More efficient drug delivery within the brain by utilizing LAT1

University of Eastern Finland

Press release, 24 September 2019

According to a new study carried out at the University of Eastern Finland, the distribution of drug molecules within the brain can be improved by utilizing LAT1, which is expressed highly in the brain. By converting drug molecules temporarily into prodrugs, derivatives that can utilize LAT1 for cell entry and subsequently release the active parent drug within the target cells. This way one can achieve many times higher concentrations compared to the treatment with the parent drugs alone, which cannot utilize LAT1. This is very important, particularly in a situation where the final target protein is located inside the cells. This study was published in Scientific Reports in the beginning of September.

The blood-brain barrier (BBB) regulates the delivery of all substances from the blood circulation into the brain. Its main function is to protect the central nervous system (CNS) from harmful substances while allowing the entrance of required nutrients, such as sugar, water and oxygen. Therefore, the majority of drug compounds, which are supposed to act within the brain, do not permeate across the BBB at sufficiently high levels in order to treat brain diseases effectively. However, the BBB expresses several transporters by which the essential nutrients are delivered from the blood circulation into the brain.

The research group led by Adjunct Professor Kristiina Huttunen from the University of Eastern Finland, School of Pharmacy, has been studying LAT1 for a good period of time. They have also proved that LAT1 can be efficiently utilized for brain-targeting and enabling the delivery of drugs across the BBB, since LAT1 is expressed highly in the brain in comparison to any other healthy organs. In the present study, the research group investigated the utilization of LAT1 in intrabrain-targeted drug delivery after the drug molecules have passed the BBB.

It was proved for the first time in this study that functional LAT1 is expressed on the cell surface of neurons, but also in the supporting cells, astrocytes and microglia. In addition, in this study it was demonstrated that the LAT1-utilizing prodrugs of several different compounds, such as anti-inflammatory drug, ketoprofen and antioxidant ferulic acid, displayed improved cellular uptake compared to their parent drugs. The same results were also achieved with astrocytes having features of Alzheimer’s disease.

“We were also able to identify structural requirements for the prodrugs that could enable targeting between the different brain cell types in future, says the first author of the study, PhD student Johanna Huttunen

Thus, by utilizing the LAT1-prodrug approach, it is possible to achieve drug concentrations relevant for the pharmacological effects in the diseased brain, which has been one of the major challenges to overcome in the CNS-drug development. Adjunct Professor Huttunen says that the best results, i.e. the development of more effective drugs to treat brain diseases, can be attained only if drug delivery within the brain is taken into account as early as possible in the drug development phase; this would be when we are structurally designing novel CNS-drugs.

For further information, please contact:

Kristiina Huttunen, Adjunct Professor, University of Eastern Finland, School of Pharmacy, Kuopio, tel. +358 407440117, kristiina.huttunen@uef.fi

Research article:

Huttunen, J.; Peltokangas, S.; Gynther, M.; Natunen, T.; Hiltunen, M.; Auriola, S.; Ruponen, M.; Vellonen, K.-S.; Huttunen, K. M. L-Type Amino Acid Transporter 1 (LAT1/Lat1)- Utilizing Prodrugs Can Improve the Delivery of Drugs into Neurons, Astrocytes and Microglia. Scientific Reports, 2019, 9(1): 12860-12872. https://doi.org/10.1038/s41598-019-49009-z

About Us

The University of Eastern Finland, UEF, is one of the largest universities in Finland. The activities of the UEF underscore multidisciplinarity, and the university is especially strong in research related to forests and the environment, health and well-being, and new technologies and materials. The UEF offers teaching in more than 100 major subjects. In addition to the high standard of teaching, the university offers its students a modern study environment, which is under constant development. The university comprises four faculties: the Philosophical Faculty, the Faculty of Science and Forestry, the Faculty of Health Sciences, and the Faculty of Social Sciences and Business Studies. The university’s campuses are located in the heart of beautiful eastern Finland in Joensuu, Kuopio and Savonlinna. The UEF is home to approximately 15 000 students and nearly 2 800 members of staff.

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    http://www.uef.fi/en
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