Research

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25 pages, 4203 KiB

Open AccessArticle

Non-Human Primate Blood–Brain Barrier and In Vitro Brain Endothelium: From Transcriptome to the Establishment of a New Model

by Catarina Chaves, Tuan-Minh Do, Céline Cegarra, Valérie Roudières, Sandrine Tolou, Gilbert Thill, Corinne Rocher, Michel Didier and Dominique Lesuisse

Pharmaceutics 2020, 12(10), 967; https://doi.org/10.3390/pharmaceutics12100967 - 14 Oct 2020

Cited by 10 | Viewed by 3059

Abstract

The non-human primate (NHP)-brain endothelium constitutes an essential alternative to human in the prediction of molecule trafficking across the blood–brain barrier (BBB). This study presents a comparison between the NHP transcriptome of freshly isolated brain microcapillaries and in vitro-selected brain endothelial cells (BECs), [...] Read more.

The non-human primate (NHP)-brain endothelium constitutes an essential alternative to human in the prediction of molecule trafficking across the blood–brain barrier (BBB). This study presents a comparison between the NHP transcriptome of freshly isolated brain microcapillaries and in vitro-selected brain endothelial cells (BECs), focusing on important BBB features, namely tight junctions, receptors mediating transcytosis (RMT), ABC and SLC transporters, given its relevance as an alternative model for the molecule trafficking prediction across the BBB and identification of new brain-specific transport mechanisms. In vitro BECs conserved most of the BBB key elements for barrier integrity and control of molecular trafficking. The function of RMT via the transferrin receptor (TFRC) was characterized in this NHP-BBB model, where both human transferrin and anti-hTFRC antibody showed increased apical-to-basolateral passage in comparison to control molecules. In parallel, eventual BBB-related regional differences were Investig.igated in seven-day in vitro-selected BECs from five brain structures: brainstem, cerebellum, cortex, hippocampus, and striatum. Our analysis retrieved few differences in the brain endothelium across brain regions, suggesting a rather homogeneous BBB function across the brain parenchyma. The presently established NHP-derived BBB model closely mimics the physiological BBB, thus representing a ready-to-use tool for assessment of the penetration of biotherapeutics into the human CNS. Full article

(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)

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16 pages, 2306 KiB

Open AccessArticle

TMS-Induced Controlled BBB Opening: Preclinical Characterization and Implications for Treatment of Brain Cancer

by Udi Vazana, Lior Schori, Uri Monsonego, Evyatar Swissa, Gabriel S. Pell, Yiftach Roth, Pnina Brodt, Alon Friedman and Ofer Prager

Pharmaceutics 2020, 12(10), 946; https://doi.org/10.3390/pharmaceutics12100946 - 05 Oct 2020

Cited by 7 | Viewed by 3190

Abstract

Proper neuronal function requires strict maintenance of the brain’s extracellular environment. Therefore, passage of molecules between the circulation and brain neuropil is tightly regulated by the blood–brain barrier (BBB). While the BBB is vital for normal brain function, it also restricts the passage [...] Read more.

Proper neuronal function requires strict maintenance of the brain’s extracellular environment. Therefore, passage of molecules between the circulation and brain neuropil is tightly regulated by the blood–brain barrier (BBB). While the BBB is vital for normal brain function, it also restricts the passage of drugs, potentially effective in treating brain diseases, into the brain. Despite previous attempts, there is still an unmet need to develop novel approaches that will allow safe opening of the BBB for drug delivery. We have recently shown in experimental rodents and in a pilot human trial that low-frequency, high-amplitude repetitive transcranial magnetic stimulation (rTMS) allows the delivery of peripherally injected fluorescent and Gd-based tracers into the brain. The goals of this study were to characterize the duration and safety level of rTMS-induced BBB opening and test its capacity to enhance the delivery of the antitumor growth agent, insulin-like growth factor trap, across the BBB. We employed direct vascular and magnetic resonance imaging, as well as electrocorticography recordings, to assess the impact of rTMS on brain vascular permeability and electrical activity, respectively. Our findings indicate that rTMS induces a transient and safe BBB opening with a potential to facilitate drug delivery into the brain. Full article

