Surfactant Microbubbles and Process for Preparing and Methods of Using the Same
Background & Summary
It has been well documented that chronically hypoxic tumor microenvironments result in both chemotherapy and radiation therapy resistance and pose a major hurdle for effective radiation therapy. In addition, therapy resistance is more pronounced at lower PO2 levels (<20 mmHg), but can be overcome almost instantaneously via localized oxygen delivery. Thus, a rapid, efficient method for locally delivering O2 immediately prior to radiotherapy would be immensely beneficial in overcoming tumor hypoxia and improving cancer response to radiotherapy. Thomas Jefferson University in collaboration with Drexel University researchers and clinicians have developed a novel solution for the targeted delivery of O2 to tumor microenvironments using patented microbubble technology. These novel microbubbles overcome tumor hypoxia immediately prior to radiotherapy, can be used for other solid tumor cancers in addition to breast cancer, and the delivery platform can be used for other bioactive gasses. These microbubbles have undergone in vitro testing with a human triple-negative breast cancer cell line culture (Eisenbrey et al., 2018). The bubbles and methods for their use are protected under issued as well as pending patents (Eisenbrey et al., 2016). Jefferson is currently seeking partners for the development of this technology.
Application and Advantages
• Overcoming tumor hypoxia in breast cancer immediately before radiation therapy, thereby improving tumor response and limiting recurrence.
• Readily translatable to most solid tumors currently treated with radiation therapy.
• Platform may be used for the delivery of any bioactive gas.
Detailed Description
Chemotherapy and radiation therapy resistance has been shown to result in decreased treatment response as well as a higher likelihood of tumor recurrence and metastasis. While systemic approaches to elevate oxygen levels have proven insufficient, a localized therapy that could slightly elevate intra-tumoral oxygen levels would dramatically increase cancer cell response to treatment and reduce the overall likelihood of cancer recurrence.
Researchers and clinicians have developed a technique whereby surfactant shelled microbubbles can be reconstituted with O2 after fabrication, and these particles remain stable long enough in solution to reach the tumor vasculature after injection. Furthermore, a stable, ultrasound sensitive carrier that can transport maximum oxygen payload will be optimized for oxygen delivery (Eisenbrey et al., 2018). Ultrasound contrast agents are gas filled microbubbles stabilized by an outer shell to limit gas diffusion. When injected intravenously, these agents are restricted to the vasculature and provide significant ultrasound enhancement due to differences in the gas’s compressibility relative to the surrounding medium. Additionally, clinically approved ultrasound imaging parameters can be used to locally and noninvasively rupture these bubbles, providing an avenue for gas delivery.
Preliminary studies using the oxygen-filled surfactant bubbles indicate that its shell is more robust in limiting gas diffusion compared to those in the literature, and their size can be readily optimized by floatation before freeze drying (Eisenbrey et al., 2018). This improved platform is highly innovate and is expected to be the first work on microbubble-based oxygen delivery to be translated to an in vivo model. While this research focuses primarily on a murine breast cancer model, such a platform could be readily translatable to most solid tumors currently treated with radiation therapy. Therefore, ultrasound-activated O2 microbubbles can elevate tumor oxygenation levels, effectively sensitizing tumors prior to radiotherapy, thus significantly improving tumoral treatment response.
Supporting Publications:
Eisenbrey, John R., et al. (2018). Sensitization of Hypoxic Tumors to Radiation Therapy
Using Ultrasound-Sensitive Oxygen Microbubbles. International Journal of Radiation Oncology• Biology• Physics, 101(1), 88-96.
Relevant Patent Filings:
Eisenbrey, John R., et al. (2016). Surfactant microbubbles and process for preparing and methods of using the same. US Patent Application No. US20160059036A1.