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.

Limited drug delivery to the brain is one of the major reasons for high failure rates of central nervous system (CNS) drug candidates. The blood–brain barrier (BBB) with its tight junctions, membrane transporters, receptors and metabolizing enzymes is a main player in drug delivery to the brain, restricting the entrance of the drugs and other xenobiotics. Current knowledge about the uptake transporters expressed at the BBB and brain parenchymal cells has been used for delivery of CNS drugs to the brain via targeting transporters. Although many transporter-utilizing (pro)drugs and nanocarriers have been developed to improve the uptake of drugs to the brain, their success rate of translation from preclinical development to humans is negligible. In the present review, we provide a systematic summary of the current progress in development of transporter-utilizing (pro)drugs and nanocarriers for delivery of drugs to the brain. In addition, we applied CNS pharmacokinetic concepts for evaluation of the limitations and gaps in investigation of the developed transporter-utilizing (pro)drugs and nanocarriers. Finally, we give recommendations for a rational development of transporter-utilizing drug delivery systems targeting the brain based on CNS pharmacokinetic principles.

L-type amino acid transporter 1 (LAT1) is selectively expressed in the blood-brain barrier (BBB) and brain parenchyma. This transporter can facilitate brain delivery of neuroprotective agents and additionally give opportunity to minimize systemic exposure. Here, we investigated structure-pharmacokinetics relationship of five newly synthesized LAT1-utilizing prodrugs of the cyclooxygenase inhibitor, ketoprofen, in order to identify beneficial structural features of prodrugs to achieve both targeted brain delivery and low peripheral distribution of the parent drug. Besides, we studied whether pharmacokinetics and bioconversion of LAT1-utilizing prodrugs in vivo can be predicted in early stage experiments. To achieve these goals, we compared the in vitro brain uptake mechanism of prodrugs, rate of BBB permeation of compounds using in situ perfusion technique, their systemic pharmacokinetics and release of parent drug in brain, plasma and liver of mice. The results revealed that both excellent LAT1-binding ability and transporter utilization in vitro can be achieved by conjugating the parent drug to aromatic amino acids such as phenylalanine in comparison to prodrugs with an aliphatic promoiety. The presence of an aromatic promoiety directly conjugated in meta- or para-position to ketoprofen led to LAT1-utilizing prodrugs capable of delivering the parent drug into the brain with higher unbound brain to plasma ratio and reduced liver exposure than with ketoprofen itself. In contrast, the prodrugs with aliphatic promoieties and with an additional carbon attached between the parent drug and phenylalanine aromatic ring did not enhance brain delivery of ketoprofen. Furthermore, we have devised a screening strategy to pinpoint successful candidates at an early stage of development of LAT1-utilizing prodrugs. The screening approach demonstrated that early stage experiments could not replace pharmacokinetic studies in vivo due to the lack of prediction of the intra-brain/systemic distribution of the prodrugs as well as the release of the parent drug. Overall, this study provides essential knowledge required for improvement of targeted brain delivery and reduction of systemic exposure of drugs via the LAT1-mediated prodrug approach.

Transporter-mediated drug resistance is a major obstacle in anticancer drug delivery and a key reason for cancer drug therapy failure. Membrane solute carrier (SLC) transporters play a crucial role in the cellular uptake of drugs. The expression and function of the SLC transporters can be down-regulated in cancer cells, which limits the uptake of drugs into the tumor cells, resulting in the inefficiency of the drug therapy. In this review, we summarize the current understanding of low-SLC-transporter-expression-mediated drug resistance in different types of cancers. Recent advances in SLC-transporter-targeting strategies include the development of transporter-utilizing prodrugs and nanocarriers and the modulation of SLC transporter expression in cancer cells. These strategies will play an important role in the future development of anticancer drug therapies by enabling the efficient delivery of drugs into cancer cells.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease impacting the lives of millions of people worldwide. The formation of amyloid β (Aβ) plagues in the brain is the main pathological hallmark of AD. The Aβ deposits are formed due to the imbalance between the production and Aβ clearance in the brain and across the blood–brain barrier (BBB). In this respect, low-density lipoprotein receptor-related protein 1 (LRP1) plays a significant role by mediating both brain Aβ production and clearance. Due to its important role in AD pathogenesis, LRP1 is considered an attractive drug target for AD therapies. In the present review, we summarize the current knowledge about the role of LRP1 in AD pathogenesis as well as recent findings on changes in LRP1 expression and function in AD. Finally, we discuss the advances in utilizing LRP1 as a drug target for AD treatments as well as future perspectives on LRP1 research.