A SPOONFUL of sugar may help the medicine go down. But it won鈥檛 always
deliver the right dose to the right place. Researchers round the globe are
designing molecular packaging to do just that, making drugs more efficient,
safer and more convenient. In future, treatments for everything from flu to
cancer will be washed down with polymers, magnets or even bacteria.
There are plenty of ways to take drugs鈥攁s liquids or pills, through
inhalers or injections. But each has drawbacks. What the body usually needs is a
slow, steady dose over a day or so. But what it often gets with traditional
delivery systems is a burst of medicine which then trails off. Patches on the
skin can release drugs slowly, but the drug circulates throughout the
body鈥攏ot just to the affected regions. This can cause terrible side
effects when the drug is toxic, as in cancer chemotherapy.
Drug traps
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A couple of decades ago, Robert Langer at the Massachusetts Institute of
Technology decided this had to change. He was one of a group of pioneers who
first turned to polymers. Polymer molecules naturally mould into net-like
structures that are ideal for trapping drugs. Many polymers are inert, and can
sit in the body without affecting it. And because much of the body is made up of
naturally occurring polymers, our immune systems don鈥檛 reject them.
Langer鈥檚 faith in polymers paid off. In the 1970s, his team used them to
improve the delivery of a new anticancer drug. The drug could be applied
directly to tumours, but it was always swept away because it was highly soluble
in bodily fluids. Langer鈥檚 group made a new delivery system by mixing the
powdered drug with a polymer dissolved in a solvent. When they removed the
solvent, a small pellet of solid polymer remained, with the drug trapped inside.
Under a microscope the pellets looked like lumps of Swiss cheese with the drug
trapped in the holes.
The pellets could be implanted in the body, and the drug would slowly seep
out over days or weeks. But Langer discovered a drawback: the delivery rate fell
over time because the polymer pellet stayed intact while the trapped drug had to
percolate up from deeper and deeper layers.
In 1983 Langer solved this problem by changing the shape of the pellets. The
new versions were hemispheres, with a coating that only allowed the drug to
percolate out through a small indentation in the flat portion (see
Diagram, p
26). Over time, the drug seeped out of the centre creating an ever-widening zone
of empty polymer. Although the drug molecules had to travel farther to escape as
time passed, the surface area of drug-laden polymer was increasing, so the
delivery rate remained constant.
Polymer drug delivery reservoirs such as these are now in use. The US Food
and Drug Administration approved two types for hormone release therapy in 1989
and 1990. These release systems鈥攐ne to treat prostate cancer, the other
endometriosis鈥攁re manufactured commercially under the trade names Lupron
Depot and Zoladex.
But the most stunning leap came from trying out biodegradable polymers. This
approach uses a polymer cage that is strong enough to contain the drug and to
withstand being implanted. Under the onslaught of the body鈥檚 biological
mechanisms, the cage erodes and releases the medicine. This new technique has
led to a breakthrough in the treatment of brain tumours. This year it became the
first brain cancer treatment to win approval from the US Food and Drug
Administration in a quarter of a century.
In his early work on biodegradable polymers, Langer had to overcome some
serious hurdles. He found that instead of wearing away gradually to release the
drug slowly, many biodegradable polymers can crumble suddenly into chunks, which
could cause dangerous overdoses. His group overcame the problem using a polymer
that is water soluble. The polymer is made of two acidic molecules, one more
water soluble than the other. By varying the ratio of the two ingredients,
Langer鈥檚 team have fine-tuned the solubility of the polymer so that it breaks
down gradually at exactly the right rate.
During the clinical tests of the new polymers, Langer worked closely with
Henry Brem of Johns Hopkins University School of Medicine in Baltimore,
Maryland. They hoped the new polymer might deliver drugs to attack brain
tumours. More than 20 000 operations to remove brain tumours take place each
year in the US alone. One drug that helps prevent tumours recurring is
carmustine. But injecting carmustine was always a problem because little of the
drug seemed to cross the blood-brain barrier. And like most chemotherapy drugs,
it is highly toxic to the rest of the body.
