In for the long haul

THE problem with most pills is that their benefits do not last long. Chemicals get released into the body, they have their effect and then they get flushed out. For acute disorders, such short-term tactics may work well, but for chronic diseases they are far from ideal. Over months and years people struggle to take their medicines on time, get their dosages mixed up and may forget to take their pills at all.

The situation is worse with chemotherapy, where toxic chemicals are put into the body. Such treatments usually require regular hospital visits for the toxins to be administered and, to maximise their impact on cancer cells, the drugs are often released in such great concentrations that they cause a lot of collateral damage to healthy tissues.

For all these reasons, techniques that increase the longevity of medications in the body would be a tremendous boon. Several technologies are now being developed to do just that.

Down the hatch

One way is to combine pills and needles. Such devices are a development of the microneedle patch, a small strip of medicated material that adheres to the skin like a plaster. The patch has microscopic needles coated in dried drugs. When the needles pierce the skin the medication leaks slowly into the body.

The patches can be effective, but they have only a restricted ability to deliver delicate drugs, like insulin, due to a limit in the size of the total dose that can be delivered across a relatively small area of skin. However, Giovanni Traverso, a gastroenterologist at Harvard Medical School, reckons that microneedle technology could be improved if he could somehow get a patch into the intestines, which, being rich in blood vessels, would provide greater absorption.

To explore the idea, Dr Traverso and his colleagues designed a tiny device coated in microneedles that could be surrounded by a soft capsule, which would dissolve and release the device once inside the stomach. From there, the researchers theorised, it would move into the intestines where the needles would painlessly bump into soft tissues and release whatever drugs were on board as it made its long journey through the body.

The team first arranged for microneedles of insulin to be poked into the intestines of pigs to see if the idea would work. Then, they dropped their microneedle pills into the stomachs of pigs to determine how long the devices would stick around. As they reported in the Journal of Pharmaceutical Sciences in September 2014, the administration of insulin this way proved to be faster-acting than ordinary injections of insulin into the skin, and their devices appeared to cause no harm. Crucially, they discovered that the devices remained inside one pig for seven days, another for 19 days and one for 56 days. The researchers are now developing a new generation of microneedles to deliver a broad range of therapeutics this way.

As part of this work, Dr Traverso’s team have also developed a material that can help deliver devices into the intestines and prevent them being destroyed by the acidity of the stomach. This material is made from a novel rubber-like polymer that is both viscous and elastic. It remains solid in a highly acidic environment but breaks apart in a more neutral one. It can be used to shepherd a microneedle device safely into the intestines where it can deliver drugs for at least a week before breaking up and passing harmlessly out of the body, the group reported in Nature Materials in July.

Under pressure

A different sort of material, known as a hydrogel, also shows promise as a delivery coating. Hydrogels too can be engineered to be robust in one sort of an environment and soluble in another, but in addition they have the ability to heal themselves if they are damaged. This means a hydrogel coating should be able to endure the high pressure of being injected through a needle into a patient. Once in place, it could repair any tears that might have occurred. The problem with hydrogel self-healing has been the speed at which the process typically takes place. Until recently, any damage incurred during injection has taken one or two weeks to be fixed, by which time any medications carried within would leak before they can be properly utilised.

Eric Appel and Robert Langer at the Koch Institute for Integrative Cancer Research in Cambridge, Massachusetts, have worked with a team of colleagues to see if they could build a hydrogel that suffered less damage as it passed through a needle and, if it did sustain damage, would heal itself faster. They found that combining a derivative of hydroxypropyl methyl cellulose, an inert polymer long used in medicine as a lubricant, with nanoparticles from polystyrene—the polymer commonly found in foam coffee cups—created a remarkably adaptable hydrogel. The polymer chains from the methyl cellulose and the nanoparticles interacted with one another in such a way that they would readily form relaxed bonds under pressure, which allowed the hydrogel to flow easily when pushed through a needle, but form solidified bonds within seconds of the pressure being released. This allows the hydrogel to transform into a very useful drug-storage capsule once it is placed in the body.

When the researchers tested their creation inside mice, they loaded it with both bovine serum albumin, a compound that readily mixes with water, and Oil Red, a proprietary colouring compound that does not mix well with water. The researchers reported in Nature Communications in February that the hydrogel was perfectly capable of carrying chemicals and leaking them into surrounding tissues. Crucially, they discovered that Oil Red exited the hydrogel via diffusion while the serum albumin did so as the edges of the hydrogel were gradually eroded by exposure to water inside the body. Dr Appel and Dr Langer suggest this feature could be used to deliver multiple medicines at different rates over the course of months or even years. Which medicines might be used needs to be explored further, but prime candidates are likely to be VEGF inhibitors, which fight macular degeneration in eyes, and Risperdal, which helps to treat schizophrenia.

Another approach to long-lasting drugs involves the use of tiny tubes. Patients with ovarian cancer usually have to be regularly turned over to give toxic chemicals, which are put into part of the abdomen, a chance to maximise the number of cancer cells that they kill. Discomfort also arises from a procedure commonly used to treat bladder cancer, where the bladder is filled with aggressive chemicals and patients told to avoid going to the toilet for as long as they possibly can.

Drug-delivery technologies could help in these cases too. One example is being developed by Heejin Lee at the Massachusetts Institute of Technology and Michael Cima at the Koch Institute for Integrative Cancer Research. They use a fine coil of silicone tubing filled with drugs and inserted without surgery using a cystoscope passed through the urethra and into the bladder. When tested on rabbits it was found that as water gradually migrated through the silicone via osmosis, it slowly forced out the drugs within through a minute hole in the tubing which had been drilled with a laser. The team have established a startup called TARIS Biomedical to develop the device for clinical use.

Dr Cima is also working with Michael Birrer and Marcela del Carmen, oncologists at the Massachusetts General Hospital in Boston, to see if a similar technology can be used to treat ovarian cancer. Although such an application would require keyhole surgery to put the device in place, it might relieve patients of some of the intense chemotherapy sessions that they must currently undertake.

As with many technologies, the devices which are being developed to deliver endurance drugs need further development and testing before they can be widely used. Microneedle capsules and hydrogels, for instance, may begin testing in humans in four or five years. The device to treat bladder cancer, however, is already in clinical trials.