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Transporter-Mediated Drug Delivery
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Transporter-Mediated Drug Delivery

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (1 November 2022) | Viewed by 33770

Special Issue Editors

Dr. Kristiina Huttunen

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Guest Editor
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O.Box 1627, FI-70211 Kuopio, Finland
Interests: transporter; solute carriers (SLC); ATP-binding cassette (ABC); drug delivery; drug targeting; ADME; pharmacokinetics; toxicokinetics; drug development
Special Issues, Collections and Topics in MDPI journals
Dr. Santosh Kumar Adla

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Guest Editor
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, POB 1627, 70211 Kuopio, Finland
Interests: transporter; solute carriers (SLC); ATP-binding cassette (ABC); drug delivery; drug targeting; ADME; pharmacokinetics; toxicokinetics; drug development

Special Issue Information

Dear Colleagues,

Membrane transporters are acknowledged to play a crucial role in the absorption, distribution, and excretion of many compounds. Therefore, they are important determinants in pharmacokinetics and toxicokinetics, as well as in drug–drug interactions (DDIs). They can facilitate or limit tissue-selective drug/toxin exposure but also be involved in reduced clearance in the case of concomitant disposition. Thus, transporters can directly affect the efficacy and/or toxicity of drugs and toxins.

Lately, the quantitative knowledge of transporter expression and function in different tissues and cells or even cell organelles has increased. However, the translation of this information on how transporters can affect the pharmaco-/toxicokinetics is still lacking or behind the times. Moreover, even less is known of species-related differences in transporter expression and function that can complicate the translation of preclinical rodent data to the clinical human situation. Furthermore, there are still many unknown or understudied transporters.

This Special Issue of Molecules aims to update the latest findings in transporter-related pharmaco-/toxicokinetics and the development of transporter-utilizing compounds for improved or targeted drug delivery. Therefore, I proudly invite you to submit your contribution to the field.

Dr. Kristiina M. Huttunen
Dr. Santosh Kumar Adla
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Membrane transporters
  • Solute carriers (SLC)
  • ATP-binding cassette (ABC)
  • Pharmacokinetics
  • Toxicokinetics
  • Species differences
  • Transporter-utilizing compounds
  • Drug delivery
  • Drug targeting
  • Drug development

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Published Papers (7 papers)