(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)

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17 pages, 2767 KiB

Open AccessArticle

Acute and Chronic Dosing of a High-Affinity Rat/Mouse Chimeric Transferrin Receptor Antibody in Mice

by Demi M. Castellanos, Jiahong Sun, Joshua Yang, Weijun Ou, Alexander C. Zambon, William M. Pardridge and Rachita K. Sumbria

Pharmaceutics 2020, 12(9), 852; https://doi.org/10.3390/pharmaceutics12090852 - 08 Sep 2020

Cited by 12 | Viewed by 3552

Abstract

Non-invasive brain delivery of neurotherapeutics is challenging due to the blood-brain barrier. The revived interest in transferrin receptor antibodies (TfRMAbs) as brain drug-delivery vectors has revealed the effect of dosing regimen, valency, and affinity on brain uptake, TfR expression, and Fc-effector function side [...] Read more.

Non-invasive brain delivery of neurotherapeutics is challenging due to the blood-brain barrier. The revived interest in transferrin receptor antibodies (TfRMAbs) as brain drug-delivery vectors has revealed the effect of dosing regimen, valency, and affinity on brain uptake, TfR expression, and Fc-effector function side effects. These studies have primarily used monovalent TfRMAbs with a human constant region following acute intravenous dosing in mice. The effects of a high-affinity bivalent TfRMAb with a murine constant region, without a fusion partner, following extravascular dosing in mice are, however, not well characterized. Here we elucidate the plasma pharmacokinetics and safety of a high-affinity bivalent TfRMAb with a murine constant region following acute and chronic subcutaneous dosing in adult C57BL/6J male mice. Mice received a single (acute dosing) 3 mg/kg dose, or were treated for four weeks (chronic dosing). TfRMAb and control IgG1 significantly altered reticulocyte counts following acute and chronic dosing, while other hematologic parameters showed minimal change. Chronic TfRMAb dosing did not alter plasma- and brain-iron measurements, nor brain TfR levels, however, it significantly increased splenic-TfR and -iron. Plasma concentrations of TfRMAb were significantly lower in mice chronically treated with IgG1 or TfRMAb. Overall, no injection related reactions were observed in mice. Full article

(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)

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24 pages, 4859 KiB

Open AccessArticle

Conjugation of Therapeutic PSD-95 Inhibitors to the Cell-Penetrating Peptide Tat Affects Blood–Brain Barrier Adherence, Uptake, and Permeation

by Mie Kristensen, Krzysztof Kucharz, Eduardo Felipe Alves Fernandes, Kristian Strømgaard, Morten Schallburg Nielsen, Hans Christian Cederberg Helms, Anders Bach, Malte Ulrikkaholm Tofte-Hansen, Blanca Irene Aldana Garcia, Martin Lauritzen and Birger Brodin

Pharmaceutics 2020, 12(7), 661; https://doi.org/10.3390/pharmaceutics12070661 - 14 Jul 2020

Cited by 21 | Viewed by 5420

Abstract

Novel stroke therapies are needed. Inhibition of the interaction between the postsynaptic density-95 (PSD-95)/disc large/ZO-1 (PDZ) domains of PSD-95 and the N-methyl-D-aspartate (NMDA) receptor has been suggested as a strategy for relieving neuronal damage. The peptides NR2B9c and N-dimer have been [...] Read more.

