Breaking the brain barrier

No human organ is better protected against intrusive chemicals than the brain. That makes it difficult to treat with drugs. Now people are finding ingenious new ways to smuggle medicines into it

IF THE body truly were a temple, then the brain would be its holiest shrine. It is, literally, the nerve-centre of the whole operation--and like the holy of holies in many religions, few may enter. To keep the organ pure, a gatekeeper known as the blood-brain barrier screens any molecule that might try to gain access.
     The blood-brain barrier is omnipresent. It consists of all the endothelial cells that line all the blood vessels that flow through the brain. These, unlike the cells lining the vessels servicing less critical organs, form tight, impenetrable junctions with their neighbours. Only a few substances necessary for the brain's proper functioning are able to get past this close-knit thicket of endothelium.
     This is normally a sensible arrangement. The brain is the body's most sensitive organ as well as its most vital one. The blood-brain barrier keeps out things that might upset it. It also keeps essential biochemicals, such as neurotransmitters (molecules that carry messages between nerve cells), in their proper place inside it. But its vigilance can be a drawback. For it also keeps out a few things that might help the brain--such as drugs.
     At the moment, the conventional way of getting round the blood-brain barrier is by the painful procedure of intracerebroventricular instillation--that is, dropping the drugs in question into a patient's brain through holes drilled in his head. But even this delicate operation can deliver medicines only to the brain's surface. Deeper centres (where disease may lie) are inaccessible to it. What is needed, therefore, is a less invasive, less expensive way of breaking through the blood-brain barrier.

Rites of passage
William Pardridge, at the Brain Research Institute of the University of California, Los Angeles, thinks he has one. His method is to get his drugs to tag along with the chosen few natural molecules that are permitted access to the inner sanctum.
     These privileged chemicals (such as the components of proteins and genes) are carried in by special receptor proteins, each tailored to a particular substance. So one way of sending drugs across the blood-brain barrier is by subverting a receptor into carrying them in, too.
     Dr Pardridge has succeeded in doing so for a range of substances, including an anti-cancer drug called daunomycin. The real job of the receptor he exploits for his trick is to transport a protein called transferrin across the barrier. (Transferrin carries atoms of iron and manganese into the brain, picking them up on one side of the barrier and releasing them on the other.) Dr Pardridge is able to make the receptor carry his drug, too, by using another protein, known as a monoclonal antibody, as a molecular roof-rack.
     Antibodies are normally manufactured by the immune system. They are designed to latch on to particular substancess in a highly specific way. This allows them to neutralise key molecules in disease-causing invaders without damaging similar, but not quite identical, molecules in the body they are supposed to be protecting.
     This requires that hundreds of billions of slightly different antibodies exist in a single animal. But by cloning the cells that make a single variety of antibody, a pure version of that antibody (ie, a monoclonal version) can be produced. Dr Pardridge uses a monoclonal antibody that sticks specifically to rat transferrin receptor (like many drug researchers, his preferred experimental animals are rodents). When the receptor crosses the barrier, the antibody is also dragged across. And by attaching drug molecules to the antibodies before they are injected, these too are pulled inside the brain.
     In fact, Dr Pardridge can do better than that. By stuffing his drugs into balls of fat called liposomes, and attaching each liposome itself to a number of antibodies, he can get as many as 10,000 drug molecules across the barrier in one packet. In a paper just published in Proceedings of the Na tional Academy of Science, he has shown that his "immunoliposomes" can successfully shuttle daunomycin into the brains of experimental rats up to 24 hours after they are injected into the rats' bloodstreams.
     Nor is the transferrin receptor the only one on which this sort of trick can be pulled. At Neuromedica, a drug-delivery firm based in Conshohockon, Pennsylvania, Victor Shashoua is studying the receptor that transports cis-docosahexaenoic acid or DHA--a naturally-occurring fatty acid that forms a significant proportion of the brain's grey matter--across the blood-brain barrier. Dr Shashoua is using this receptor to sneak dopamine into the brain.
     Dopamine is one of the most important neurotransmitters, and a lack of it is implicated in several diseases, including tardive dyskinesia, a progressive loss of motor control which afflicts more than 300,000 people in America alone.
     Attempts to boost the level of dopamine in the brain in order to treat such diseases have often been thwarted by the blood-brain barrier. But Dr Shashoua has been able to increase the brain's uptake of dopamine almost eightfold by attaching it to DHA, and getting the receptor to carry it across. He hopes his DHA-dopamine combination, known as "Doprexin", may make a drug that combats tardive dyskinesia.
     If hitching a lift on a receptor fails, though, a drug designer has two other options for getting into the brain without the aid of a drill. One is to disguise the drug as something that is normally allowed in. The other is to exploit natural weaknesses in the barrier.
     Disguising a molecule usually means making it look more like a fat. Fatty molecules are able to slide across the blood-brain barrier because the membranes surrounding endothelial cells are also composed of fats. It is a general property of fats that one can easily dissolve in another. So, if a drug can be modified to make it more fatty without affecting its action, it can often be absorbed into the brain without having to involve any receptors.
     This trick was first performed over a century ago (though the details were not properly understood at the time). The result--a modified, fat-loving form of morphine that was once used as cough mixture--was named "Heroin" by Bayer, a German drug company which marketed it. It can cross the blood-brain barrier 100 times more easily than morphine. Now the trick is being recreated--ironically to assist the passage of enkephalin, one of the family of neurotransmitters that heroin mimics in order to produce its effects.
     The work is being done by Nicholas Bodor, at the Centre for Drug Discovery at the University of Florida in Gainesville. Enkephalin would make a good drug because it is a natural pain-relieving substance. But, like morphine, it is spurned by the blood-brain barrier. So Dr Bodor is attaching lipophilic chemical groups to it in order to ease its passage into the brain.
     Dr Bodor's chemical disguises are very cunning. Though fat-like in the blood and thus easily ushered through the endothelium, they are transformed by enzymes on the other side into water-soluble compounds known as pyridinium salts. This means that once through, the enkephalin is locked in by the barrier and should thus build up inside the brain.
     A paper recently published by Dr Bodor in the Journal of Medicinal Chemistry shows that enkephalin travelling through the blood in such chemical incognito does indeed concentrate in the brain, rather than the peripheral nervous system. And recent clinical trials in Britain have demonstrated that this method can work with drugs other than enkephalin. Oestrogen-- the principal female hormone--can also be effectively and selectively delivered to the brain by tinkering with it to make it more fat-soluble. This reduces the likelihood of complications from high hormone levels in other tissues.

