Drug therapies for many central nervous system diseases, from Alzheimer’s to Parkinson’s, often fall short because they cannot penetrate a naturally occurring firewall in the brain. Much like a computer firewall rejects potentially malicious computer code, the blood-brain barrier (BBB) protects the brain from what it identifies as harmful substances in the bloodstream. The BBB, an intricate network of tightly packed, specialized blood vessels, rejects 98% of all small-molecule drugs and 100% of large-molecule nerve drugs. Only a handful of lightweight drugs that dissolve easily in fat pass through the BBB.
One conventional method to deliver drugs to the brain involves placing a catheter or tube in the brain. Drugs flow into the brain via the catheter but do not travel far from the catheter site and, once in the brain tissue, are rapidly removed to the bloodstream. Another drug delivery technique involves disrupting the BBB using toxic substances. This approach risks damaging nerve cells as well as delivering drugs throughout the entire brain.
Non-invasive disruption of the BBB would provide a new avenue to treat central nervous system diseases while minimizing side effects and avoiding damage to healthy brain tissue. The tools for such a method are now under investigation by a research team from Harvard Medical School and the Sunnybrook Health Sciences Center, University of Toronto.
The group, led by Kullervo Hynynen, a professor of medical biophysics and director of imaging research at the Center for Image-Guided Therapeutics, Sunnybrook Health Sciences Center, University of Toronto, uses focused ultrasound to open the BBB temporarily, and deliver drug therapies to specific areas in the brain.
Waves and Bubbles
"For 50 years we didn’t think ultrasound could penetrate through the skull," says Hynynen. "Only in the last few years have we been able to focus sound waves so that they do minimal damage to surrounding tissue and pass through the skull."
The success of focused ultrasound to open the BBB rests on delivering hundreds of tightly controlled sound waves to locations in the brain rather than using a single wave. Hynynen and his group developed an array of ultrasound transducers to produce the multiple waves. A computed tomography (CT) scan provides information on the skull’s thickness, and a computer calculates how strong a wave pulse is needed to penetrate the skull. Because multiple transducers generate the sound waves, the power levels are quite low, usually less than 10 mW. These very low power levels are important because they reduce the potential for tissue heating, which may be harmful.
Ultrasound alone could force an opening in the BBB by creating gas bubbles in the blood vessels, but that would require potentially unsafe high-intensity waves. To limit damage to surrounding brain structures, Hynynen and his team inject an imaging agent in the form of microbubbles into the bloodstream. Interactions between the sound waves and the bubbles gently open the BBB, which remains open for about 6 hours.
Another important aspect to Hynynen’s technique is the use of magnetic resonance imaging (MRI) to monitor the entire BBB disruption. As the process begins, targets are selected based on MRI, and the images assist the researchers as they steer the focused sound waves to the target. "No other technique does this. This will really change the game," says Hynynen.
Delivering Cancer Drugs
Hynynen’s use of microbubbles also offers a way to transport drugs to specific locations. "By combining [Hynynen’s] approach with new ultrasound-sensitive drug carriers, highly selective brain treatment can be achieved," says Stephen Meairs, M.D., a professor of neurology at the University of Heidelberg and an expert in ultrasound brain perfusion imaging.
In experiments with rats, Hynynen’s group has successfully delivered chemotherapy drugs through the BBB. In one set of experiments, a metastatic breast cancer drug called Herceptin, a drug that does not normally cross the BBB, was transported across the BBB into a target area in the brain. Because breast cancer is the second most common cause of brain metastases, the potential to treat the cancer spread locally is promising. In other experiments, the cancer drug doxorubicin (DOX), which has shown potential in treating glioma cells (the deadliest form of primary brain tumors), was also delivered across the BBB. DOX is highly effective when used for whole-body chemotherapy but fails in clinical practice when treating brain cancers because it cannot pass through the BBB.
Although the researchers have solved the majority of technical issues, Hynynen says one challenge facing the team is how to control the size of the BBB opening. Currently, a human must monitor the BBB opening and signal when to stop generating sound waves. In the coming months, Hynynen hopes to automate the process so that a computer will control the BBB opening.
Hynynen anticipates a measured rollout of the technique starting with clinical trials next year. "Tumor treatments will likely be first, and we will proceed cautiously because human blood vessels might respond differently than animal vessels," he says.
Meairs sees a bright future for the ultrasound technique: "This will likely revolutionize treatment for a multitude of brain disorders because technology is already available to rapidly translate his [Hynynen’s] results from animal research to human applications."
This work is supported in part by the National Institute of Biomedical Imaging and Bioengineering.
Vykhodtseva N, McDannold N, Hynynen K. Progress and problems in the application of focused ultrasound for blood-brain barrier disruption. Ultrasonics. 48 (2008) 279–96.