If drugs could be targeted to exactly the right place in the body, we could probably do with significantly smaller doses – and consequently fewer side effects. To allow for such precise delivery, we need tiny nanocarriers and even smaller nanotrackers to monitor them. Researchers in Finland are working on both of these.
A minuscule marker molecule carries radioactive fluorine-18 atoms. The molecule is only a few hours old. It cannot be much older, as fluorine-18 is not particularly stable. The half-life of its radiation is only two hours. No more than six hours after its creation, the fluorine-18 is sufficiently decomposed that a PET camera would not be able to detect it in the body of a laboratory animal.
This is not the only reason the molecule is in a rush. It, and thousands of its kind, are trackers, which spread through the body in the bloodstream at a speed of approximately 4.5 centimetres per second. Their goal is to find fragments of porous silicon. The fragments are much larger than the molecule, approximately 150 nanometres (i.e., 0.001 millimetre) in diameter. At this scale, blood flows at a dizzying pace.
A five-minute journey
At its target, the tracker should be able to grasp the silicon and remain attached to it. Otherwise the molecule will continue on its way to the kidneys, the bladder and eventually out of the body.
In total, its trip takes about five minutes. Within that time, most of the trackers will have made their way through the kidneys and into the urine.
However, approximately 20% of them will have adhered to porous silicon fragments.
“An accuracy of 20% is enough to give us an idea of where the silica has accumulated in the body,” explains university researcher Anu Airaksinen from the University of Helsinki’s Laboratory of Radiochemistry, who leads a research group that is working on nanotrackers.
In a hospital, this would be determined through PET imaging. As the University does not have a PET camera, researchers on the Kumpula Campus determine the location of the trackers from tissue samples.
In general, Airaksinen’s team has tremendous independence. They synthesise their own fluorine-18 atoms in the cyclotron in the Laboratory's basement, attach them to the trackers and follow their progress in animal models.
Back to Turku
This story really begins in Turku, where university researcher Jarno Salonen began to study porous silicon at the University of Turku’s Laboratory of Industrial Physics in the mid-1990s.
In the early 2000s, Salonen was reading an article which described how silicon-based compounds could be used to manufacture nanoscale carriers. He wanted to see if the same would be possible with porous silicon. It was.
A porous silicon nanocarrier looks rather like an extremely small wiffle ball, with deep recesses instead of holes. The drugs are carried in these recesses.
Bouncing silicon balls
Packaging drugs at the molecular scale comes with many benefits. A very small dose is sufficient if targeted accurately, and the drug compounds cannot crystallise inside the minuscule nanocarrier. This makes them more effective.
Porous silicon also has numerous benefits when compared with the lipid membranes which are currently used as nanocarriers. Silicon is denser than lipids, and it is easier to manipulate. Whereas the lipid releases its entire drug load at once, a silicon carrier can be structured so that the drug will be released slowly, or only when a specific external factor, such as heat, is present.
For treatment, the silicon balls must first be filled with drugs. This is what the researchers on the Viikki Campus are doing.
A key to a lock
Professor Jouni Hirvonen and university lecturer Hélder Santos from the University of Helsinki’s Faculty of Pharmacy know porous silicon well. Hirvonen has worked with Salonen since 2003, and Santos joined them in 2007.
The Viikki researchers receive the nanocarriers from Turku, and pack them with drugs. At the moment, there are three lines of research: the use of nanocarriers is being investigated in the treatment of cancer, diabetes and cardio-vascular disease.
Filling the carriers with drugs is not a problem.
“We use standard drugs. We haven’t had any problems with them,” says Hirvonen.
Hirvonen showers praise on Salonen’s carrier.
“Porous silicon is an excellent material: it’s stable, but compatible with biological tissues. You can do a lot with it.”
Despite the excellence of the carrier, the system is still under construction.
“We need to get the drug to the right place in the body, as quickly as possible. It needs to remain stable in the body.”
For this purpose, the researchers manipulate the surface of the silicon carriers, with the intention of making them react only with the intended cells.
“You could think of different cells as different types of locks. We’re trying to equip the carriers with keys that would only fit the right locks.”
