How to Hit 'Unreachable' Targets

Blood Brain BarrierPhoto by Doug Nicholson/Media Source

Precision-guided microbubbles can ease open the blood-brain barrier to deliver therapy directly to the brain

Our brain is well guarded, tucked under the solid armour of our skull and protected by the sturdy blood-brain barrier — an extra layer of cells lined up tightly around cerebral blood vessels, allowing only certain substances to pass through to the brain. It’s a top-notch security detail. But when the brain is threatened by an internal affliction such as a cancerous tumour, these protections create unyielding obstacles to treatment. Some chemotherapy, for example, will only have up to a 20-per-cent chance of making it into the brain. Even the best medicine is of no use if it can’t reach its target.

U of T has a rich history of discovery at the intersection of biology and physics, where refining that medical “target practice” has its sweet spot. Many of the clinical advances in use today — focused ultrasound, microbubble contrast agents for cardiac and cancer diagnoses — were shaped by discoveries from U of T’s outstanding medical biophysicists. Among them is cancer radiation pioneer Harold Johns, who led the physics division at the Ontario Cancer Institute/ Princess Margaret Hospital and established U of T’s Department of Medical Biophysics, which has research leaders embedded at Princess Margaret Cancer Centre, Sunnybrook Health Sciences Centre and across the city.

Getting through the blood-brain barrier is the latest frontier. Medical Biophysics Professor and Sunnybrook Research Institute Senior Scientist Kullervo Hynynen set out to resolve this challenge with the powers of focused ultrasound — alongside the emerging technique of microbubble contrast agents — that are now combining to create an exciting new therapeutic approach for brain tumours. Hynynen had used focused ultrasound — essentially high-frequency sound waves which are made to converge at a specific spot within the body — to heat up and destroy tumours in the soft tissue of the body without cutting through the skin, all while monitoring heat levels with magnetic resonance imaging. But how to breach that blood-brain security detail? For this, he turned to a new approach whereby researchers send microscopic bubbles of harmless gas encapsulated by lipids into the bloodstream, and guide them to specific areas using focused ultrasound. Hynynen merged these techniques — and is now a global leader in this promising new field.

Hynynen discovered that by using this combination of tools — the microbubbles as envoys, focused ultrasound as the commander-in-chief and magnetic resonance imaging as a quality-control inspector — he could send the bubbles up close to the blood-brain barrier and make them vibrate, causing the tight junctions between the cells to loosen for long enough to let substances like chemotherapy pass directly through to the brain.

After researching and refining the procedure in animal models, Hynynen is now collaborating with Surgery Professor and Sunnybrook Neurosurgeon Todd Mainprize to study feasibility and safety in patients with brain tumours, who are already scheduled for traditional neurosurgery at Sunnybrook. This innovation — piloted in a landmark surgery in late 2015 — wouldn’t be possible without a vast foundation of scientific inquiry. And it depends on a dedication to continued research if it’s to progress into regular practice. The potential is huge. If we can get medical therapies past the heavy fortifications around our brain — through a relatively non-invasive, temporary and reversible procedure — it could enable much more targeted treatments for diseases like cancer and even neurological conditions like Alzheimer’s.


Hitting the Mark  

1956      MicrobubblesHarmonic-imaging microbubbles (courtesy Sunnybrook Research Institute)

Legendary Cobalt-60 teletherapy pioneer Harold Johns is recruited to U of T and the Ontario Cancer Institute (which officially opened to patients in 1958 and would later become the Princess Margaret Cancer Centre). Johns led the creation of the “Cobalt X-otron,” which had the ability to target tumours deep inside the body without damaging the skin.


Following her influencial work on Hodgkin’s disease, Radiation Oncology Professor Vera Peters publishes the first controlled study showing that treating early-stage breast cancer with minor surgery (lumpectomy) followed by radiation is just as effective as performing a more invasive radical mastectomy.


U of T Professor Mark Henkelman is the first Canadian to have access to a magnetic resonance imaging prototype, to research its usefulness in cancer. With over 200 publications on MRI, he remains the most frequently cited expert on the subject in Canada.


Toronto opens a second cancer-focused hospital site, the Toronto Bayview Regional Cancer Centre (now known as the Odette Cancer Centre at Sunnybrook Health Sciences Centre).


Medical Biophysics Professor, current Department Chair and Sunnybrook Senior Scientist Peter Burns develops harmonic imaging, a technology now found on most scanners worldwide, with a special ability to image microbubbles.


Decades after pioneering and developing digital mammo­graphy, Medical Biophysics Professor and Sunnybrook Senior Scientist Martin Yaffe publishes a landmark study in the New England Journal of Medicine. It shows the increased accuracy of digital over film mammography in diagnosing breast cancer.


Informed by Medical Biophysics Professor and Sunnybrook Senior Scientist Kullervo Hynynen’s extensive research, Neurosurgeon Todd Mainprize performs landmark surgery using focused ultrasound, microbubbles and magnetic resonance imaging to deliver chemotherapy across a cancer patient’s blood-brain barrier.