Researchers in Finland are working to develop targeted drugs to act as neuroprotective agents in inflammatory brain diseases and neurodegenerative diseases. Heading a project funded under a high-risk funding trial of the Academy of Finland, Academy Research Fellow Kristiina Huttunen is studying the role of prodrugs as an effective drug delivery method to cross the blood-brain barrier. Together with her team at the University of Eastern Finland (UEF) School of Pharmacy, Huttunen is investigating transporter proteins as enablers of controlled prodrug delivery to target sites in the brain. Prodrugs temporarily alter the characteristics of a pharmaceutical substance so that it can act as a substrate of transporter proteins and be targeted more effectively.
“The blood-brain barrier prevents harmful substances in the blood circulation from entering the brain and the central nervous system. Unfortunately, the barrier often also blocks drugs from reaching desired target brain cells. In our research, we’re developing amino acid prodrugs that utilise the transporter protein LAT1, which is selectively expressed in the blood-brain barrier and in brain cells. LAT1 delivers the drug naturally to the brain across the barrier and releases the active substance only when it reaches the target site,” explains Huttunen.
Researchers at the UEF have long investigated the utilisation of the LAT1 transporter protein in targeted drug delivery. Kristiina Huttunen’s project builds on previous work, further elaborating on the possible cell population targets in the brain for neuroprotective agents that take advantage of the transporter protein.
“At present, most pharmaceutical substances used to treat neural diseases cannot cross the blood-brain barrier, which means that not enough drugs make their way to the brain. To compensate, the drug dose may be increased to the point where its toxic effects become visible in other parts of the body as well. Correspondingly, if the dose is too negligible, the drug won’t produce the desired effects,” says Huttunen.
New method could also benefit cancer therapy
Next, Huttunen and her research team is proceeding from the design, synthesis and cellular characterisation phase to animal testing in order to better predict the effects of the drugs in the human body. Huttunen hopes that the prodrugs being developed will be of clinical benefit to the treatment of inflammatory brain diseases and disorders of the central nervous system (CNS). At present, she says, there are no such prodrugs available on the market.
“In future, our prodrug method could also be used in other drugs that target the brain. If successful, the transporter-utilising prodrug technology could also benefit other forms of therapy that require targeted drugs, such as cancer therapy.”
Targeting drugs increases the neuroprotective effects, but it also reduces toxic side-effects. Huttunen is keen to point out that their method to transport and release the drugs is as natural as possible.
“I’m studying entirely new types of perforin inhibitors from which the prodrugs will be developed. Perforin is an endogenous protein that is involved in immunosurveillance, destroying foreign cells such as viruses, bacteria and cancer cells. Perforin is produced by lymphocytes as the body’s immune system is activated. In autoimmune diseases and many degenerative CNS diseases, perforin abnormally attacks healthy cells, which creates the need for perforin inhibitors. Prodrugs that utilise the LAT1 transporter protein can help transport perforin inhibitors to the central nervous system where they can block the damaging effects of perforin without interfering with the immune system elsewhere in the body.”
Drug development always includes risks
There are always risks involved in trying to develop new pharmaceutical drugs, says Huttunen. What’s more, the risks grow larger as the research reaches deeper and deeper. Usually, drugs that have been brought into clinical testing may turn out either too ineffective or too toxic.
“We need good operational tools and measurement methods to be able to design novel drug molecules and prodrugs. Drug development always raises questions about the drugs’ efficiency and their pharmacokinetic behaviour in the body. Sure, we can try to predict these characteristics, but despite all our prediction software and expertise, we still can’t control every aspect.”
Huttunen and her team thankfully have decades of experience in prodrug development and ample access to previous research on the LAT1 protein, which significantly reduces the risk of research failure. Huttunen’s team makes use of computer-assisted structure-activity analysis, which reduces the risks even further.
“Right now, we’re studying possible structure-activities of LAT1 that may overlap with other amino acid transporter proteins. Such overlaps could impair drug targeting to the brain. Experience has shown us what types of structures will allow the prodrugs to release the active drug site-selectively in target tissues. Our research – if successful – can yield significant results, so I think the risk is well worth taking,” Huttunen says.
The Academy of Finland’s high-risk funding came as a pleasant surprise to Huttunen.
“It’s really great that the Academy places high-risk projects in their own category – the risks involved in different research fields come in many different types and sizes.”
Finnish text: Anna-Riikka Oravakangas
Photo: Anita Westerback
- Academy of Finland supports scientific risk-taking with purpose-made funding (Academy press release, 2 Sep 2015)