB rupture immediately before 10 Gy radiation, oxygen-carrying MBs immediately before 10 Gy radiation, and oxygen-carrying MBs with US-mediated MB rupture immediately before 10 Gy radiation. Tumor progression was monitored with 3-dimensional US, and overall survival was noted.

Results: All groups except those treated with oxygen-carrying MB rupture and radiation had continued rapid tumor growth after treatment. Tumors treated with radiation alone showed a mean increase in volume ± SD of 337% ± 214% during the week after treatment. Tumors treated with oxygen-carrying MBs and radiation without MB rupture showed an increase in volume of 383% ± 226%. Tumors treated with radiation immediately after rupture of oxygen-carrying MBs showed an increase in volume of only 41% ± 1% (P = 0.045), and this group also showed a 1 week increase in survival time.

Conclusions: Adding US-ruptured oxygen-carrying MBs to radiation therapy appears to delay tumor progression and improve survival in a murine model of metastatic breast cancer.

Keywords: contrast-enhanced ultrasound; hypoxia; oxygen delivery; radiosensitivity.

Figure 1.

Treatment planning for 10 Gy radiation to the selected region of interest using the small-animal radiation research platform (SARRP).

Figure 2.

Examples of US imaging of O₂ MB + US + 10 Gy therapy to an MDA-MB-231 metastatic brain tumor within the murine skull. In all panels, the image on the right is the anatomic B-mode grayscale image, whereas the image on the left is the contrast mode image optimized to visualize the MBs within the tumor. A, Microbubbles were visualized along the periphery of the tumor on injection, as denoted by arrows. B, Destructive pulse to induce MB cavitation. C, Reperfusion of MBs after destructive pulses, with MB visualization shown with arrows.

Figure 3.

Examples of 3D US imaging of brain tumors with user-defined renderings. A, 3D tumor volume from the O₂ MB +10 Gy group on the day of treatment. B, 3D tumor volume from the O₂ MB +10 Gy group 7 days after treatment. C, 3D tumor volume from the O₂ MB + US + 10 Gy group on the day of treatment. D, 3D tumor volume from the O₂ MB + US + 10 Gy group 7 days after treatment.

Figure 4.

Normalized tumor volume plotted against the time of observation after treatment (n = 3). Error bars indicate standard error. The line length corresponds to animal survival, where the end of each line represents the death of the last subject in that group or the last data point collected.