Mopping up
Brem鈥檚 group built a delivery system from discs of the new biodegradable
polymer. Several discs containing carmustine were implanted in patients鈥� brains
during surgery, and as the discs degraded, they released the drug gradually to
the surrounding brain tissue over several weeks. This localised treatment seemed
promising because the most common type of brain tumours tend to reappear in the
same place again and again. An implant might even stop the tumours for good by
mopping up any cancerous cells left after surgery, especially if used with
traditional treatments such as radiation therapy.
The real promise of the brain tumour drugs became clear last year. Brem鈥檚
group showed that patients treated with the implants had a 50 per cent greater
survival rate than a group that simply had the tumour removed and empty polymer
discs implanted. What鈥檚 more, there were no side effects. The FDA approved the
implants this year. They are now made and marketed by Guilford Pharmaceutical in
the US.
Langer鈥檚 work on biodegradable polymers could also eventually save lives in
transplant surgery. Liver donors are in such short supply that nearly a quarter
of people on transplant waiting lists in the US die before a liver becomes
available. But now doctors can take cells from healthy liver tissue and grow
them on a scaffold of polymers, which acts as a template for cell growth. The
cells could even come from the patient and be made healthy by genetic
engineering, before being cultured into much bigger quantities and put back in
the body.
Survival booster
One possible problem with this approach is that the replaced tissue cannot
survive alone. It needs to grow new blood vessels, which is where drug delivery
comes in. This year Langer鈥檚 group devised a way to seed the newly implanted
tissue with microscopic biodegradable polymer spheres that contain epidermal
growth factor, which stimulates blood vessel growth. The growth factor escapes
slowly to the local area, increasing the implant鈥檚 chance of survival. In tests
on rats this method doubled the proportion of successful liver implants.
Tiny biodegradable spheres such as these are also paving the way for new lung
cancer treatments. Robert Auerbach at the University of Wisconsin has developed
a system using polymer spheres, 10 to 20 micrometres in diameter, that contain
drugs such as carmustine. In 1992 he tested the treatment on mice with lung
tumours by injecting the microspheres directly into each mouse鈥檚 trachea. The
anticancer drugs diffused slowly into the lungs and reduced the tumours by up to
90 per cent. Again, there was no sign of the typical toxic reactions to such
drugs in animals, such as loss of bone marrow and even death.
Biodegradable polymers look set to change traditional vaccines. Many
vaccines, tetanus for instance, are given in several doses because they take a
long time to work. But it would be much better if the drug were released
gradually. In 1993, Langer鈥檚 team put the tetanus toxin into microscopic spheres
of biodegradable polymer which would release it steadily. When they tested this
on mice it produced antibody levels 17 times higher than those produced by fluid
vaccines.
Of course not everyone wants a steady release of drugs. For example, diabetic
patients suffer from jumps in blood sugar levels after meals, and inject insulin
to return the levels to normal. But it would be much more convenient to store
the drugs in a pocket inside the body, to be released in bursts when
necessary.
In the early 1980s, Langer鈥檚 group found what they hoped would be the answer.
They took flexible polymer pellets and impregnated them with insulin and a
regular array of tiny magnetic spheres. Once implanted, the polymer could be
activated by spinning a bar magnet outside the body. As the implant magnets
pulsed to the rhythm of the powerful bar magnet, they deformed the polymer and
pumped out insulin 30 times faster than when the pellet was at rest.
In animal tests, blood sugar levels dropped within 20 minutes when the
magnetic insulin spheres were 鈥渟witched on鈥�. A private company has a licence to
develop the method. According to Langer, development has been slow because
insulin is potentially very dangerous and an accidental overdose during human
trials could be fatal. But he hopes the technique will lead to a safe
treatment鈥攑erhaps a programmable magnetic device worn like a wristwatch
that would trigger the drug delivery.
