Delivering More Drugs to Brain Tumors

The brain and its adjacent blood vessels are separated by a protective barrier–it keeps viruses and other infections out but also limits entry of most medications, making tumors and other diseases of the brain particularly difficult to treat. But researchers in Taiwan have found a way to transport more anticancer therapeutics to the brain than previously possible through a novel combination of ultrasound and magnetic particles.

The new research shows how independently successful approaches can work in concert to be markedly more effective. Focused ultrasound waves, along with a solution of microbubbles injected into the bloodstream, had already been proven to briefly disturb the blood-brain barrier. Now, Kuo-Chen Wei, of Chang Gung University College of Medicine, has combined the ultrasound method with a technique that uses a magnetic field to attract drug-coated, magnetically charged nanoparticles to the precise spot where they’re most needed. The disrupted blood-brain barrier allows far more of these larger nanoparticles to enter the brain, and the magnetic field guides them directly to the tumors.

“Typical anticancer drugs can’t [accumulate in] the brain because of the blood-brain barrier,” Wei says. “If we could increase the local concentration of the drug and decrease the systemic side effects, that would be more practical for treatment.”

In rats, at least, he and his colleagues have done just that. Their results, published online today in Proceedings of the National Academy of Sciences and last month in the journal Neuro-Oncology, show that the ultrasound-magnetic targeting approach drives more therapeutic particles through the blood-brain barrier, increasing drug concentrations in the tumor region of the rat brain by 20-fold over the amount that passively diffused from the bloodstream in untreated rats.

“Right now, there’s a huge limitation on using drugs in the brain for disorders of all kinds–Alzheimer’s, epilepsy, Parkinson’s, anything you can think of,” says Nathan MacDannold, a radiologist who runs the Focused Ultrasound Laboratory at Brigham and Women’s Hospital in Boston. “Opening up a new way to get drugs into the brain could be a very big deal, if we can do it safely and translate it to humans.”

Even executing the technique in rats required a massive amount of effort and technological innovation. Wei and his group had to build their own drug-dosed magnetic nanoparticles, which they made by first coating the particles with iron oxide to make them magnetic and then adding a layer of the brain-tumor drug epirubicin. But they also had to build a platform that combined both focused ultrasound directed only toward the area of the tumor, and a magnetic field immediately over the same spot. (Opening up the blood-brain barrier anywhere else in the brain could allow toxic cancer-killing drugs to kill healthy cells.)

Using magnetic particles has an additional benefit. Magnetic resonance imaging (MRI) scans can detect the therapeutic nanoparticles, potentially allowing researchers to estimate how much of the drug has been absorbed into the brain.

Clinical use of the technique, however, is still a long way off. “If we want to push this method to clinical trial, several problems must be resolved,” Wei says. The system has to be scaled up to be used on larger animals–not an easy proposition, since the magnetic fields must penetrate more deeply to reach their brains. The entire process must also be fine-tuned so it can be replicated precisely, over and over. The magnetic field technology must be honed to make it both more portable and more accurate, to ensure that it doesn’t attract toxic particles to anywhere other than the cancerous tumors. And the focused ultrasound technology has yet to be proven effective at blood-brain barrier disruption in the larger, thicker human brain, let alone safe.

“I applaud them for what they’re doing,” says Pierre Mourad, a physicist who specializes in medical acoustics at the University of Washington in Seattle. “They’ve managed to do an exhaustive first pass at a novel way of addressing the difficult problem of increasing dose delivery into the brain.”

But Mourad says he’s disappointed that the group focused strictly on brain tumors. “For many malignant primary brain tumors, increased uptake of drug into the tumor isn’t the problem.” Rather, he says, even after a malignant tumor has been surgically removed, there are still cancerous cells throughout the brain that can cause a recurrence of disease. The magnetic-targeting method only directs therapy to tumors that are visible, leaving the rogue cells behind.

“I’d want to solve movement disorders with these procedures,” Mourad says–diseases such as Parkinson’s and Alzheimer’s, in which very discrete bits of the brain go bad. Parkinson’s, for instance, typically affects distinct, well-known locations. “There are decent drugs to address it, but delivery and dose is the big problem,” says Mourad. “That’s where I would go first with this exciting technology.”

Brigham and Women’s McDannold also sees broader applications. “Technology that can get drugs into the brain where we currently can’t, and deliver them in a controlled way, opens up possibilities for drugs of all types,” he says.