Drug companies working on promising new treatments for brain disorders like Alzheimer's disease, tumors and depression are learning a hard lesson: it is easier to make a medicine that will act on the brain than it is to make one that will get into the brain. Dr. William Pardridge, a brain researcher at the University of California at Los Angeles, estimates that 95 percent of drugs discovered using the latest technologies will not get into the brain.
"Companies are not developing strategies to get them there," he said. " It's like a captain that takes a ship to sea without a compass."
Delivering drugs into the brain is a tricky business, because long ago mammals' brains evolved an elaborate security system to keep things out. The system, known as the blood-brain barrier, provides a stable environment for the brain, protecting it from the ebb and flow of hormones, nutrients, toxins, microorganisms and other substances that find their way into the bloodstream. The barrier is essential for survival.
But now that there are medicines to fight cancer, infections, mental illness and neurological disorders, the blood-brain barrier has turned into a mixed blessing. So scientists are working to outsmart it. Results have been mixed. A protective mechanism that has been eons in the making is not easily undone, and no single strategy has emerged as the key to the barrier. Still, tests are under way on a number of interesting approaches.
Dr. Thomas Jacobs, director of the stroke and brain tumor programs at the National Institutes of Health, said that in the past five years major advances have been made in the understanding of how brain cells communicate with each other and how they are affected by various diseases. That knowledge has made it possible to develop highly specific drugs for brain disorders.
But he asked,"How do we get these very sophisticated drugs into the area of the brain where they'll be most effective?"
Jacobs agreed with Pardridge and other researchers in the field who say that major drug companies do not pay enough attention to the blood-brain barrier." I can see why they don't,"he said. "Their charge, the way they're looking at the survival and mission of their companies, is to develop new therapeutics, and they're hoping someone else will solve the problem or they can get around it or it won't be an issue."
Although the phrase blood-brain barrier might conjure an image of a wall in the neck, the barrier is not one checkpoint. It is billions of them, formed by cells lining hundreds of miles of capillaries that pipe blood to the brain. Unlike capillaries anywhere else in the body, those in the brain are lined by cells so tightly sealed together that they are essentially seamless. In addition to these so-called tight junctions, the lining cells, called endothelial cells, have far fewer of the porelike openings in other capillaries. And the capillaries in the skull are separated from brain cells by a dense matrix of protein that forms part of the barrier.
The net effect is to filter out a wide array of substances, including large molecules that cannot slip through the tight junctions, and water soluble ones that are repelled by the fatty cell membranes.
Penicillin, many cancer drugs and hormones can't get in. But alcohol, caffeine and nicotine, which dissolve in fat, zip through. Antidepressants and other drugs used to treat mental and emotional disorders are also fat soluble. But the brain needs some things that are water soluble, including glucose, required for energy, and the amino acids the body uses to build proteins. The brain has evolved transport systems that escort those molecules through the barrier.
Several ways of getting through or around the blood-brain barrier are being tested in people. As is often the case in medical research, these experimental treatments are being tried in patients who have almost nothing to lose: people with cancerous brain tumors that resist standard therapy.
The immediate goal is to find better treatments for those patients, but scientists say they hope the research will also lead to new ways to send drugs into the brain for other disorders.
The oldest technique takes the blood-brain barrier by storm, flooding it with a solution that shocks it open for a brief period, during which doctors shoot in a mixture of cancer drugs that cannot normally get through.
Only five medical centers in the United States offer the treatment, as part of a research program set up by Dr. Edward Neuwelt, a neurosurgeon at Oregon Health Sciences University in Portland. "It's an involved technology," he said.
The treatment requires cutting a slit in the patient's groin, inserting a catheter into an artery and threading it into vessels in the neck, so that drugs can be pumped into the brain. This can be done only by a specially trained team in an operating room, with the patient under general anesthesia. The procedure can cause seizures, and damage eyesight and hearing.
Patients must be strong enough, and determined enough, to endure the risks and rigors 24 times during the 12 to 18 months it takes to complete a course of therapy. They also need an insurer willing to foot the bill, about $250,000.
"I'm doing this because I had no other choice," said Sandy Scherer, 47, who has had 14 treatments at the University of Minnesota Cancer Center in Minneapolis. Ms. Scherer, a middle school teacher from Albert Lea, Minn., learned two years ago that breast cancer had spread to her brain. Radiation temporarily stalled the tumors, but her doctors had nothing else to offer.