Many other groups are investigating the use of polymers for drug delivery. At
the Artificial Organ Laboratory in Brown University, Rhode Island, Edith
Mathiowitz has devised a way to release two drugs simultaneously. She has made
microscopic polymer spheres that are double walled, with an inner core made of a
different polymer from the outer coating. Mathiowitz is at an early
stage鈥攕he tested the way the spheres degrade in rats only last year. But
she hopes many kinds of delivery systems could evolve from her work.
For instance, different drugs could be trapped in the core and in the outer
layer. This could deliver two drugs at the same time but at different rates. The
core or the outer polymer could be stable and the other layer biodegradable to
give new kinds of release patterns.
Designer jewellery
Mathiowitz is also hunting 鈥渂io-adhesive鈥� polymers鈥攖hose that have the
right shapes and chemical bonds to attach to mucus linings such as those in the
lungs or intestines. This would give implants longer to release their
contents.
More sophisticated approaches to holding drugs in polymers are
emerging. Julio San Roman of the Institute of Polymer Science in Madrid and his
colleagues have found a way of binding the drug molecules onto the polymer,
rather than trapping them in a polymer cage. The new designer polymers are like
charm bracelets, with a simple backbone that supports dangling groups, including
the drug molecules.
San Roman鈥檚 group has synthesised stable polymers with drugs such as
paracetamol. Although the polymers float through the body with impunity, the
bonds holding the drugs are attacked and severed by the body鈥檚 enzymes. As the
drugs are slowly released, the remaining polymer backbone becomes ionised and
water soluble, so it is quickly and harmlessly excreted.
When the researchers tested these systems on mice last year, they found they
delivered sustained amounts of drugs for up to 10 times longer than traditional
methods. They hope it will be possible to inject aqueous solutions of similar
polymer drugs into the joints of people with arthritis, where they would
steadily deliver the medicine for weeks or months.
Roman鈥檚 polymers have another odd but useful property鈥攖hey are about 25
times as effective at preventing blood aggregation as aspirin. In 1994, San
Roman used them to coat prosthetic blood vessel grafts to discourage the
build-up of platelets.
Among the more bizarre of the emerging ideas for packaging drugs is to use
salmonella, a bacterium that can cause anything from food poisoning to typhoid
fever. The properties that make salmonella so deadly also make it an excellent
carrier for vaccines鈥攊t can penetrate the entire body, eliciting immune
responses in crucial areas like the mucosal linings, lymph nodes, liver and
spleen.
Of course, it is essential to tame the live bacteria. Genetic engineering can
create active but harmless hybrids of salmonella by selective breeding and
mutations. Genetic material from organisms to be inoculated against can be added
to the mutated salmonella, which will produce proteins that trigger immune
responses to the organism.
This might lead to a new vaccine for whooping cough, for instance. In 1992,
Mark Roberts of the Department of Biochemistry at Imperial College in London
mutated a salmonella vaccine strain to produce a protein usually made by
whooping cough bacteria. In tests, this method immunised mice against whooping
cough. The same approach should work for parasites and viruses鈥攁nything
from leishmania to flu.
In 1990, Bruce Forrest of United Biomedical in Hauppauge, New York, ran
limited human tests of a salmonella/cholera vaccine using volunteers. Although
the vaccine appeared to be safe and reduced the often fatal diarrhoea induced by
cholera, it did not provide complete immunity. And because of the potential
danger, few other clinical trials have been carried out. But Roberts says more
trials will soon be under way. The next will be a long study of the safety and
effectiveness of an oral typhoid vaccine using a weakened salmonella strain.
From a spoonful of sugar to friendly germs, drug delivery has become
high-tech. New wonder drugs have been hailed as the greatest milestones in
medicine. But new delivery systems for medicines are poised to steal the
limelight. Physicians are realising what advertisers have known for years: the
package may be as important as the contents.
