The Operating Theatre Journal - Journal - Page 29
A thyroxine derivative enhances brain drug delivery
A new study from the University of Eastern Finland shows that the delivery of drugs into the brain, and especially into glial cells, can be enhanced
with prodrugs that temporarily incorporate thyroxine or a thyroxine-like molecule. The transporter protein OATP1C1, which is found in the brain,
can be utilised in the delivery of such prodrugs. The results were published in Journal of Medicinal Chemistry.
For the 昀椀rst time ever, researchers used the organic anion-transporting polypeptide 1C1 (OATP1C1) to enhance drug delivery into the brain. In the
study, prodrugs were used to transport anti-in昀氀ammatory drugs into the brain, where they were ef昀椀ciently delivered into glial cells. Glial cells
support neurons and are known to be activated in many brain diseases to produce mediators that maintain in昀氀ammation. Hence, in order to have
an impact on chronic in昀氀ammation in the brain, it is crucial to deliver anti-in昀氀ammatory drugs into precisely the right cell types. The concept is
completely new even on a global scale.
Researchers at the University of Eastern Finland School of Pharmacy have long been attempting to enhance brain drug delivery by using the L-type
amino acid transporter 1, i.e., the LAT1 protein and prodrugs that utilise it, amino acid derivatives. However, the OATP1C1 transporter protein
used in the new study was found to be far more effective at transporting thyroxine derivatives than LAT1.
The study employed computational molecular modelling to create protein models that were used to design and synthesize new prodrugs.
Drug transport mechanisms remain surprisingly poorly understood
“A surprising observation from our study was that increasing the molecular size of drugs enhanced their delivery into the brain and into glial cells.
Up until now, it has been thought that a large molecular size isn’t exactly helpful in brain drug delivery,” says Research Group Director, Associate
Professor Kristiina Huttunen of the University of Eastern Finland.
“This study highlights how poorly we still understand drug transport mechanisms in our system. This is also a major reason why many new drugs,
especially those intended to affect the central nervous system, unfortunately never make it to the market. The more we know about these
transport mechanisms, the better we can take their effects into account when seeking to in昀氀uence the distribution of drugs in our body. This
should also be taken into account very early on in drug development.”
The study constitutes part of a research project funded by the Research Council of Finland.
For further information, please contact:
Associate Professor Kristiina Huttunen, University of Eastern Finland, School of Pharmacy, tel. +358-40-3553684, kristiina.huttunen@uef.昀椀
Research article:
Arun Kumar Tonduru*, Seyed Hamed Maljaei, Santosh Kumar Adla, Landry Anamea, Janne Tampio, Adéla Králová, Aaro J. Jalkanen, Catarina
Espada, Inês Falcato Santos, Ahmed B. Montaser, Jarkko Rautio, Thales Kronenberger, Antti Poso, and Kristiina M. Huttunen. Targeting Glial Cells
by Organic Anion-Transporting Polypeptide 1C1 (OATP1C1)-Utilizing l-Thyroxine-Derived Prodrugs
J. Med. Chem. 2023, XXXX, XXX, XXX-XXX
https://doi.org/10.1021/acs.jmedchem.3c01026
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Issue 398
November
2023
29
