L-Type amino acid transporter 1 as a target for drug delivery

被引:120
作者
Puris, Elena [1 ,2 ]
Gynther, Mikko [1 ]
Auriola, Seppo [1 ]
Huttunen, Kristiina M. [1 ]
机构
[1] Univ Eastern Finland, Sch Pharm, POB 1627, FI-70211 Kuopio, Finland
[2] Ruprecht Karls Univ Heidelberg, Inst Pharm & Mol Biotechnol, D-69120 Heidelberg, Germany
基金
芬兰科学院;
关键词
drug delivery systems; L-type amino acid transporter 1; membrane transporter; targeting; BLOOD-BRAIN-BARRIER; NEUTRON-CAPTURE THERAPY; CARRIER-MEDIATED TRANSPORT; L-LEUCINE TRANSPORT; L-DOPA; UTILIZING PRODRUGS; LAT1; EXPRESSION; ESTER PRODRUGS; VALPROIC ACID; CANCER;
D O I
10.1007/s11095-020-02826-8
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Our growing understanding of membrane transporters and their substrate specificity has opened a new avenue in the field of targeted drug delivery. The L-type amino acid transporter 1 (LAT1) has been one of the most extensively investigated transporters for delivering drugs across biological barriers. The transporter is predominantly expressed in cerebral cortex, blood-brain barrier, blood-retina barrier, testis, placenta, bone marrow and several types of cancer. Its physiological function is to mediate Na+ and pH independent exchange of essential amino acids: leucine, phenylalanine, etc. Several drugs and prodrugs designed as LAT1 substrates have been developed to improve targeted delivery into the brain and cancer cells. Thus, the anti-parkinsonian drug, L-Dopa, the anti-cancer drug, melphalan and the anti-epileptic drug gabapentin, all used in clinical practice, utilize LAT1 to reach their target site. These examples provide supporting evidence for the utility of the LAT1-mediated targeted delivery of the (pro)drug. This review comprehensively summarizes recent advances in LAT1-mediated targeted drug delivery. In addition, the use of LAT1 is critically evaluated and limitations of the approach are discussed.
引用
收藏
页数:17
相关论文
共 114 条
[21]   Structure-based ligand discovery for the Large-neutral Amino Acid Transporter 1, LAT-1 [J].
Geier, Ethan G. ;
Schlessinger, Avner ;
Fan, Hao ;
Gable, Jonathan E. ;
Irwin, John J. ;
Sali, Andrej ;
Giacomini, Kathleen M. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (14) :5480-5485
[22]   Value of 11C-methionine PET in imaging brain tumours and metastases [J].
Glaudemans, Andor W. J. M. ;
Enting, Roelien H. ;
Heesters, Mart A. A. M. ;
Dierckx, Rudi A. J. O. ;
van Rheenen, Ronald W. J. ;
Walenkamp, Annemiek M. E. ;
Slart, Riemer H. J. A. .
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, 2013, 40 (04) :615-635
[23]  
GOLDENBERG GJ, 1979, J BIOL CHEM, V254, P1057
[24]  
GREIG NH, 1987, CANCER RES, V47, P1571
[25]   AN INTERINDIVIDUAL COMPARISON OF O-(2-[18F]FLUOROETHYL)-L-TYROSINE (FET)- AND L-[METHYL-11C]METHIONINE (MET)-PET IN PATIENTS WITH BRAIN GLIOMAS AND METASTASES [J].
Grosu, Anca-Ligia ;
Astner, Sabrina T. ;
Riedel, Eva ;
Nieder, Carsten ;
Wiedenmann, Nicole ;
Heinemann, Felix ;
Schwaiger, Markus ;
Molls, Michael ;
Wester, Hans-Juergen ;
Weber, Wolfgang A. .
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 2011, 81 (04) :1049-1058
[26]   Large neutral amino acid transporter enables brain drug delivery via prodrugs [J].
Gynther, Mikko ;
Laine, Krista ;
Ropponen, Jarmo ;
Leppanen, Jukka ;
Mannila, Anne ;
Nevalainen, Tapio ;
Savolainen, Jouko ;
Jarvinen, Ton-Ti ;
Rautio, Jarkko .
JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (04) :932-936
[27]   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 [J].
Gynther, Mikko ;
Puris, Elena ;
Peltokangas, Soile ;
Auriola, Seppo ;
Kanninen, Katja M. ;
Koistinaho, Jari ;
Huttunen, Kristiina M. ;
Ruponen, Marika ;
Vellonen, Kati-Sisko .
PHARMACEUTICAL RESEARCH, 2019, 36 (01)
[28]   Amino Acid Promoieties Alter Valproic Acid Pharmacokinetics and Enable Extended Brain Exposure [J].
Gynther, Mikko ;
Peura, Lauri ;
Vernerova, Monika ;
Leppanen, Jukka ;
Karkkainen, Jussi ;
Lehtonen, Marko ;
Rautio, Jarkko ;
Huttunen, Kristiina M. .
NEUROCHEMICAL RESEARCH, 2016, 41 (10) :2797-2809
[29]   Systemic and Brain Pharmacokinetics of Perforin Inhibitor Prodrugs [J].
Gynther, Mikko ;
Pickering, Darryl S. ;
Spicer, Julie A. ;
Denny, William A. ;
Huttunen, Kristiina M. .
MOLECULAR PHARMACEUTICS, 2016, 13 (07) :2484-2491
[30]   Brain uptake of ketoprofen-lysine prodrug in rats [J].
Gynther, Mikko ;
Jalkanen, Aaro ;
Lehtonen, Marko ;
Forsberg, Markus ;
Laine, Krista ;
Ropponen, Jarmo ;
Leppanen, Jukka ;
Knuuti, Johanna ;
Rautio, Jarkko .
INTERNATIONAL JOURNAL OF PHARMACEUTICS, 2010, 399 (1-2) :121-128