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Roles of Transporters and Receptors in Drug Delivery to the Brain in Health and Disease

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biologics and Biosimilars".

Deadline for manuscript submissions: closed (20 April 2024) | Viewed by 15344

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Special Issue Editors

Prof. Dr. Gert Fricker

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Guest Editor

Department of Pharmaceutical Technology and Biopharmacy, Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Im Neuenheimer Feld 329, D-69120 Heidelberg, Germany
Interests: transport proteins in physiological barriers being relevant for drug transport; ABC-transporter signaling; development of colloidal carriers, such as surface decorated liposomes and nanoparticles to improve CNS drug delivery
Special Issues, Collections and Topics in MDPI journals

Dr. Elena Puris

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Department of Pharmaceutical Technology and Biopharmacy, Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Im Neuenheimer Feld 329, D-69120 Heidelberg, Germany
Interests: CNS drug delivery; blood–brain barrier; CNS pharmacokinetics; intra-brain delivery; membrane transporters
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Drug delivery to the brain, restricted by the blood–brain barrier (BBB) with its tight junctions, membrane transporters, receptors, and metabolizing enzymes, remains one of the major reasons for high failure rates of the central nervous system (CNS) drug candidates. Solute carriers (SLCs) and ATP-binding cassette family (ABC) transporters play crucial roles in drug delivery to the brain. Knowledge about transporters and receptors expressed at the BBB and brain parenchymal cells has opened new opportunities for the improvement of drug delivery to the brain. However, the expression and function of transporters and receptors at the brain barriers can be altered in neuropathological conditions, which can affect drug delivery efficacy to the brain.

This Special Issue aims to provide readers with an overview of the latest developments in the field of transporter- and receptor-mediated drug delivery to the brain, current knowledge about the changes in expression and function of transporters and receptors expressed at the brain barriers in CNS diseases, as well as advances in the methodologies for evaluation of carrier-mediated drug delivery to the brain.

We look forward to receiving your contributions.

Prof. Dr. Gert Fricker
Dr. Elena Puris
Guest Editors

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Keywords

membrane receptors
brain drug delivery
blood–brain barrier
solute carriers
ABC transporters

Published Papers (9 papers)

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Research

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21 pages, 5055 KiB

Open AccessArticle

The Active Glucuronide Metabolite of the Brain Protectant IMM-H004 with Poor Blood–Brain Barrier Permeability Demonstrates a High Partition in the Rat Brain via Multiple Mechanisms

by Jianwei Jiang, Lijun Luo, Ziqian Zhang, Xiao Liu, Naihong Chen, Yan Li and Li Sheng

Pharmaceutics 2024, 16(3), 330; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics16030330 - 27 Feb 2024

Viewed by 689

Abstract

Background: Glucuronidation is an essential metabolic pathway for a variety of drugs. IMM-H004 is a novel neuroprotective agent against ischemic stroke, and its glucuronide metabolite IMM-H004G exhibits similar pharmacological activity. Despite possessing a higher molecular weight and polarity, brain exposure of IMM-H004G is much higher than that of IMM-H004. This study aimed to investigate the brain metabolism and transport mechanisms of IMM-H004 and IMM-H004G. Methods: First, the possibility of IMM-H004 glucuronidation in the brain was evaluated in several human brain cell lines and rat homogenate. Subsequently, the blood–brain barrier carrier-mediated transport mechanism of IMM-H004 and IMM-H004G was studied using overexpression cell models. In addition, intracerebroventricular injection, in situ brain perfusion model, and microdialysis/microinjection techniques were performed to study the distribution profiles of IMM-H004 and IMM-H004G. Results: IMM-H004 could be metabolized to IMM-H004G in both rat brain and HEB cells mediated by UGT1A7. However, IMM-H004G could not be hydrolyzed back into IMM-H004. Furthermore, the entry and efflux of IMM-H004 in the brain were mediated by the pyrilamine-sensitive H⁺/OC antiporter and P-gp, respectively, while the transport of IMM-H004G from the blood to the brain was facilitated by OATP1A2 and OATP2B1. Ultimately, stronger concentration gradients and OATP-mediated uptake played a critical role in promoting greater brain exposure of IMM-H004G. Conclusions: The active glucuronide metabolite of the brain protectant IMM-H004 with poor blood–brain barrier permeability demonstrates a high partition in the rat brain via multiple mechanisms, and our findings deepen the understanding of the mechanisms underlying the blood–brain barrier metabolism and transport of active glucuronide conjugates. Full article