A chink in the armour
The third way to bypass the blood-brain barrier--exploiting existing weaknesses in it--is perhaps the neatest. This is because such weaknesses are often caused by the diseases that the drugs are intended to cure.
     Occasionally, particularly in cases of cancer, the barrier lets down its guard. The blood vessels supplying gliomas--malignant brain tumours which strike almost 200,000 Americans each year--are more likely to leak than those in healthy brain tissue. This is because the diseased endothelium is much more responsive to a naturally occurring chemical called bradykinin, which causes endothelial cells to pull apart.
     Scientists at Alkermes, a drug-delivery firm based in Cambridge, Massachusetts, are exploiting this weakness in tumours in order to push anti-cancer agents across. Their weapon is RMP-7, a bradykinin look-alike, which has been biochemically tailored to increase its stability and potency. A swift intravenous dose of RMP-7 can open up the blood-brain barrier just long enough for toxic anti-cancer drugs such as carboplatin to sweep inside the tumour. And since the action is specific to the tumour, the rest of the brain--untouched by malignancy--is also unaffected by RMP-7.
     The RMP-7-carboplatin combination has been put through its paces in several clinical trials in Europe and America. Results from European studies (announced late in December) show that almost 90% of patients with recurrent malignant brain tumours that have failed to respond to surgery and radiotherapy do respond to monthly intravenous injections of RMP-7 and carboplatin. Indeed, in three-quarters of the cases the tumours were either completely stalled or even reversed. The new treatment appears to double the chance of survival. And there is not a drill in sight.