Intra-Brain Targeting

Solute Carriers (SLCs) are highly and selectively expressed in the brain in relation to other healthy tissues. For example, L-type Amino Acid Transporter 1 (LAT1), Organic Anion Transporting Polypeptides (OATPs), Monocarboxylate Transporters (MCTs), Organic Cation Transporters (OCTs) and Organic Anion Transporters (OATs) are highly and/or selectively expressed on the blood-brain-barrier, and in certain brain cells, such as neurons, astrocytes, and microglia or in activated immune cells. Therefore, those transporters can be utilized for brain-targeted as well as intra-brain targeted drug delivery.

The main aim of our research group is to study the utilization of these transporters in

1. Targeted (pro)drug delivery of neuroprotective agents across the BBB
2. Targeted (pro)drug delivery into target cell types within the brain

The research in this area is expected to increase the efficacy of drug therapies related to central nervous system (CNS)- diseases due to the increased drug accumulation to the desired tissues and cells. However, it is expected to decrease simultaneously unpleasant adverse effects that arise from unselective drug delivery and the distribution of drugs to off-target organs. We are especially interested in CNS-diseases, in which neuroinflammation is related, such as neurodegenerative disorders (such as Alzheimer’s Disease, Parkinson’s Disease, Multiple Sclerosis, etc.), stroke and acute brain infections.

Selected Publications

Utilization of LAT1 as a carrier to Target (Pro)drugs into the Brain

Hugele, A.; Löffler, S.; Molina, B. H.; Guillon, M.; Montaser, A. B.; Auriola, S.; Huttunen, K. M. Aminopeptidase B Can Bioconvert L-Type Amino Acid Transporter 1 (LAT1)-Utilizing Amide Prodrugs in the Brain. Frontiers in Pharmacology, 2022, 13, 1034964. https://doi.org/10.3389/fphar.2022.1034964

Montaser, A. B.; Kuiri, J.; Natunen, T.; Hruška, P.; Potěšil, D.; Auriola, S.; Hiltunen, M.; Terasaki, T.; Lehtonen, M.; Jalkanen, A.; Huttunen, K. M. Enhanced drug delivery by a prodrug approach effectively relieves neuroinflammation in mice. Life Sciences, 2022, 310, 121088. https://doi.org/10.1016/j.lfs.2022.121088

Tampio, J.; Löffler, S.; Guillon, M.; Hugele, A.; Huttunen, J.; Huttunen, K. M. Improved l-Type amino acid transporter 1 (LAT1)-mediated delivery of anti-inflammatory drugs into astrocytes and microglia with reduced prostaglandin production. International Journal of Pharmaceutics, 2021, 601: 120565. https://doi.org/10.1016/j.ijpharm.2021.120565

 

Montaser, A.; Järvinen, J.; Loeffler, S.; Huttunen, J.; Auriola, S.; Lehtonen, M.; Jalkanen, A. J.; Huttunen, K. M. L-type amino acid transporter 1 enables the efficient brain delivery of small-sized prodrug across the blood-brain barrier and into human and mouse brain parenchymal cells. ACS Chemical Neuroscience, 2020, 11(24): 4301-4315. https://doi.org/10.1021/acschemneuro.0c00564

 

Tampio, J.; Huttunen J.; Montaser, A.; Huttunen, K. M. Targeting of Perforin Inhibitor into the Brain Parenchyma via Prodrug Approach Can Decrease Oxidative Stress and Neuroinflammation, and Improve Cell Survival. Molecular Neurobiology, 2020, 57(11), 4563-4577. https://doi.org/10.1007/s12035-020-02045-7

Montaser, A.; Lehtonen, M.; Gynther, M.; Huttunen, K. M. L-type amino acid transporter L-utilizing prodrugs of ketoprofen can efficiently reduce brain prostaglandin levels. Pharmaceutics, 2020, 12(4): E334 (1-12). https://doi.org/10.3390/pharmaceutics12040344

Montaser, A.; Huttunen J.; Ibrahim, S. A; Huttunen, K. M. Astrocyte-Targeted Transporter-Utilizing Derivatives of Ferulic Acid Can Have Multifunctional Effects Ameliorating Inflammation and Oxidative Stress in the Brain. Oxidative Medicine and Cellular Longevity, 2019, 3528148, 1-13. http://doi.org/10.1155/2019/3528148

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. http://doi.org/10.1038/s41598-019-49009-z

Puris E, Gynther M, de Lange ECM, Auriola S, Hammarlund-Udenaes M, Huttunen KM, Loryan I. Mechanistic Study on the Use of the l-Type Amino Acid Transporter 1 for Brain Intracellular Delivery of Ketoprofen via Prodrug: A Novel Approach Supporting the Development of Prodrugs for Intracellular Targets. Molecular Pharmaceutics, 2019, 16 (7), 3261-3274. http://doi.org/10.1021/acs.molpharmaceut.9b00502

Puris E, Gynther M, Huttunen J, Auriola S, Huttunen KM. L-type amino acid transporter 1 utilizing prodrugs of ferulic acid revealed structural features supporting the design of prodrugs for brain delivery. European Journal of Pharmaceutical Sciences, 2019, 129, 99-109. http://doi.org/10.1016/j.ejps.2019.01.002

Gynther M, Puris E, Peltokangas S, Auriola S, Kanninen KM, Koistinaho J, Huttunen KM, Ruponen M, Vellonen KS. Alzheimer's Disease Phenotype or Inflammatory Insult Does Not Alter Function of L-Type Amino Acid Transporter 1 in Mouse Blood-Brain Barrier and Primary Astrocytes. Pharmaceutical Research, 2018, 36 (1), 1-17. doi.org/10.1007/s11095-018-2546-7

Huttunen K. M. Identification of Human, Rat and Mouse Hydrolyzing Enzymes Bioconverting Amino Acid Ester Prodrug of Ketoprofen. Bioorganic Chemistry, 2018, 81, 494-503. https://doi.org/10.1016/j.bioorg.2018.09.018

Puris, E.; Gynther, M.; Huttunen, J.; Petsalo, A.; Huttunen, K. M. L-Type Amino Acid Transporter 1 Utilizing Prodrugs: How to Achieve Effective Brain Delivery and Low Systemic Exposure of Drugs. Journal of Controlled Release, 2017, 261, 93-104. https://doi.org/10.1016/j.jconrel.2017.06.023

Gynther, M.; Pickering, D. S.; Spicer, J. A.; Denny, W. A.; Huttunen, K. M. Systemic and Brain Pharmacokinetics of Perforin Inhibitor Prodrugs. Molecular Pharmaceutics, 2016, 13 (7): 2484-2491. http://dx.doi.org/10.1021/acs.molpharmaceut.6b00217

Gynther, M.; Peura, L.; Vernerová, M.; Leppänen, J.; Lehtonen, M.; Rautio, J.; Huttunen, K. M. Improved Pharmacokinetics of Valproic Acid by Amino Acid Prodrugs. Neurochemical Research, 2016, 41 (10), 2797-2809. http://dx.doi.org/10.1007/s11064-016-1996-8

Peura, L.; Malmioja, K.; Huttunen, K. M.; Leppänen, J.; Hämäläinen, M.; Forsberg, M. M.; Rautio, J.; Laine, K. Design, Synthesis and Brain Uptake of LAT1-Targeted Amino Acid Prodrugs of Dopamine. Pharmaceutical Research, 2013, 30 (10), 2523-2537. http://dx.doi.org/10.1007/s11095-012-0966-3