(This article belongs to the Special Issue Roles of Transporters and Receptors in Drug Delivery to the Brain in Health and Disease)

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21 pages, 2506 KiB

Open AccessArticle

Cu(ATSM) Increases P-Glycoprotein Expression and Function at the Blood-Brain Barrier in C57BL6/J Mice

by Jae Pyun, HuiJing Koay, Pranav Runwal, Celeste Mawal, Ashley I. Bush, Yijun Pan, Paul S. Donnelly, Jennifer L. Short and Joseph A. Nicolazzo

Pharmaceutics 2023, 15(8), 2084; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics15082084 - 03 Aug 2023

Cited by 2 | Viewed by 1565

Abstract

P-glycoprotein (P-gp), expressed at the blood-brain barrier (BBB), is critical in preventing brain access to substrate drugs and effluxing amyloid beta (Aβ), a contributor to Alzheimer’s disease (AD). Strategies to regulate P-gp expression therefore may impact central nervous system (CNS) drug delivery and brain Aβ levels. As we have demonstrated that the copper complex copper diacetyl bis(4-methyl-3-thiosemicarbazone) (Cu(ATSM)) increases P-gp expression and function in human brain endothelial cells, the present study assessed the impact of Cu(ATSM) on expression and function of P-gp in mouse brain endothelial cells (mBECs) and capillaries in vivo, as well as in peripheral organs. Isolated mBECs treated with Cu(ATSM) (100 nM for 24 h) exhibited a 1.6-fold increase in P-gp expression and a 20% reduction in accumulation of the P-gp substrate rhodamine 123. Oral administration of Cu(ATSM) (30 mg/kg/day) for 28 days led to a 1.5 & 1.3-fold increase in brain microvascular and hepatic expression of P-gp, respectively, and a 20% reduction in BBB transport of [3H]-digoxin. A metallomic analysis showed a 3.5 and 19.9-fold increase in Cu levels in brain microvessels and livers of Cu(ATSM)-treated mice. Our findings demonstrate that Cu(ATSM) increases P-gp expression and function at the BBB in vivo, with implications for CNS drug delivery and clearance of Aβ in AD. Full article

(This article belongs to the Special Issue Roles of Transporters and Receptors in Drug Delivery to the Brain in Health and Disease)

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25 pages, 2979 KiB

Open AccessArticle

Differential Expression of ABC Transporter Genes in Brain Vessels vs. Peripheral Tissues and Vessels from Human, Mouse and Rat

by Wandong Zhang, Qing Yan Liu, Arsalan S. Haqqani, Ziying Liu, Caroline Sodja, Sonia Leclerc, Ewa Baumann, Christie E. Delaney, Eric Brunette and Danica B. Stanimirovic

Pharmaceutics 2023, 15(5), 1563; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics15051563 - 22 May 2023

