# Clinically Translatable Ultrasound-Sensitive Microbubble Approaches for Overcoming Tumor Hypoxia

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $617,101

## Abstract

Project Summary:
In 2017 head and neck squamous cell carcinoma (HNSCC) will result in 49,700 new cases in the United States
and an estimated 500,000 cases worldwide. Radiation is standard of care in many cases. Unfortunately, a
significant percentage of HNSCCs are also hypoxic, making them markedly more resistant to radiotherapy than
healthy tissue. This resistance has been shown to impair treatment response associated with a higher risk of
recurrence and metastasis. While approaches using systemic oxygen (O2) delivery have largely stalled, our
group has shown substantial improvements in tumor control and survival in breast cancer models using an
ultrasound sensitive, surfactant-based O2 microbubble platform to overcome tumor hypoxia immediately prior
to radiotherapy. After intravenous injection, ultrasound can be used to noninvasively rupture the bubbles,
triggering a localized intratumoral release of O2. While promising, clinical translation of this platform is not yet
feasible as oxygenation is limited to 2-3 minutes. Our hypothesis is we can overcome these limitations using a
combination therapy of oxygen delivery with lonidamine and metformin (two pharmaceutical agents that
selectively target the metabolic pathway in tumors primarily by mitochondrial respiration). We expect the
addition of these agents will prolong oxygenation while also improving systemic anti-tumor immune responses
(via the abscopal effect) and extend therapeutic effects beyond the primary tumor to metastatic disease.
The proposed work is logically divided into three logical aims each of which is supported by sufficient
preliminary data to not require inter-dependence across any aims. In Aim 1 we will modify our previous design
to also encapsulate lonidamine (whose bioavailability has limited clinical translation). Microbubbles will be
optimized to maximize stability and payload before being acoustically characterized and validated in hypoxic
cell culture. Aim 2 will comprise of in vivo O2 monitoring experiments with and without oral metformin to
compare previous O2 microbubble designs and controls in order to define optimal radiotherapy treatment
parameters and clinical feasibility. Biodistribution studies will also be performed to evaluate local delivery of
lonidamine. Finally, in Aim 3, the platform and selected timing and acoustic parameters will be validated in vivo
in tumor-bearing mice using established and well-characterized HNSCC models. We will determine the ability
of O2 microbubbles to effectively sensitize tumors to radiation (evaluated by tumor growth kinetics and effects
on survival), while also exploring the platform's effects on increased immune response in the tumor
microenvironment in immunocompetent mice. At the conclusion of this project, we will have developed and
validated a minimally invasive and clinically translatable method to overcome tumor hypoxia prior to
radiotherapy. We expect that this platform will improve patient outcomes by improving res...

## Key facts

- **NIH application ID:** 9893869
- **Project number:** 5R01EB026881-03
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** John Eisenbrey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $617,101
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893869

## Citation

> US National Institutes of Health, RePORTER application 9893869, Clinically Translatable Ultrasound-Sensitive Microbubble Approaches for Overcoming Tumor Hypoxia (5R01EB026881-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9893869. Licensed CC0.

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