Key Points
- Altering the frequency of focused ultrasound increased the number of anti-tumor immune cells that reached the brain in a preclinical glioma model.
- Author Yutong Guo, PhD, was awarded the Foundation’s 2022 Lockhart Postdoctoral Fellowship in Focused Ultrasound and Immuno-Oncology.
A recent paper highlights focused ultrasound’s flexibility as a platform for drug delivery to the brain. The publication, in the September 2024 edition of Nature Communications, demonstrated how focused ultrasound can be tuned to control the immune system’s response during blood-brain barrier (BBB) opening for therapeutic delivery. The researchers used advanced mathematical models and preclinical experiments to test how certain changes, like ultrasound frequency and microbubble size, impact the brain’s inflammatory response. The team then used this knowledge to optimize the accumulation of cytotoxic T-cells in brain tumors in mice.
When using BBB opening with focused ultrasound (FUS), there are a wide range of variables that can affect the brain tissue’s response. For example, FUS-BBB opening can trigger inflammation. This inflammatory response is a double-edged sword: there are circumstances where enhancing the body’s immune response is beneficial (e.g., when targeting cancer cells) and other times when brain inflammation may be detrimental. Understanding how the ultrasound treatment impacts inflammation could therefore increase both the safety and efficacy of FUS-BBB opening for a wide range of patients.
“Our approach, which integrates mathematical modeling with in vivo experiments, provides new insights into microbubble dynamics and their interactions with the blood-brain barrier and has the potential to guide the development of more effective diagnostic and therapeutic interventions for a range of brain diseases,” said the article’s first author, Yutong Guo, PhD, who was chosen as the recipient of the Focused Ultrasound Foundation’s 2022 Andrew J. Lockhart Postdoctoral Fellowship in Focused Ultrasound and Immuno-Oncology.
In this study, the investigators determined that microbubble size and type, as well as ultrasound frequency and pressure, alter the immune system’s response to FUS-BBB. At different ultrasound frequencies, immune activity varied while levels of drug delivery to the brain (as measured by MRI) remained constant. Based on these results, the researchers developed an immune-stimulatory FUS-BBB opening protocol that enhanced the delivery of genetically engineered immune cells (CAR-T cells) to brain tumors in mice.
“Our work demonstrates the untapped potential of ultrasound frequency tuning to selectively influence immune responses and optimize drug and cell delivery through the blood-brain barrier,” said Costas Arvanitis, PhD, the PI of the study. “We are paving the way for safer and more effective therapies for neurological diseases.”
“This study is groundbreaking because it enables precise control over the brain’s inflammatory response during FUS-BBB opening without compromising drug delivery,” added Jessica Foley, PhD, the Foundation’s Chief Scientific Officer. “By tailoring immune activation, we can harness its benefits for some patients while minimizing harmful inflammation for others.”
This work was funded by several National Institutes of Health (NIH) grants, the Parker Institute for Cancer Immunotherapy, Ian’s Friends Foundation, the Leducq Foundation, the Engineering and Physical Sciences Research Council, the Wallace H. Colter Distinguished Faculty Chairship, and the German Research Foundation. Yutong Guo received the Focused Ultrasound Foundation’s Lockhart Postdoctoral Fellowship.
Dr. Guo added, “I am extremely grateful to the Focused Ultrasound Foundation for awarding me the Lockhart Postdoctoral Fellowship, which provided the opportunity to explore focused ultrasound immunotherapy in greater depth and supported our research in advancing innovations in focused ultrasound technology and its applications for treating brain diseases.”
Read “Ultrasound frequency-controlled microbubble dynamics in brain vessels regulate the enrichment of inflammatory pathways in the blood-brain barrier” in Nature Communications (open source)
Read Georgia Tech’s Press Release
See Media Coverage from Technology Networks and MedicalXpress
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Image Source: Guo, Y., Lee, H., Kim, C. et al. Ultrasound frequency-controlled microbubble dynamics in brain vessels regulate the enrichment of inflammatory pathways in the blood-brain barrier. Nat Commun 15, 8021 (2024). https://doi.org/10.1038/s41467-024-52329-y