One of the most vexing puzzles in drug delivery is how to get therapeutics into the brain. The problem is that this sensitive organ is surrounded by an almost impermeable blood-brain barrier, a tightly knit web of blood vessels that insulates the brain from toxic substances in the bloodstream. The barrier also keeps out potentially lifesaving drugs to treat cancer, Alzheimer's, and AIDS. "Finding a new means to deliver drugs to the brain would be a major advancement," says Nicholas Bodor, executive director of the Center for Drug Discovery at the University of Florida.
The strategies for unlocking the gateway to the brain are an eclectic collection. Medtronic Inc. in Minneapolis makes an implantable pump that sends drugs to the brain through the spine. Scientists at Scios Nova Inc. in Mountain View, Calif., are testing biodegradable polymers that are surgically implanted in the brain and slowly release drugs as they dissolve. Others are trying to transplant brain tissue from fetuses to replace missing neurochemicals. They're also trying to chemically alter drugs so they'll slip past the blood-brain barrier and to design new molecules that will transport drugs into the brain.
OPEN UP. One plan being pursued by John W. Kozarich, a professor of chemistry at the University of Maryland and scientific consultant to Alkermes Inc. in Cambridge, Mass., may be simpler than any of these--and provide the greatest potential for treating a wide range of diseases. Instead of engineering new drugs or devices, his researchers are working on a chemical "crowbar" that temporarily opens the blood-brain barrier. The key, says Iozarich, is reengineering a shopworn tool of medicine: a natural substance called bradykinin that dilates blood vessels.
Bradykinin works by targeting so-called receptors, or key proteins, on blood vessels. When it attaches itself to these receptors, the vessels expand, lowering blood pressure. Alkermes is trying to alter bradykinin slightly so that it binds primarily to receptors that affect the permeability of the brain's blood vessels.
Now in safety trials, Alkermes' drug, called RMP-7, is injected intravenously. For about 30 minutes, it opens the blood-brain barrier wide enough for tiny molecules to pass through. In 1990, RMP-7 opened rats' blood-brain barrier wide enough to let the common cancer drug cisplatin shrink brain tumors. The first results in humans, released in August, were ambiguous: A harmless marker substance did not cross the blood-brain barrier when given along with RMP-7. But Kozarich remains optimistic: "There are hints in the trials that there is permeability--we just haven't done the right experiment yet."
Even so, RMP-7 is fraught with risks. When opening the blood-brain barrier, it's difficult to know which other substances cross with the drugs. In past experiments with compounds that radically open the barrier, there were high incidences of seizures and brain inflammation, says Bodor. Alkermes is trying to avoid this problem by tailoring the dosage mf RMP-7 to let only certain-size molecules pass--and limiting the time the barrier stays open. The company hopes RMP-7 will be approved for commercial use by 1996.
Scientists doubt that any single delivery technology will revolutionize the treatment of brain ailments. Instead, they believe that specific technologies will offer hope in treating individual diseases. Either way, researchers have a powerful incentive. As the population rapidly ages, big profits and the satisfaction of saving lives await whoever can outsmart the brain.