Cited by 5 | Viewed by 1484

Abstract

Background: ATP-binding cassette (ABC) transporters comprise a superfamily of genes encoding membrane proteins with nucleotide-binding domains (NBD). These transporters, including drug efflux across the blood–brain barrier (BBB), carry a variety of substrates through plasma membranes against substrate gradients, fueled by hydrolyzing ATP. The expression patterns/enrichment of ABC transporter genes in brain microvessels compared to peripheral vessels and tissues are largely uncharacterized. Methods: In this study, the expression patterns of ABC transporter genes in brain microvessels, peripheral tissues (lung, liver and spleen) and lung vessels were investigated using RNA-seq and Wes^TM analyses in three species: human, mouse and rat. Results: The study demonstrated that ABC drug efflux transporter genes (including ABCB1, ABCG2, ABCC4 and ABCC5) were highly expressed in isolated brain microvessels in all three species studied; the expression of ABCB1, ABCG2, ABCC1, ABCC4 and ABCC5 was generally higher in rodent brain microvessels compared to those of humans. In contrast, ABCC2 and ABCC3 expression was low in brain microvessels, but high in rodent liver and lung vessels. Overall, most ABC transporters (with the exception of drug efflux transporters) were enriched in peripheral tissues compared to brain microvessels in humans, while in rodent species, additional ABC transporters were found to be enriched in brain microvessels. Conclusions: This study furthers the understanding of species similarities and differences in the expression patterns of ABC transporter genes; this is important for translational studies in drug development. In particular, CNS drug delivery and toxicity may vary among species depending on their unique profiles of ABC transporter expression in brain microvessels and BBB. Full article

(This article belongs to the Special Issue Roles of Transporters and Receptors in Drug Delivery to the Brain in Health and Disease)

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20 pages, 2359 KiB

Open AccessArticle

Permeability of Metformin across an In Vitro Blood–Brain Barrier Model during Normoxia and Oxygen-Glucose Deprivation Conditions: Role of Organic Cation Transporters (Octs)

by Sejal Sharma, Yong Zhang, Khondker Ayesha Akter, Saeideh Nozohouri, Sabrina Rahman Archie, Dhavalkumar Patel, Heidi Villalba and Thomas Abbruscato

Pharmaceutics 2023, 15(5), 1357; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics15051357 - 28 Apr 2023

Cited by 9 | Viewed by 1884

Abstract

Our lab previously established that metformin, a first-line type two diabetes treatment, activates the Nrf2 pathway and improves post-stroke recovery. Metformin’s brain permeability value and potential interaction with blood–brain barrier (BBB) uptake and efflux transporters are currently unknown. Metformin has been shown to be a substrate of organic cationic transporters (Octs) in the liver and kidneys. Brain endothelial cells at the BBB have been shown to express Octs; thus, we hypothesize that metformin uses Octs for its transport across the BBB. We used a co-culture model of brain endothelial cells and primary astrocytes as an in vitro BBB model to conduct permeability studies during normoxia and hypoxia using oxygen–glucose deprivation (OGD) conditions. Metformin was quantified using a highly sensitive LC-MS/MS method. We further checked Octs protein expression using Western blot analysis. Lastly, we completed a plasma glycoprotein (P-GP) efflux assay. Our results showed that metformin is a highly permeable molecule, uses Oct1 for its transport, and does not interact with P-GP. During OGD, we found alterations in Oct1 expression and increased permeability for metformin. Additionally, we showed that selective transport is a key determinant of metformin’s permeability during OGD, thus, providing a novel target for improving ischemic drug delivery. Full article

(This article belongs to the Special Issue Roles of Transporters and Receptors in Drug Delivery to the Brain in Health and Disease)

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17 pages, 1251 KiB

Open AccessArticle

Altered Blood–Brain Barrier Dynamics in the C9orf72 Hexanucleotide Repeat Expansion Mouse Model of Amyotrophic Lateral Sclerosis

by Yijun Pan, Yoshiteru Kagawa, Jiaqi Sun, Bradley J. Turner, Cheng Huang, Anup D. Shah, Ralf B. Schittenhelm and Joseph A. Nicolazzo

Pharmaceutics 2022, 14(12), 2803; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14122803 - 14 Dec 2022

