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 National 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 .

---