One doctor suggested the experimental treatment."We agreed there was no choice, " Ms. Scherer said."If it worked it would be wonderful. If not, at least I'd be giving information to somebody else instead of sitting home and wasting away until I was gone."
At the halfway mark, her results were mixed. Some tumors shrank and a few disappeared, but others showed no chance.
The procedure, which Neuwelt developed the 1970s and 1980s, uses a sugar called mannitol to disrupt the blood-brain barrier. Mannitol works by osmosis, drawing water out of the cells that line the capillaries. As the cells shrink, they pull away from each other, opening the tight junctions and letting molecules of the chemotherapy drugs slip through. The barrier may stay open as long as 30 minutes, until the cells plump up again.
Since 1980, more than 600 patients have undergone the procedure. The best results have been with a rare brain tumor known as primary central nervous system lymphoma (which is different from the lymphoma associated with AIDS). Patients live longer than those given standard chemotherapy.
September 13, 2006 - Beset by a host of debilitating and potentially fatal disorders, the human brain is in desperate need of a few good drugs.
The catch, however, is that nature has set up a roadblock known as the blood-brain barrier — intended to keep harmful agents out — that prevents clinicians from administering effective medicine.
Now, scientists have hit upon a scheme that could be used to sneak drugs past the barrier to treat afflictions such as Parkinson's, Alzheimer's, brain tumors and stroke. The idea, according to Eric V. Shusta, a University of Wisconsin-Madison professor of chemical and biological engineering, is to exploit human antibodies by transforming them into "Trojan horses" capable of ferrying payloads of drugs from the blood across the barrier and into the parts of the brain where they will do the most good.
Describing the new work in San Francisco today (Sept. 13) at a meeting of the American Chemical Society, Shusta described a system where antibodies capable of penetrating the blood-brain barrier could be used to carry drugs, DNA or even therapeutic nanoparticles to the brain.
"There are many drugs that show promise in the Petri dish," Shusta explains. "We just can't deliver them."
The scheme being explored by Shusta and his colleagues rests on the ability of antibodies, protein molecules that circulate in the blood and whose job, typically, is to seek out and neutralize foreign pathogens and toxins before they do harm. Antibodies are good at such work because they are built to recognize the surface features of targeted cells.
Using engineered yeast as microscopic factories to produce human antibodies customized to recognize the surface features of cells that compose the blood-brain barrier, Shusta has developed a set of unique antibodies that may one day be used to ferry drugs to specified regions of the brain.
"Antibodies bind tightly and specifically to cells, and we're trying to find those that home in on the blood-brain barrier endothelial cells," Shusta says.
When antibodies bind to cells, they can sometimes gain access to the cell and, potentially, open a gateway for the delivery of drugs or other therapeutic agents.
"We'd like to use the bloodstream to deliver drugs, but most small molecule pharmaceuticals as well as larger protein and gene medicines cannot pass the blood-brain barrier," he says.
With roughly 400 miles of blood vessels, the human brain is equipped with its own expansive delivery network for therapy — provided scientists are able to figure out a way to get past the blood-brain barrier. With different cell surface features in different parts of the circulatory system and also in different regions of the brain, it might be possible to customize antibodies to carry drugs to only those parts of the brain that would benefit from treatment.
So far, Shusta and his colleagues have identified a panel of unique antibodies that avidly bind to the plasma membranes of brain endothelial cells. In some cases, the antibodies engineered by the Wisconsin team have demonstrated the capacity to gain access to the cell, showing their "potential to act as molecular Trojan horses and allow blood-to-brain transfer of a wide range of pharmaceuticals."
The idea of using antibodies to tote drugs into the brain is not new, according to Shusta, but the antibodies used to date are not particularly efficient. The work of Shusta's group, however, has shown it is possible to identify novel transporting antibodies that could one day provide effective alternatives. "Ours is a novel system," Shusta adds. "We're still trying to work out the specifics, but we're pretty excited."
The work in Shusta's lab was supported by grants from the Whitaker Foundation, the Camille and Henry Dreyfus Foundation and the National Institutes of Health.