A porous silicon nanocarrier looks like a tiny wiffle ball, with deep indentations in which the ball carries the drugs to their target. Porous silicon particles, or PSi's, can contain one drug and be coated with another, which may enable the treatment of several diseases simultaneously. In addition to cancer treatments, the PSi method is being tested for cardio-vascular disease and diabetes.
The walls of cancer cells are typically more permeable than those of other cells in the body. This means that carriers which are too large to pass through normal cells can be used for cancerous ones.
But first, the carrier must identify the correct cells.
An entirely different issue is circumventing the body’s defensive systems so that white blood cells do not attack the carriers.
This means that there are many challenges – but the benefits are equally numerous.
Current chemotherapy is not a precision tool. In addition to the tumour, the toxin used in the treatment is carried throughout the body, making patients ill.
With the help of nanocarriers, the cytotoxins could instead be delivered exclusively to cancerous cells. Then the dosage could be a fraction of current recommendations, and side-effects much less pronounced.
The biggest benefit of nanocarriers is that their applications are essentially limitless. In theory, every patient could receive drugs personalised specifically for his or her system.
This could revolutionise vaccinations, for example.
Nanocarriers transfer medicine to its target, e.g., a cancer drug to a cancerous cell. The goal is to develop personalised, targeted medication for each patient to minimise side-effects. Precision drugs can also help activate cellular pathways which can lead to the destruction of cancerous cells.
But let’s not get ahead of ourselves. At the moment, the development of nanocarriers is at the animal experimentation stage. The next step would be human trials, but just launching an experiment with human subjects can cost a million euros.
“We’re looking for partners,” Hirvonen explains.
“It hasn’t been easy.”
The situation may soon change, however, as the pharmaceutical use of porous silicon is about to be approved by the EU. This means that the path from research to production is open – at least in theory.
Another issue is accuracy. At the moment, only about 1% of nanocarriers reach their target. But this is not a hopeless figure.
“If we think that we could increase a 0.5% accuracy to 2%, that’s already a four-fold improvement,” Hirvonen points out.
Improving accuracy is therefore a key issue for the development of nanocarriers. Let’s go back to Kumpula and to Anu Airaksinen to hear her team explain what should be done.
Airaksinen has developed trackers which seek out the carriers in the body and attach to them. The research group is taking a novel approach. Previously, nano-delivered drugs were tracked by stamping them before administration. As the molecules used in the stamping quickly lose their efficacy, it was only possible to track the first few hours of the nanodrug's journey.
However, it may take several days for the nanocarriers to accumulate in their target. A tracker administered retroactively could help study the progress of the drug over a much longer timespan.
“With the trackers, we can monitor where the nanodrug ends up after a longer period of time. We can also send several batches of trackers to monitor the drug.”
The method is simple; the only instrument needed is a PET scanner which is standard equipment in any modern hospital.
Nanotrackers track the nanocarrier as it moves through the body. The trackers are even smaller than the tiny carriers. The trackers can reveal where the nanodrug ends up over a longer timespan and can be monitored with a PET scanner which is standard equipment in hospitals. Nanotrackers may also be able to monitor the lipid and polymer carriers which are already in use.
On the brink of a breakthrough
However, a tracker administered retroactively must be able to attach to the carrier inside the body, where the conditions are more challenging than in a test tube.
This was successfully attempted for the first time in spring 2015, when Outi Keinänen, a doctoral student in Airaksinen’s research group, was on a researcher exchange in Amsterdam.
“They had a special PET camera for small animals. Keinänen asked me whether she should try it, and I said of course," Airaksinen recounts.
The result was a success and Airaksinen received the good news as an image attachment in her email.
“I was delighted!”
Airaksinen’s team is also focusing on accuracy. The trackers need to be made even better. Even though an accuracy of 20% is sufficient, it should be the standard regardless of the type of cell targeted by the nanodrugs in the porous silicon carrier. It may also be possible to use the nanotrackers on other materials.
“We could also attach trackers to the lipid or polymer carriers which are already in use,” Airaksinen estimates.
That would bring us one step closer to a breakthrough in better medication.
Read the article about the work of Hélder Santos’ research group in this issue: PSi hits the spot.
This article was published in Finnish in the Y/08/16 issue of Yliopisto magazine.