Investigation of nanobubble nucleation by radiation therapy

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Abstract This project investigates a little-known physical property of ionizing radiation, which has the potential to increase the therapeutic ratio of radiation therapy (RT). Several decades ago, it was observed that ionizing radiation could nucleate gas nanobubbles (NBs) in water and other liquids. Seminal experiments revealed the presence of NB in irradiated water, which manifested as a decrease in the ultrasound power required to achieve acoustic cavitation. These results raise a crucial yet unanswered question: Does ionizing radiation nucleate NBs in vivo, inside irradiated tissues? Radiation is widely used in medicine. The premise that NBs may be nucleated in patients during diagnostic scans or radiation therapy is significant because NBs could induce biological effects. In addition, their presence in the tissues may lower the threshold for acoustic cavitation, which suggest a novel mechanism for increasing the efficacy of radiation therapy. The first Aim of this project is to gather rigorous and comprehensive evidence of NB nucleation in irradiated cells in vitro. Sensitive assays, including darkfield microscopy and ultrasound imaging, will be used to detect NBs in cells after exposure to ionizing radiation. This study will generate quantitative estimates of the efficiency of NB nucleation for different types of radiation, including their kinetics and stability under different conditions. The second Aim is to explore the use of radiation- induced NB to enhance the therapeutic efficacy of RT. Given that exogenously administered NBs are already used to increase the efficacy of high-intensity focused ultrasound (HIFU), intrinsically induced NBs nucleated during exposure to ionizing radiation should have similar enhancing effect for HIFU. Therapeutic efficacy of this combined treatment will be assessed by treating multicellular tumor spheroids sequentially with RT and HIFU, then quantitatively assessing the biological response of the cells. The proposed combination uses treatment modalities approved for use in humans and requires no extrinsic agents to be administered. This combination of radiation-induced NB nucleation and ultrasound-driven NB cavitation is a highly innovative and practical solution to the issue of treatment-resistant tumors.