The blood-brain barrier (BBB) is maintained by the endothelial tight junctions within the brain (junctions between capillaries outside the brain and support cells inside the brain). Most small-molecule and almost all large-molecule drugs do not cross the BBB. The BBB problem is the rate-limiting factor preventing the development of effective new drugs for many neurological diseases. The future development of such new drugs will be accelerated by the development of BBB drug-targeting technology.
Conventional drugs are nearly exclusively small-molecule drugs. Small-molecule drugs provide symptom relief for many brain disorders including PD, the different types of epilepsy, anxiety and depression. However, far more disorders (stroke, Alzheimer disease, brain tumors, PD, and genetic disorders) remain intractable to treatment or refractory to cure with conventional small-molecule drugs.
Large-molecule drugs have the potential to be curative in-patients with many neurologic disorders, including, perhaps PD, but none of these large-molecule drugs cross the blood brain barrier (BBB). Although it is not widely recognized, more than 98% of small-molecule drugs do not cross the BBB.
Despite the importance of the BBB to the future development of effective drugs, this area is under-developed within the neurosciences. Thus it is not unusual for an entire conference to be convened on a given neurologic disorder (eg, PD), with no discussion devoted to the issue of targeting drugs through the BBB.
The lack of integration of BBB science within the overall field of drug development has become a rate-limiting factor in the translation of progress in the molecular neurosciences into the development of more effective drugs.
If solutions to the BBB problem were found, then the number of drugs available for clinical trials would increase by a ten-fold order of magnitude. What is needed is the development of brain drug-targeting technology that enables the noninvasive delivery of small- or large-molecule drugs, including gene medicines, through the BBB of the human brain.
The usual approach to solving the brain drug delivery problem is to "lipidize" the drug, making it fat-soluble (because the BBB and the brain consist largely of fat). In "lipidization" the polar (water-soluble) groups on the drug are masked with lipid groups. The water-soluble parts of the drug restrict BBB transport, and the masking of these groups with lipid, and the conversion of a water-soluble drug into a lipid-soluble drug is the traditional solution to the BBB problem. However, there are few, if any, examples of drugs in modern practice that can cross the BBB with this "lipidization" approach. The limitations of this approach include the instability of the "lipidized" drug in blood and the rapid removal of the "lipidized" drug from blood owing to its increased lipid solubility. An alternative approach, which can be used for either small- or large-molecule drugs, is to reformulate the drug so that the molecule can access one of the transport systems within the brain capillary endothelial wall, which forms the BBB in vivo.
There are 3 different classes of transport systems within the BBB:
The carrier-mediated transport systems include the glucose and amino acid carriers and mediate the movement of small-molecule nutrients and vitamins between the blood and the brain.
The receptor systems include the BBB insulin receptor and the transferrin receptor (which carries iron). These systems mediate the movement of large-molecule peptides between the blood and the brain.
The active efflux systems include transporters such as P-glycoprotein, and mediate the efflux of small molecules from the brain to the blood.
These transport systems are natural portals of entry to the brain of drugs that are formulated to enable binding and transport by these systems. Based on the knowledge that these systems exist, drugs may be reformulated to enable transport into the brain via the BBB transporters. For example, a monoamine drug (such as dopamine) does not cross the BBB. However, the neutral amino acid analog of dopamine (levodopa) may cross the BBB using the neutral amino acid transporter. Once inside the brain, the amino acid analog (levodopa) may be changed to yield dopamine. Apart from the neutral amino acid transporter, there are more than a dozen other carrier-mediated transport systems within the BBB that could be portals of entry for drugs that are appropriately designed to access these systems.
Chimeric peptides are formed, when a drug that is normally not transported through the BBB is conjugated (hooked-up) to a brain drug-targeting vector. The latter can be a naturally occurring peptide, a modified protein, or a special anti-body (a mono-clonal anti-body) that can then "piggy back" the drug across the BBB.
Additional brain drug-targeting technology will be facilitated by the discovery of tissue-specific gene expression at the brain capillary endothelial cell, which forms the BBB. The discovery of such BBB-specific gene expression will enable the production of brain-specific drug-targeting vectors. BBB selective genes included novel gene sequences and known genes that were not previously shown to be selectively expressed at the BBB. The identification of tissue-specific gene expression at the BBB will lead to future discovery of new targets for brain drug delivery, and may also elucidate mechanisms of brain function at the cellular level.
