Sensitization of hypoxic tumors to radiation therapy using ultrasound sensitive oxygen microbubbles

Publication date: Available online 31 January 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): John R. Eisenbrey, Rawan Shraim, Ji-Bin Liu, Jingzhi Li, Maria Stanczak, Brian Oeffinger, Dennis B. Leeper, Scott W. Keith, Lauren J. Jablonowski, Flemming Forsberg, Patrick O'Kane, Margaret A. Wheatley
Much of the volume of solid tumors typically exists in a chronically hypoxic microenvironment which has been shown to result in both chemo- and radiotherapy resistance. Systemic delivery of oxygen prior to therapy has proven largely ineffective in reversing this resistance. Surfactant-shelled oxygen microbubbles that can be injected intravenously and used to locally elevate tumor oxygen levels when triggered by noninvasive ultrasound have been previously reported. In this work, we show that these agents successfully and consistently increase breast tumor oxygenation levels in a murine model by 20 mmHg, significantly more than control injections of saline or untriggered oxygen microbubbles (p < 0.001). Using photoacoustic imaging, we also show that oxygen delivery is independent of hemoglobin transport, enabling oxygen delivery to avascular regions of the tumor. Finally, we show that overcoming hypoxia by this method immediately prior to radiation therapy nearly triples radiosensitivity. This improvement in radiosensitivity results in roughly 30 days of improved tumor control, providing statistically significant improvements in tumor growth and animal survival (p < 0.03). Findings from this study demonstrate the potential advantages of ultrasound-triggered oxygen delivery to solid tumors and warrant future efforts into clinical translation of the microbubble platform.



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