Sunnybrook physicians are about to test a pioneering technique to get anti-cancer drugs through the blood-brain barrier
A significant obstacle to delivering chemotherapy to the brain is about to be breached at Sunnybrook. In what he called "one of the most exciting studies that we've done," Dr. Todd Mainprize is going to be using something almost deceptively simple: microscopic bubbles of air, with the aid of ultrasound, to emporarily break through the body's most effective protection system, the blood-brain barrier.
"In the brain, unlike most of the body, the lining of those very small blood vessels are sealed,"explains Dr. Mainprize, a neurosurgeon and the acting head of neurosurgery. Its purpose is to keep out toxins, "so very few chemicals can get into the brain," he says, "that the brain doesn't want, including drugs."
Microbubbles have been around for a long time, originally designed to enhance the images doctors can see when doing conventional ultrasound scanning. These bubbles, usually three to five micrometers in diameter, increase the contrast between the blood and tissue, allowing for clearer pictures of what is going on deep inside the body.
When made up of useful chemicals instead of air, microbubbles have also become a potent new form of drug delivery, bursting apart inside organs when hit with ultrasound waves and releasing their contents, where needed.
What Dr. Mainprize is doing, however, is using the microbubble's capacity for oscillation to tear apart the protein seals, or tight junctions, that attach the blood vessels of the capillaries together and allow chemotherapy drugs a way into the surrounding tissue.
Where that will prove extremely useful, he says, is in those regions right around a brain tumour, an approximately two-centimetre rim within which cancer cells are sparser – about one for every 10 brain cells, or less – yet still dangerous. While the tumour itself can be removed, "what we can't get at," says Dr. Mainprize, "are these cells, the ones where about 10 per cent are cancer cells. The blood-brain barrier is still intact, which means it's a challenge to target chemotherapy there."
As a result, the tumour can come back, and more often it does so within that immediate rim. "If we could treat that two-centimetre core more effectively," he speculates, "we could, in theory, significantly improve survival from the current 14- month average. Because it would likely come back, now it would come back at a further distance, where the cancer cell ratio is more like one in 100. It would take longer for the tumour to grow back, for example. That's our hope."
• Low-frequency ultrasound pulses (represented by blue bars) disrupt the microbubbles, causing them to oscillate in size and open the tight junctions of select areas of the blood brain barrier. This allows targeted delivery of drug treatment.
Illustration by Dr. Ryan Alkins
Six patients will be recruited for a Phase One, proof-of-principle and safety trial. Each one of them will put on a helmet containing cool water and about a thousand ultrasound transducers and then lie within a regular magnetic resonance imaging (MRI) machine. Microbubbles will be injected through a vein in the patient's wrist and begin their journey throughout the body. Once the microbubbles reach the targeted area in the brain they will receive low-frequency ultrasound pulses through the skull, causing them to oscillate in size, opening those protein connections and disrupting the blood-brain barrier. The patient will then receive chemotherapy which can now penetrate the tumour-affected brain through the opened blood-brain barrier. The patient will then undergo surgery.
Studies have shown that immediately after the application of ultrasound to the microbubbles, those tight junctions disappear. They begin forming again after about six hours, and in 24 hours, they are all back. "The body just grows them back," says Dr. Mainprize.
The technique was originally discovered by Dr. Kullervo Hynynen, director of physical sciences at Sunnybrook. He not only discovered that it was possible to get ultrasound through bone, something previously thought impossible, but also that it could force microbubbles to disrupt the blood-brain barrier.
The microbubble method is one Dr. Mainprize hopes might improve on previous attempts to enhance chemotherapy delivery to brain cancer patients. These have included the laying of drug-soaked wafers onto the cavity left by surgical removal of the tumour. The wafers slowly dissolve and permeate the brain, but, according to Dr. Mainprize, "have not been that effective."
Convection-enhanced delivery, meanwhile, is designed to "circumvent the circulation altogether," he says, "putting a kind of 'catheter' into the brain and just slowly and carefully pushing fluid into the brain tissue area."
Another method, osmotic disruption, involves a sugar alcohol called mannitol. It achieves the opposite effect of a microbubble, temporarily shrinking the cells and simultaneously stretching open the tight junctions. But like intra-arterial chemotherapy that lets high doses of drugs into brain arteries through tiny "catheters", it is not very selective, disrupting the entire blood-brain barrier.
"What we can do, with microbubbles and ultrasound," says Dr. Mainprize, "is open up the blood-brain barrier by a millimetre in a particular area, or we can open up much wider areas. We can pick where we want to do it."
There have been enormous advances over the past decade in figuring out the pathology of glioblastoma, the most common and aggressive form of malignant brain tumour, such as "which pathways are disrupted, how they are disrupted and how that affects the growth of the cell," says Dr. Mainprize. "And we now have a variety of molecular inhibitors and potential therapeutic targets, but they haven't translated into a very good clinical response. Part of that may be that we just can't deliver them to the area where we want to deliver them."
"If we could open up the blood-brain barrier and deliver chemotherapy at the same time patients are getting an MRI scan, which people with brain cancer get every two or three months, we may impact survival for these patients."
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