Meet the human brain’s security system: the infamous blood-brain barrier (BBB). Consisting of a dynamic network of specialized endothelial cells lining brain capillaries, the BBB serves as a nearly impermeable interface between the brain and the circulatory system. Its tight junctions keep potentially toxic substances from reaching our most important organ. However, the barrier also prevents the delivery of medications for brain cancers and diseases.
Earlier this month, a research team led by Dr. Todd Mainprize and Dr. Kullervo Hynynen of Sunnybrook Hospital, Toronto, developed a groundbreaking technique to finally beat the brain’s bouncer. Using ultrasound waves and miniscule air bubbles, they penetrated the BBB, allowing chemotherapeutic drugs to enter a cancer-afflicted brain.
In this pilot procedure, “microbubbles” and drug liposomal doxorubicin are intravenously delivered into the patient’s bloodstream. After locating the target tumor via MRI, scientists direct a beam of high-intensity focused ultrasound into the brain, inducing the microbubbles to vibrate, expand, and contract. Such motions at 200,000 times per second create tiny tears in the endothelial layer, allowing for the chemo to cross through.
“The blood-brain barrier has been a persistent obstacle to delivering valuable therapies to treat disease such as tumors,” said Mainprize. “We are encouraged that we were able to temporarily open this barrier in a patient to deliver chemotherapy directly to the brain tumor.”
The microbubbles circulate outside the BBB and are eventually absorbed in the lungs. As for the tiny endothelial fissures, the BBB gaps close again after eight to twelve hours. Surgeons performed traditional tumor-removal operations the next day to analyze how much of the chemo entered.
Comparisons of chemotherapy concentrations in brain regions with and without BBB breach are currently being conducted. Meanwhile, the success of this first case has encouraged the team to replicate the trial four more times, rather than nine as initially planned.
With… this technique, you can selectively open almost anywhere in the brain and deliver whatever you want
“This is only the first patient, but the results have been so conclusive, it appears to be quite safe. We’ll see how the others go and we may just stop before 10 patients,” Mainprize told Medscape Medical News. As this is an early clinical trial, Mainprize and his team must now evaluate its effectiveness and safety. After all, the BBB evolved to keep out neurotoxic substances that may be harmless elsewhere in the body. Risk assessment will compare the benefits of treatment with the brain’s twelve-hour vulnerability post-procedure.
Last year, medical scientists from Pitié-Salpêtrière Hospital in Paris were able to carry out a similar procedure for four patients with glioblastoma. Though effective, the treatment required the invasive brain implantation of ultrasound inducers. Mainprize and Hynynen’s revised technique is more targeted and non-invasive. Their patient wore a head frame and helmet of transducers, part of Insightec’s ExAblate Neuro system, to send the ultrasound waves through the skull.
“This is a very important step in the development of MR-guided focused ultrasound technology,” said Eyal Zadicario, Director of Neuro Programs, Insightec. “We continue to push the technology into new clinical applications that can have significant impact where it matters most—to patients.”
The implementation of this “ultrasonic screwdriver” ignites excitement for novel therapeutics that could not previously be delivered. According to Hynynen, 98% of molecules that could be used for brain treatments are not utilized because they cannot cross the BBB.
“[Penetrating the BBB] will allow us to use many, many more medications in the brain than we can currently use,” Hynynen remarked in a Globe & Mail interview.
In addition to facilitating direct drug delivery, this BBB-breaching phenomenon could also activate the brain’s immune system. Hynynen’s research has found that a BBB breach activates the brain to reduce amyloid plaques and improve memory in mouse models of Alzheimer’s disease. For brain cancer, Alzheimer’s, major depression, and stroke, the enormous implications of this method hold the potential to revolutionize neuromedicine.
“With… this technique, you can selectively open almost anywhere in the brain and deliver whatever you want,” said Mainprize. “Essentially, whatever you can think of is a potential study that may help in the future.”