Tiny Pellets Could Deliver Alzheimer's Drugs

August 25, 1998

ITHACA, N.Y. --Tiny polymer pellets, some microscopic in size, containing a natural protein, hold the promise of one day being able to treat such neurodegenerative diseases as Alzheimer's. The system is startlingly effective because it targets, within a fraction of an inch, the area of the brain where cell death is causing the devastating illness.

The protein is called nerve growth factor (NGF), a well-studied member of a family of chemicals called neurotrophins that are essential for the survival of the nervous system. About two decades ago Alzheimer's patients were found to have a pronounced loss of nerve cells in the forebrain. These cells, it was discovered, could be regenerated with NGF. Since then, the problem has been how to deliver the potent protein to the affected area of the brain.

At the American Chemical Society meeting in Boston this week, two Cornell University researchers report methods for potentially delivering NGF deep within the forebrain by using a biocompatible polymer (a type of plastic). Mark Saltzman, professor of chemical engineering, has developed a pellet, about 1 millimeter across -- less than the size of a pea -- containing up to 10 milligrams of NGF, that when embedded in rat brains has been "very effective" at regenerating dying cells. Cornell polymer chemist Nadya Belcheva has taken the same idea, but reduced it to the microscopic level by coating individual molecules of NGF with a polymer. These microspheres might one day be injected into the affected areas of the brain.

Saltzman's research springs from his work with neurosurgeons on the treatment of tumors by implanting pellets containing chemotherapy agents in the brain. The pellet releases programmed amounts of the drugs to a tightly confined area where the tumor has been removed. A similar system, Saltzman theorized, might also be effective in using NGF to treat Alzheimer's, a disease in which memory loss and cognitive disturbances are thought to be linked to the loss of nerve cells, called cholinergic neurons, in the septal region of the basal forebrain.

The delivery problem, says Saltzman, is that NGF "has a short half life of the order of minutes in the blood, and very little of a dose, perhaps less than 0.1 percent, reaches the brain,

and that amount goes all over the brain." Because NGF, which is a water-soluble protein, penetrates slowly through capillaries in the brain, very little arrives at the target tissues.

The researcher, together with Cornell graduate student Melissa Mahoney, developed a polymer pellet in which molecules of NGF were embedded, something like a sponge in which the holes are filled with solid particles. "When you put this pellet into tissue, the molecules are slowly released over a period of months," says Saltzman. "One of the nice things about the system is that we can manipulate it to release at the rate we want."

This is done, he explains, both by changing how much NGF is put into the pellet and by manipulating the structure of the polymer. "It's similar to the traffic patterns in Boston: As you try to get from one place to another you face blockages from one-way streets to barriers," he says. "We can control the molecules' pathways out of the polymer in just the same way by using restricted openings and crowding."

Saltzman tested the delivery system by transplanting dying forebrain nerve cells from one rat brain to another, and placing the polymer capsule next to the cells. Because rats do not suffer from Alzheimer's, the researcher looked for the activity of an enzyme called CHAT (for cholinacetyltransferase) that is important in synthesizing the neurotransmitter acetylcholine. A neurotransmitter is a chemical that aids the transmission of nerve impulses. Cells close to the NGF pellet had enzyme production 100 percent greater than rat brain cells without the implanted pellet, Saltzman reports.

However, the researcher says, the NGF molecules penetrated only about 1 to 2 millimeters in the rat brains, a large area in a rat but very small in the volume of a human brain. "We have to find a way of delivering locally large concentrations of NGF to a larger zone by protecting it from the normal mechanisms of clearance in the brain so that it would be able to migrate further and have activity on a larger scale."

Cornell researcher Belcheva has developed one solution by coating the surface of the NGF molecule with a water-soluble polymer called polyethyleneglycol, giving the protein a protective plastic shell. This has the potential of being injected directly into the brain via a large-bore needle or catheter. Belcheva has modified the NGF molecule chemically so that it will bind with the polymer. The microspheres have not yet been tested in rat brains.

Saltzman speculates that this drug delivery system might well offer a one-time treatment that would remain in the brain for the remainder of a patient's life. The polymer-pellet delivery system, he says, could in theory deliver drugs directly to the areas of the brain implicated in a number of degenerative diseases, including Parkinson's, Huntington's chorea and amyotrophic lateral sclerosis. Says Saltzman: "The good news is that we know from our studies of chemotherapy that even in very ill patients these kinds of delivery systems can be very well tolerated."

Cornell University

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