Science Spin September 2009

Getting drugs where they are needed

Cancer and cardiovascular diseases in all their various forms are among the leading causes of death in the developed world, and could well become more so as we live longer and defeat other diseases. Medical research is continually coming up with new treatments for both diseases, and a great deal of this research looks to improve the delivery of drug therapy to patients.

Currently, powerful drugs to treat these diseases are administered intravenously or orally. These methods allow only limited control over how the drug is distributed in the body. The drug can therefore circulate in the patient's bloodstream and interact with different tissues and organs, not just the diseased one being treated but with healthy organs too.

NEW

Now a new image-guided method of delivery may become available in a few years time, if a major European project called SonoDrugs is successful. SonoDrugs is aimed at developing drug delivery vehicles that can be tracked using ultrasound or magnetic resonance imaging (MRI), with ultrasound used to release the drugs at the desired location.

An important element of this project is the use of tiny bubbles (microcapsules) to carry the drugs. These are so small that they can be produced only by nanotechnology. So, in tandem with the imaging techniques, nanotechnology is offering the hope of significant improvement to treatment outcomes and to the comfort of the patient undergoing the therapy.

Nanotechnology involves the manipulation of materials down to the atomic and molecular level. Sizes are expressed in nanometres (nm). A nanometre is one thousand-millionth of a metre. These new materials can behave quite differently to conventional ones, and, therefore offer exciting possibilities for innovation. The other side of the coin is that this very novelty means that safety in use has to be ensured.

Nanotechnology has already produced new cosmetics and industrial materials that are available for the general public to buy. With scientists eagerly examining other applications, we can expect many new developments over the coming years, notably in medicine and healthcare. The SonoDrugs project is a good example.

DELIVERY

Using an innovative combination of ultrasound and tiny capsules of drugs, SonoDrugs researchers are aiming to provide doctors with a method of delivering treatment at the point in the body where it is needed, rather than having the drug dispersed around much or all of the entire body.

This fine-tuning offers obvious possible advantages: perhaps a lower dose can be used to provide the same level of efficacy as a larger dose delivered by other means; perhaps the therapy may be much more effective at the same dose delivered conventionally; or even in some cases, maybe both advantages will apply.

It is hoped that such treatments will mean a lowering of the mortality rate from cancer and cardiovascular ailments, and also mean that fewer days are taken off work by patients being treated. So apart from the improved quality of the patient's life, the overall benefit to economies could be substantial, not least because of fewer days lost from work by patients recovering from treatments.

The European Union has given an impetus to this kind of research by providing €10.9 million over four years under the 7th Framework Programme to the SonoDrugs project, roughly two-thirds of its total €15.9 million total cost. T

he project began last November (2008), with industrial partners from The Netherlands, France, Finland and Germany. Medical centres in The Netherlands and Germany are also involved, as are university researchers in Belgium, Cyprus, Finland, France, Italy, the Netherlands and the United Kingdom. Ireland is not a partner, but doubtless any effective and improved drug-delivery techniques developed under SonoDrugs will eventually benefit some Irish patients.

Dutch multinational Philips is leading the project, and Hans Hofstraat, Vice-President of Philips Research, talked to journalists about it at the EuroNanoForum in Prague this summer.

CAPSULES

"The key is the combination of imaging techniques with nanotechnology," said Dr Hofstraat. Once the tiny capsules containing the drug or drugs have been dispersed though the blood stream, they are activated at the point in the body where they are needed by bursts of ultrasound, frequencies higher than can be heard by the human ear.

"The big advantage of ultrasound is that it can be used for treating the whole body," he said. "Light cannot reach inside the human body, but ultrasound can be focused on any part. It does not go through bones easily, but ultrasound equipment can be moved around, so that is not a problem."

Dr Hofstraat explained that the drug delivery technology being developed in the SonoDrugs project will utilise drug-loaded particles, typically between 100 nm and 2000 nm in diameter, that are designed to carry drugs along the bloodstream to the site to be treated. At these very small diameters the particles are easily transported by normal blood flow through even the finest capillaries in the vascular system, and they can penetrate deep into diseased tissues.

GUIDANCE

First of all the capsules have to be manoeuvred into position, and real-time guidance is essential. It is envisaged that the medical staff will be able to use either ultrasound or Magnetic Resonance Imaging (MRI), whichever is better suited to the particular procedure, to watch for the arrival of the nanoparticles at the part of the body to be treated. Once in place, melting or rupturing of the tiny capsules releases the drug.

Whether the nanoparticles melt or rupture depends on what they are made of. Under the SonoDrugs project, two types of carrier are to be made.The first of these will have a shell made of a material that melts or becomes porous at a temperature that is just a few degrees above normal human body temperature. The heat required to melt or increase the porosity of the shell in order to release the contained drug will be provided by the local heating effect of the focused ultrasound.

The second type of nanoparticles will be larger in diameter than the first. It will have a shell made of a material that ruptures because of pressure-induced stresses generated by the focused ultrasound pulses. Often called microbubbles, gas-filled particles of this type are already used as a contrast agent for ultrasound imaging.

One question asked of Dr Hofstraat was what happened to the melted or ruptured nanoparticles after they had done their job of delivering the drug to the correct spot.
"The outer shell is biocompatible and will be removed by the liver, kidneys and other organs without doing any harm," said Dr Hofstraat. "We still have to do the toxicology tests, though, and we expect it will take about ten years for the technology to become available [for use in hospitals]."

All EU projects have to undergo a risk assessment, and nanotoxicology is a young science. The question of the safe use of nanotechnology was a theme running though the Prague EuroNanoForum. Paul Reip of Intrinsiq Materials Ltd UK, who spoke about detailed work on how to measure safety of nanomaterials, pointed out that Nature already produces nanomaterials.

"There are a lot of nanoparticles out there already that we happily live with," he said. "The question is, what about engineered nanoparticles?"

Anna Nolan attended EuroNanoForum as a guest of the European Commission.