Primary malignant brain tumors are leading cause of death from cancer among children and young adults with few therapeutic options. Treatments are limited by the blood-brain barrier, a unique structure within the brain made up of closely connected cells that line the inside of blood vessels.
The blood-brain barrier blocks the passage of toxins, viruses and other harmful microorganisms. But it also prohibits anti-cancer drugs, such as immunotherapy, from entering the brain.
An emerging technique
To overcome these limitations, biomedical engineers at Washington University in St. Louis used an emerging technique that combines the application of focused ultrasound (FUS) with intravenously injected microbubbles that amplify and localize the effects of ultrasound to open the blood-brain barrier. Interacting with FUS, the microbubbles exert gentle pressure on blood vessels to create a small temporary opening that allows medications to pass through.
Their preclinical study published in Pharmacy shows that the combined method facilitated the delivery of a immune checkpoint inhibitor in the brain of a large animal model. TO previous preclinical study conducted by a separate research group found that the combined microbubble-FUS method improved delivery of a different immune checkpoint inhibitor into the brain of a small animal model, increasing mouse survival.
“The study by the University of Washington team shows that one of the most promising immunotherapy drugs for cancer treatment was safely delivered into the brains of large animals. This delivery method could pave the way for immune checkpoint inhibitors to treat brain cancer in the future,” said Randy King, Ph.D., program director of NIBIB’s Division of Applied Science and Technology.
Evaluation in a large animal model.
The researchers used three healthy young pigs as an animal model because pig brains are similar in structure and function to human brains. The procedure involved these steps: microbubbles were administered intravenously; focused ultrasound was applied to the right side of the brain; and then an immune checkpoint inhibitor, which was labeled with a fluorescent dye, was injected intravenously. The dye is used to track the drug and see if it reaches the target area in the brain.
The first experiment evaluated whether the procedure opened the blood-brain barrier in vivo. Using magnetic resonance imaging (MRI) and a contrast agent, the researchers confirmed that the barrier opened temporarily and that the opening increased 4.8 times in regions where ultrasound was applied compared to regions without ultrasound.
The second experiment was performed ex vivo to evaluate whether the immunotherapy drug reached the brain regions where the ultrasound was directed. A different type of image (fluorescence) showed that the concentration of the immunotherapy drug doubled in areas where ultrasound was applied compared to regions where it was not applied, showing that the drug reached the target area.
Credit: Hong Chen, Ph.D., associate professor at Washington University in St. Louis
“Both experiments showed that the blood-brain barrier opened enough for the therapeutic drug to pass through. Although we did not measure how long the barrier was open, ideally it would be a few days to match the half-life of therapeutic drugs in the blood and maximize the amount of drugs that can reach the brain,” said the study’s senior author, Hong Chen, Ph.D., an associate professor at Washington University in St. Louis.
The last two experiments evaluated the safety of the procedure. In vivo MRI and ex vivo tissue analysis revealed that the procedure did not cause significant acute tissue damage.
There were some limitations to the study: The pigs used for the experiments were healthy and the study used ultrasound focused on a single point at each targeted brain location, which limited the volume of area it could cover.
The researchers suggested that future studies evaluate drug delivery in a porcine model of brain tumors and perform high-volume ultrasound, which can more efficiently deliver the drug to the entire brain tumor.
“Now that we know the drug can access brain tissue, we would also like to quantify how much of the drug was delivered to the brain; that will be a critical step if our research moves into clinical trials,” Chen said.
This research was partially supported by grants from NIBIB (R01EB027223, R01EB030102).
This prominent scientist describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is critical to promoting new and better ways to prevent, diagnose, and treat diseases. Science is an unpredictable and incremental process: each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without knowledge of fundamental basic research.
Study reference: Siaka Fadera et al. Focused ultrasound-mediated delivery of anti-programmed cell death ligand 1 antibody to the brain of a porcine model. Pharmaceutical 2023, 15, 2479. https://doi.org/10.3390/pharmaceutics15102479
