School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls-University, 69120, Heidelberg, Germany.
Pharm Res. 2020 May 6;37(5):88. doi: 10.1007/s11095-020-02826-8.
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.
我们对膜转运蛋白及其底物特异性的认识不断加深，为靶向药物递送领域开辟了新途径。L 型氨基酸转运蛋白 1（LAT1）是研究最多的用于将药物递送到生物屏障中的转运蛋白之一。该转运蛋白主要在大脑皮层、血脑屏障、血视网膜屏障、睾丸、胎盘、骨髓和几种类型的癌症中表达。其生理功能是介导 Na 和 pH 独立交换必需氨基酸：亮氨酸、苯丙氨酸等。已经开发了几种设计为 LAT1 底物的药物和前药，以改善靶向递送到大脑和癌细胞中的效果。因此，抗帕金森病药物左旋多巴、抗癌药物美法仑和抗癫痫药物加巴喷丁等在临床实践中使用的药物都利用 LAT1 到达其靶部位。这些例子为（前）药物的 LAT1 介导的靶向递送的实用性提供了支持证据。本综述全面总结了 LAT1 介导的靶向药物递送的最新进展。此外，还对 LAT1 的应用进行了批判性评估，并讨论了该方法的局限性。
