Focused radiation therapy is frequently used in the treatment of cancer both to eradicate the primary tumor and to prevent and treat metastasis. Unfortunately, many tumors are hypoxic, which increases their resistance to radiotherapy, resulting in decreased treatment response as well as a higher likelihood of recurrence and metastasis. Thus, a technique that could locally increase tumor oxygen levels immediately prior to radiation therapy is expected to significantly improve patient outcomes. We propose to develop and optimize an injectable, ultrasound sensitive oxygen-filled microbubble platform for overcoming tumor hypoxia immediately prior to radiotherapy. The main hypothesis of this project is that directed ultrasound-triggered destruction of oxygen-filled microbubbles can be used to elevate tumor oxygenation levels immediately prior to radiotherapy and that this sensitization will significantly improve treatment response. The first portion of this project wil be to optimize and characterize surfactant shelled oxygen-filled microbubbles in vitro for maximum tumor oxygenation. Parameters such as stability, size, concentration, and shell composition will all be characterized and optimized to provide maximum oxygen delivery. Acoustic triggering parameters will also be investigated to maximize localized microbubble destruction. In vitro experiments will be performed to determine the ability of the platform to sensitize cell cultures t radiation. Finally, the platform and selected acoustic parameters will be used in an in vitro setup to characterize the microbubble's ability to locally elevate oxygen concentrations in solution. The second portion of this project will be to validate the platform's ability to elevate tumoral oxygen levels in a mouse tumor model. Selected acoustic parameters will be translated to a commercial ultrasound scanner and used to locally trigger microbubble destruction in vivo. Changes in the tumor oxygenation levels will then be monitored using noninvasive photo-acoustic imaging and invasive needle-based oxygen probes and compared to non-triggered or nitrogen-filled microbubble controls. The final portion of this project will then be to determine the platform's ability to sensitize the selected tumor model to radiation therapy. The platform will be used to increase tumor oxygenation levels immediately prior to radiation therapy. Tumor response will then be evaluated based on size, histology, and animal survival, and compared to respective controls. Tumor hypoxia-associated radiation resistance is a major unmet challenge to improving therapy. This application proposes a multidisciplinary, high-risk/high reward solution to this clinical imperative, which will improve patient outcomes by improving tumoral response to radiotherapy and potentially reduce the prevalence of recurrence and metastasis after treatment. At the conclusion of this project, we expect to have developed and validated a minimally invasive method for overcoming tumor hypoxia prior to radiotherapy.

Public Health Relevance

While radiation therapy is frequently used in the treatment of cancer, the hypoxic natures of solid tumors make them more resistant to radiotherapy than healthy tissue. We propose to develop and optimize an injectable, ultrasound sensitive, oxygen-filled microbubble platform for overcoming tumor hypoxia immediately prior to radiotherapy. This minimally-invasive approach could considerably sensitize tumors to radiotherapy, thereby improving tumor response and limiting the likelihood of recurrence.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1-RTRB-R (M1))
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Bernhard, Eric J
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Thomas Jefferson University
Schools of Medicine
United States
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Eisenbrey, John R; Shraim, Rawan; Liu, Ji-Bin et al. (2018) Sensitization of Hypoxic Tumors to Radiation Therapy Using Ultrasound-Sensitive Oxygen Microbubbles. Int J Radiat Oncol Biol Phys 101:88-96
Daecher, Annemarie; Stanczak, Maria; Liu, Ji-Bin et al. (2017) Localized microbubble cavitation-based antivascular therapy for improving HCC treatment response to radiotherapy. Cancer Lett 411:100-105