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Research

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18 pages, 5009 KiB  
Article
Comparative Modelling of Organic Anion Transporting Polypeptides: Structural Insights and Comparison of Binding Modes
by Arun Kumar Tonduru, Santosh Kumar Adla, Kristiina M. Huttunen, Thales Kronenberger and Antti Poso
Molecules 2022, 27(23), 8531; https://doi.org/10.3390/molecules27238531 - 3 Dec 2022
Cited by 2 | Viewed by 2764
Abstract
To better understand the functionality of organic anion transporting polypeptides (OATPs) and to design new ligands, reliable structural data of each OATP is needed. In this work, we used a combination of homology model with molecular dynamics simulations to generate a comprehensive structural [...] Read more.
To better understand the functionality of organic anion transporting polypeptides (OATPs) and to design new ligands, reliable structural data of each OATP is needed. In this work, we used a combination of homology model with molecular dynamics simulations to generate a comprehensive structural dataset, that encompasses a diverse set of OATPs but also their relevant conformations. Our OATP models share a conserved transmembrane helix folding harbouring a druggable binding pocket in the shape of an inner pore. Our simulations suggest that the conserved salt bridges at the extracellular region between residues on TM1 and TM7 might influence the entrance of substrates. Interactions between residues on TM1 and TM4 within OATP1 family shown their importance in transport of substrates. Additionally, in transmembrane (TM) 1/2, a known conserved element, interact with two identified motifs in the TM7 and TM11. Our simulations suggest that TM1/2-TM7 interaction influence the inner pocket accessibility, while TM1/2-TM11 salt bridges control the substrate binding stability. Full article
(This article belongs to the Special Issue Transporter-Mediated Drug Delivery)
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20 pages, 3809 KiB  
Article
Comparison of Experimental Strategies to Study l-Type Amino Acid Transporter 1 (LAT1) Utilization by Ligands
by Johanna Huttunen, Mahmoud Agami, Janne Tampio, Ahmed B. Montaser and Kristiina M. Huttunen
Molecules 2022, 27(1), 37; https://doi.org/10.3390/molecules27010037 - 22 Dec 2021
Cited by 5 | Viewed by 3642
Abstract
l-Type amino acid transporter 1 (LAT1), expressed abundantly in the brain and placenta and overexpressed in several cancer cell types, has gained a lot of interest in drug research and development, as it can be utilized for brain-targeted drug delivery, as well [...] Read more.
l-Type amino acid transporter 1 (LAT1), expressed abundantly in the brain and placenta and overexpressed in several cancer cell types, has gained a lot of interest in drug research and development, as it can be utilized for brain-targeted drug delivery, as well as inhibiting the essential amino acid supply to cancer cells. The structure of LAT1 is today very well-known and the interactions of ligands at the binding site of LAT1 can be modeled and explained. However, less is known of LAT1′s life cycle within the cells. Moreover, the functionality of LAT1 can be measured by several different methods, which may vary between the laboratories and make the comparison of the results challenging. In the present study, the usefulness of indirect cis-inhibition methods and direct cellular uptake methods and their variations to interpret the interactions of LAT1-ligands were evaluated. Moreover, this study also highlights the importance of understanding the intracellular kinetics of LAT1-ligands, and how they can affect the regular function of LAT1 in critical tissues, such as the brain. Hence, it is discussed herein how the selected methodology influences the outcome and created knowledge of LAT1-utilizing compounds. Full article
(This article belongs to the Special Issue Transporter-Mediated Drug Delivery)
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19 pages, 3669 KiB  
Article
Neurosteroids: Structure-Uptake Relationships and Computational Modeling of Organic Anion Transporting Polypeptides (OATP)1A2
by Santosh Kumar Adla, Arun Kumar Tonduru, Thales Kronenberger, Eva Kudova, Antti Poso and Kristiina M. Huttunen
Molecules 2021, 26(18), 5662; https://doi.org/10.3390/molecules26185662 - 17 Sep 2021
Cited by 6 | Viewed by 3230
Abstract
In this study, we investigated the delivery of synthetic neurosteroids into MCF-7 human breast adenocarcinoma cells via Organic Anionic Transporting Polypeptides (OATPs) (pH 7.4 and 5.5) to identify the structural components required for OATP-mediated cellular uptake and to get insight into brain drug [...] Read more.
In this study, we investigated the delivery of synthetic neurosteroids into MCF-7 human breast adenocarcinoma cells via Organic Anionic Transporting Polypeptides (OATPs) (pH 7.4 and 5.5) to identify the structural components required for OATP-mediated cellular uptake and to get insight into brain drug delivery. Then, we identified structure-uptake relationships using in-house developed OATP1A2 homology model to predict binding sites and modes for the ligands. These binding modes were studied by molecular dynamics simulations to rationalize the experimental results. Our results show that carboxylic acid needs to be at least at 3 carbon-carbon bonds distance from amide bond at the C-3 position of the androstane skeleton and have an amino group to avoid efflux transport. Replacement of hydroxyl group at C-3 with any of the 3, 4, and 5-carbon chained terminal carboxylic groups improved the affinity. We attribute this to polar interactions between carboxylic acid and side-chains of Lys33 and Arg556. The additional amine group showed interactions with Glu172 and Glu200. Based on transporter capacities and efficacies, it could be speculated that the functionalization of acetyl group at the C-17 position of the steroidal skeleton might be explored further to enable OAT1A2-mediated delivery of neurosteroids into the cells and also across the blood-brain barrier. Full article
(This article belongs to the Special Issue Transporter-Mediated Drug Delivery)
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41 pages, 6162 KiB  
Article
The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes
by Douglas B. Kell
Molecules 2021, 26(18), 5629; https://doi.org/10.3390/molecules26185629 - 16 Sep 2021
Cited by 23 | Viewed by 8974
Abstract
Over the years, my colleagues and I have come to realise that the likelihood of pharmaceutical drugs being able to diffuse through whatever unhindered phospholipid bilayer may exist in intact biological membranes in vivo is vanishingly low. This is because (i) most real [...] Read more.
Over the years, my colleagues and I have come to realise that the likelihood of pharmaceutical drugs being able to diffuse through whatever unhindered phospholipid bilayer may exist in intact biological membranes in vivo is vanishingly low. This is because (i) most real biomembranes are mostly protein, not lipid, (ii) unlike purely lipid bilayers that can form transient aqueous channels, the high concentrations of proteins serve to stop such activity, (iii) natural evolution long ago selected against transport methods that just let any undesirable products enter a cell, (iv) transporters have now been identified for all kinds of molecules (even water) that were once thought not to require them, (v) many experiments show a massive variation in the uptake of drugs between different cells, tissues, and organisms, that cannot be explained if lipid bilayer transport is significant or if efflux were the only differentiator, and (vi) many experiments that manipulate the expression level of individual transporters as an independent variable demonstrate their role in drug and nutrient uptake (including in cytotoxicity or adverse drug reactions). This makes such transporters valuable both as a means of targeting drugs (not least anti-infectives) to selected cells or tissues and also as drug targets. The same considerations apply to the exploitation of substrate uptake and product efflux transporters in biotechnology. We are also beginning to recognise that transporters are more promiscuous, and antiporter activity is much more widespread, than had been realised, and that such processes are adaptive (i.e., were selected by natural evolution). The purpose of the present review is to summarise the above, and to rehearse and update readers on recent developments. These developments lead us to retain and indeed to strengthen our contention that for transmembrane pharmaceutical drug transport “phospholipid bilayer transport is negligible”. Full article
(This article belongs to the Special Issue Transporter-Mediated Drug Delivery)
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19 pages, 2051 KiB  
Article
Intrinsic and Chemotherapeutic Stressors Modulate ABCC-Like Transport in Trypanosoma cruzi
by Kelli Monteiro da Costa, Eduardo J. Salustiano, Raphael do Carmo Valente, Leonardo Freire-de-Lima, Lucia Mendonça-Previato and José Osvaldo Previato
Molecules 2021, 26(12), 3510; https://doi.org/10.3390/molecules26123510 - 9 Jun 2021
Cited by 2 | Viewed by 2624
Abstract
Trypanosoma cruzi is the etiologic agent for Chagas disease, which affects 6–7 million people worldwide. The biological diversity of the parasite reflects on inefficiency of benznidazole, which is a first choice chemotherapy, on chronic patients. ABC transporters that extrude xenobiotics, metabolites, and mediators [...] Read more.
Trypanosoma cruzi is the etiologic agent for Chagas disease, which affects 6–7 million people worldwide. The biological diversity of the parasite reflects on inefficiency of benznidazole, which is a first choice chemotherapy, on chronic patients. ABC transporters that extrude xenobiotics, metabolites, and mediators are overexpressed in resistant cells and contribute to chemotherapy failure. An ABCC-like transport was identified in the Y strain and extrudes thiol-conjugated compounds. As thiols represent a line of defense towards reactive species, we aimed to verify whether ABCC-like transport could participate in the regulation of responses to stressor stimuli. In order to achieve this, ABCC-like activity was measured by flow cytometry using fluorescent substrates. The present study reveals the participation of glutathione and ceramides on ABCC-like transport, which are both implicated in stress. Hemin modulated the ABCC-like efflux which suggests that this protein might be involved in cellular detoxification. Additionally, all strains evaluated exhibited ABCC-like activity, while no ABCB1-like activity was detected. Results suggest that ABCC-like efflux is not associated with natural resistance to benznidazole, since sensitive strains showed higher activity than the resistant ones. Although benznidazole is not a direct substrate, ABCC-like efflux increased after prolonged drug exposure and this indicates that the ABCC-like efflux mediated protection against cell stress depends on the glutathione biosynthesis pathway. Full article
(This article belongs to the Special Issue Transporter-Mediated Drug Delivery)
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Review