Cited by 6 | Viewed by 2297

Abstract

For peripherally administered drugs to reach the central nervous system (CNS) and treat amyotrophic lateral sclerosis (ALS), they must cross the blood–brain barrier (BBB). As mounting evidence suggests that the ultrastructure of the BBB is altered in individuals with ALS and in animal models of ALS (e.g., SOD1^G93A mice), we characterized BBB transporter expression and function in transgenic C9orf72 BAC (C9-BAC) mice expressing a hexanucleotide repeat expansion, the most common genetic cause of ALS. Using an in situ transcardiac brain perfusion technique, we identified a 1.4-fold increase in ³H-2-deoxy-D-glucose transport across the BBB in C9-BAC transgenic (C9) mice, relative to wild-type (WT) mice, which was associated with a 1.3-fold increase in brain microvascular glucose transporter 1 expression, while other general BBB permeability processes (passive diffusion, efflux transporter function) remained unaffected. We also performed proteomic analysis on isolated brain microvascular endothelial cells, in which we noted a mild (14.3%) reduction in zonula occludens-1 abundance in C9 relative to WT mice. Functional enrichment analysis highlighted trends in changes to various BBB transporters and cellular metabolism. To our knowledge, this is the first study to demonstrate altered BBB function in a C9orf72 repeat expansion model of ALS, which has implications on how therapeutics may access the brain in this mouse model. Full article

(This article belongs to the Special Issue Roles of Transporters and Receptors in Drug Delivery to the Brain in Health and Disease)

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Review

Jump to: Research

33 pages, 1774 KiB

Open AccessReview

Uptake Transporters at the Blood–Brain Barrier and Their Role in Brain Drug Disposition

by Md Masud Parvez, Armin Sadighi, Yeseul Ahn, Steve F. Keller and Julius O. Enoru

Pharmaceutics 2023, 15(10), 2473; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics15102473 - 16 Oct 2023

Cited by 3 | Viewed by 1713

Abstract

Uptake drug transporters play a significant role in the pharmacokinetic of drugs within the brain, facilitating their entry into the central nervous system (CNS). Understanding brain drug disposition is always challenging, especially with respect to preclinical to clinical translation. These transporters are members of the solute carrier (SLC) superfamily, which includes organic anion transporter polypeptides (OATPs), organic anion transporters (OATs), organic cation transporters (OCTs), and amino acid transporters. In this systematic review, we provide an overview of the current knowledge of uptake drug transporters in the brain and their contribution to drug disposition. Here, we also assemble currently available proteomics-based expression levels of uptake transporters in the human brain and their application in translational drug development. Proteomics data suggest that in association with efflux transporters, uptake drug transporters present at the BBB play a significant role in brain drug disposition. It is noteworthy that a significant level of species differences in uptake drug transporters activity exists, and this may contribute toward a disconnect in inter-species scaling. Taken together, uptake drug transporters at the BBB could play a significant role in pharmacokinetics (PK) and pharmacodynamics (PD). Continuous research is crucial for advancing our understanding of active uptake across the BBB. Full article

(This article belongs to the Special Issue Roles of Transporters and Receptors in Drug Delivery to the Brain in Health and Disease)

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19 pages, 2126 KiB

Open AccessEditor’s ChoiceReview

Strategies for Drug Delivery into the Brain: A Review on Adenosine Receptors Modulation for Central Nervous System Diseases Therapy

by Mercedes Fernandez, Manuela Nigro, Alessia Travagli, Silvia Pasquini, Fabrizio Vincenzi, Katia Varani, Pier Andrea Borea, Stefania Merighi and Stefania Gessi

Pharmaceutics 2023, 15(10), 2441; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics15102441 - 10 Oct 2023

Viewed by 1734

Abstract

The blood–brain barrier (BBB) is a biological barrier that protects the central nervous system (CNS) by ensuring an appropriate microenvironment. Brain microvascular endothelial cells (ECs) control the passage of molecules from blood to brain tissue and regulate their concentration-versus-time profiles to guarantee proper neuronal activity, angiogenesis and neurogenesis, as well as to prevent the entry of immune cells into the brain. However, the BBB also restricts the penetration of drugs, thus presenting a challenge in the development of therapeutics for CNS diseases. On the other hand, adenosine, an endogenous purine-based nucleoside that is expressed in most body tissues, regulates different body functions by acting through its G-protein-coupled receptors (A1, A2A, A2B and A3). Adenosine receptors (ARs) are thus considered potential drug targets for treating different metabolic, inflammatory and neurological diseases. In the CNS, A1 and A2A are expressed by astrocytes, oligodendrocytes, neurons, immune cells and ECs. Moreover, adenosine, by acting locally through its receptors A1 and/or A2A, may modulate BBB permeability, and this effect is potentiated when both receptors are simultaneously activated. This review showcases in vivo and in vitro evidence supporting AR signaling as a candidate for modifying endothelial barrier permeability in the treatment of CNS disorders. Full article

