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Seeking a pathway into the brain

The body's defenses against disease also block treatments

By Carolyn Y. Johnson
Globe Staff / June 22, 2009
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With tactics that range from subterfuge to ultrasound beams, scientists are searching for a solution to one of medicine’s most intractable problems: how to get drugs into the brain.

Standing in the way is the blood-brain barrier, a formidable defense system that keeps out pathogens and toxins but also bars many potential therapies from reaching the seat of maladies such as brain cancer or Alzheimer’s disease.

“The system is supposed to protect us from substances that could be noxious to the brain. Unfortunately, it is also quite efficient in removing various drugs that can actually help in curing certain diseases,’’ said Adam Chodobski, a professor of emergency medicine at the Warren Alpert School of Medicine at Brown University, who studies the blood-brain barrier.

A wall of tightly packed cells, which line the tiny blood vessels that permeate the brain, is the first line of defense. Between those cells is a kind of mortar called a “tight junction,’’ which prevents molecules in the blood from slipping through. Protein pumps act as sentinels, expelling substances that don’t belong, and other brain cells also play a role in the barrier.

The barrier is not a solid wall - it lets in oxygen and nutrients, for example, which brain cells can’t live without. And some harmful microbes and cancer cells can get across, as well as a small fraction of medications. Many drugs can’t pass through, however, meaning that doctors who need to deliver a specific drug to the brain may need to drill a hole in the brain. Several technologies exist, including injections and implantable wafers that secrete chemotherapy, but the invasiveness of the procedures limits the number of applications.

Patients and doctors alike want safer and easier treatments, and scientists have been trying a number of approaches. A paper this month in the journal Science described the findings of a team of French scientists, who found inspiration in the deadly bacterium that infiltrates the brain to cause meningitis.

The researchers found that the organism bypasses the barrier with a number of tricks. It uses tiny, hair-like structures on its surface to cling to the blood vessel wall. Then, the bacterium signals the blood-brain barrier to redistribute the proteins that make up the mortar between its cells, effectively opening a gate and allowing the bacterium to slip into the brain.

“The cells do not want to open the route for the bacteria; it is just the bacteria are basically cheating the cells,’’ said Dr. Xavier Nassif, a professor of microbiology at the Université Paris Descartes who coauthored the paper. “Maybe one day we can use something like what the bacteria are doing in order to bring medicine across the blood-brain barrier.’’

Dr. William Pardridge, a professor at the David Geffen School of Medicine at the University of California at Los Angeles, who has spent years working on ways to get across the blood-brain barrier, cautions that such an approach disrupts the barrier, which might allow harmful substances to enter.

His approach is to create a molecular Trojan horse, which can sneak a drug into the brain by attaching it to a molecule that is normally ferried past the barrier.

The company he founded, ArmaGen Technologies, has developed the technology and seen drug effects in animal models of disease, but very little drug crosses into the brain. In rats, Pardridge said, brain uptake is less than 1 percent of dose per gram of brain.

Depending on the drug and the disease, delivery methods that bring only a small amount of drug into the brain may raise safety questions and concerns about costs, since patients might have to receive high doses, according to Beth Hill, senior director of exploratory biologics delivery at Centocor Research and Development, a subsidiary of Johnson & Johnson.

Other attempts to get drugs into the brain have also raised the question of whether it is possible to get enough of the drug across the barrier for it to be useful.

At Brigham and Women’s Hospital, researchers are working on using targeted ultrasound, which disrupts the blood-brain barrier. While the technique has been successful in animal experiments, “one of the big questions is can we get enough across,’’ said Nathan McDannold, assistant professor of radiology.

McDannold and colleagues are injecting microbubbles used in ultrasound imaging into the blood. Then, they use targeted ultrasound, which concentrates pressure waves at a single point, similar to using a magnifying glass to concentrate the energy of the sun at a focal point.

While the exact mechanism by which the bubbles are able to disrupt the blood brain barrier remains “a bit of a mystery,’’ according to McDannold, it allows drugs that normally can’t cross the barrier to enter.

One drug of special interest is Herceptin, which has been used to treat some kinds of breast cancer successfully.

Patients don’t do well, however, if the cancer spreads to the brain, because the drug cannot penetrate the blood-brain barrier.

McDannold and colleagues showed that it was possible to use the technique to get the drug across the barrier in mice, and are continuing the work now in rats implanted with tumor cells to see if enough drug can cross the barrier to have a therapeutic effect.

Still other work is examining the nature of the barrier itself, and the role it plays in traumatic brain injury.

Joanna Chodobska and Adam Chodobski at Brown University have been looking at the barrier’s function after traumatic brain injury, when it allows an influx of inflammatory cells.

Their data indicate that some of those cells, called neutrophils, may harm the brain.

“First responders . . . appear actually to increase the size of the injury and promote neuronal death and increase edema - swelling of the brain, one of the main factors in traumatic brain injury and one of the main causes for morbidity and mortality,’’ Chodobski said.

Robert S. Langer, an institute professor at the Massachusetts Institute of Technology, sees crossing the blood-brain barrier as a big problem with no easy solutions.

Langer helped develop the Gliadel Wafer, which releases chemotherapy directly in the brain after being implanted during surgery.

“I don’t think it’s an insurmountable problem, but it’s an extremely difficult problem,’’ Langer said. The main obstacle is getting enough of the drug across the barrier, and he thinks a solution may lie at the very beginning of the drug development process.

“I would try to think of ways to build delivery into the drug early on,’’ Langer said.

Carolyn Y. Johnson can be reached at cjohnson@globe.com.