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52 pages, 1446 KiB  
Review
Transporter-Mediated Drug Delivery
by Gergely Gyimesi and Matthias A. Hediger
Molecules 2023, 28(3), 1151; https://doi.org/10.3390/molecules28031151 - 24 Jan 2023
Cited by 23 | Viewed by 5741
Abstract
Transmembrane transport of small organic and inorganic molecules is one of the cornerstones of cellular metabolism. Among transmembrane transporters, solute carrier (SLC) proteins form the largest, albeit very diverse, superfamily with over 400 members. It was recognized early on that xenobiotics can directly [...] Read more.
Transmembrane transport of small organic and inorganic molecules is one of the cornerstones of cellular metabolism. Among transmembrane transporters, solute carrier (SLC) proteins form the largest, albeit very diverse, superfamily with over 400 members. It was recognized early on that xenobiotics can directly interact with SLCs and that this interaction can fundamentally determine their efficacy, including bioavailability and intertissue distribution. Apart from the well-established prodrug strategy, the chemical ligation of transporter substrates to nanoparticles of various chemical compositions has recently been used as a means to enhance their targeting and absorption. In this review, we summarize efforts in drug design exploiting interactions with specific SLC transporters to optimize their therapeutic effects. Furthermore, we describe current and future challenges as well as new directions for the advanced development of therapeutics that target SLC transporters. Full article
(This article belongs to the Special Issue Transporter-Mediated Drug Delivery)
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17 pages, 653 KiB  
Review
Endogenous Biomarkers for SLC Transporter-Mediated Drug-Drug Interaction Evaluation
by Yang Li, Zahra Talebi, Xihui Chen, Alex Sparreboom and Shuiying Hu
Molecules 2021, 26(18), 5500; https://doi.org/10.3390/molecules26185500 - 10 Sep 2021
Cited by 21 | Viewed by 5057
Abstract
Membrane transporters play an important role in the absorption, distribution, metabolism, and excretion of xenobiotic substrates, as well as endogenous compounds. The evaluation of transporter-mediated drug-drug interactions (DDIs) is an important consideration during the drug development process and can guide the safe use [...] Read more.
Membrane transporters play an important role in the absorption, distribution, metabolism, and excretion of xenobiotic substrates, as well as endogenous compounds. The evaluation of transporter-mediated drug-drug interactions (DDIs) is an important consideration during the drug development process and can guide the safe use of polypharmacy regimens in clinical practice. In recent years, several endogenous substrates of drug transporters have been identified as potential biomarkers for predicting changes in drug transport function and the potential for DDIs associated with drug candidates in early phases of drug development. These biomarker-driven investigations have been applied in both preclinical and clinical studies and proposed as a predictive strategy that can be supplanted in order to conduct prospective DDIs trials. Here we provide an overview of this rapidly emerging field, with particular emphasis on endogenous biomarkers recently proposed for clinically relevant uptake transporters. Full article
(This article belongs to the Special Issue Transporter-Mediated Drug Delivery)
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