(This article belongs to the Special Issue Roles of Transporters and Receptors in Drug Delivery to the Brain in Health and Disease)

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14 pages, 1606 KiB

Open AccessReview

Distribution of Monocarboxylate Transporters in Brain and Choroid Plexus Epithelium

by Masaki Ueno, Yoichi Chiba, Ryuta Murakami, Yumi Miyai, Koichi Matsumoto, Keiji Wakamatsu, Genta Takebayashi, Naoya Uemura and Ken Yanase

Pharmaceutics 2023, 15(8), 2062; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics15082062 - 31 Jul 2023

Cited by 1 | Viewed by 1053

Abstract

The choroid plexus (CP) plays central roles in regulating the microenvironment of the central nervous system by secreting the majority of cerebrospinal fluid (CSF) and controlling its composition. A monolayer of epithelial cells of CP plays a significant role in forming the blood–CSF barrier to restrict the movement of substances between the blood and ventricles. CP epithelial cells are equipped with transporters for glucose and lactate that are used as energy sources. There are many review papers on glucose transporters in CP epithelial cells. On the other hand, distribution of monocarboxylate transporters (MCTs) in CP epithelial cells has received less attention compared with glucose transporters. Some MCTs are known to transport lactate, pyruvate, and ketone bodies, whereas others transport thyroid hormones. Since CP epithelial cells have significant carrier functions as well as the barrier function, a decline in the expression and function of these transporters leads to a poor supply of thyroid hormones as well as lactate and can contribute to the process of age-associated brain impairment and pathophysiology of neurodegenerative diseases. In this review paper, recent findings regarding the distribution and significance of MCTs in the brain, especially in CP epithelial cells, are summarized. Full article

(This article belongs to the Special Issue Roles of Transporters and Receptors in Drug Delivery to the Brain in Health and Disease)

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15 pages, 1051 KiB

Open AccessReview

Endocrine Regulation of Microvascular Receptor—Mediated Transcytosis and Its Therapeutic Opportunities: Insights by PCSK9—Mediated Regulation

by Alexander D. Mazura and Claus U. Pietrzik

Pharmaceutics 2023, 15(4), 1268; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics15041268 - 18 Apr 2023

Viewed by 1323

Abstract

Currently, many neurological disorders lack effective treatment options due to biological barriers that effectively separate the central nervous system (CNS) from the periphery. CNS homeostasis is maintained by a highly selective exchange of molecules, with tightly controlled ligand-specific transport systems at the blood–brain barrier (BBB) playing a key role. Exploiting or modifying these endogenous transport systems could provide a valuable tool for targeting insufficient drug delivery into the CNS or pathological changes in the microvasculature. However, little is known about how BBB transcytosis is continuously regulated to respond to temporal or chronic changes in the environment. The aim of this mini-review is to draw attention to the sensitivity of the BBB to circulating molecules derived from peripheral tissues, which may indicate a fundamental endocrine-operating regulatory system of receptor-mediated transcytosis at the BBB. We present our thoughts in the context of the recent observation that low-density lipoprotein receptor-related protein 1 (LRP1)-mediated clearance of brain amyloid-β (Aβ) across the BBB is negatively regulated by peripheral proprotein convertase subtilisin/kexin type 9 (PCSK9). We hope that our conclusions will inspire future investigations of the BBB as dynamic communication interface between the CNS and periphery, whose peripheral regulatory mechanisms could be easily exploited for therapeutic purposes. Full article

(This article belongs to the Special Issue Roles of Transporters and Receptors in Drug Delivery to the Brain in Health and Disease)

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