Novel stroke therapies are needed. Inhibition of the interaction between the postsynaptic density-95 (PSD-95)/disc large/ZO-1 (PDZ) domains of PSD-95 and the N-methyl-D-aspartate (NMDA) receptor has been suggested as a strategy for relieving neuronal damage. The peptides NR2B9c and N-dimer have been designed to hinder this interaction; they are conjugated to the cell-penetrating peptide Tat to facilitate blood–brain barrier (BBB) permeation and neuronal uptake. Tat-N-dimer exhibits 1000-fold better target affinity than Tat-NR2B9c, but the same magnitude of improvement is not observed in terms of therapeutic effect. Differences in BBB permeation by Tat-NR2B9c and Tat-N-dimer may explain this difference, but studies providing a direct comparison of Tat-NR2B9c and Tat-N-dimer are lacking. The aim of the present study was therefore to compare the BBB uptake and permeation of Tat-NR2B9c and Tat-N-dimer. The peptides were conjugated to the fluorophore TAMRA and their chemical stability assessed. Endothelial membrane association and cell uptake, and transendothelial permeation were estimated using co-cultures of primary bovine brain capillary endothelial cells and rat astrocytes. In vivo BBB permeation was demonstrated in mice using two-photon microscopy imaging. Tissue distribution was evaluated in mice demonstrating brain accumulation of TAMRA-Tat (0.4% ID/g), TAMRA-Tat-NR2B9c (0.3% ID/g), and TAMRA-Tat-N-dimer (0.25% ID/g). In conclusion, we demonstrate that attachment of NR2B9c or N-dimer to Tat affects both the chemical stability and the ability of the resulting construct to interact with and permeate the BBB. Full article

(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)

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23 pages, 4093 KiB

Open AccessArticle

Combination of Alanine and Glutathione as Targeting Ligands of Nanoparticles Enhances Cargo Delivery into the Cells of the Neurovascular Unit

by Gergő Porkoláb, Mária Mészáros, András Tóth, Anikó Szecskó, András Harazin, Zsolt Szegletes, Györgyi Ferenc, András Blastyák, Lajos Mátés, Gábor Rákhely, Mária A. Deli and Szilvia Veszelka

Pharmaceutics 2020, 12(7), 635; https://doi.org/10.3390/pharmaceutics12070635 - 07 Jul 2020

Cited by 15 | Viewed by 4019

Abstract

Inefficient drug delivery across the blood–brain barrier (BBB) and into target cells in the brain hinders the treatment of neurological diseases. One strategy to increase the brain penetration of drugs is to use vesicular nanoparticles functionalized with multiple ligands of BBB transporters as [...] Read more.

Inefficient drug delivery across the blood–brain barrier (BBB) and into target cells in the brain hinders the treatment of neurological diseases. One strategy to increase the brain penetration of drugs is to use vesicular nanoparticles functionalized with multiple ligands of BBB transporters as vehicles. Once within the brain, however, drugs must also be able to reach their therapeutic targets in the different cell types. It is, therefore, favorable if such nanocarriers are designed that can deliver their cargo not only to brain endothelial cells, but to other cell types as well. Here, we show that alanine-glutathione dual-targeting of niosomes enhances the delivery of a large protein cargo into cultured cells of the neurovascular unit, namely brain endothelial cells, pericytes, astrocytes and neurons. Furthermore, using metabolic and endocytic inhibitors, we show that the cellular uptake of niosomes is energy-dependent and is partially mediated by endocytosis. Finally, we demonstate the ability of our targeted nanovesicles to deliver their cargo into astroglial cells after crossing the BBB in vitro. These data indicate that dual-labeling of nanoparticles with alanine and glutathione can potentially be exploited to deliver drugs, even biopharmacons, across the BBB and into multiple cell types in the brain. Full article

(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)

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19 pages, 4773 KiB

Open AccessArticle

Identification of Cell-Surface Proteins Endocytosed by Human Brain Microvascular Endothelial Cells In Vitro

by Shingo Ito, Mariko Oishi, Seiryo Ogata, Tatsuki Uemura, Pierre-Olivier Couraud, Takeshi Masuda and Sumio Ohtsuki

Pharmaceutics 2020, 12(6), 579; https://doi.org/10.3390/pharmaceutics12060579 - 23 Jun 2020

Cited by 12 | Viewed by 4030

Abstract

Cell-surface proteins that can endocytose into brain microvascular endothelial cells serve as promising candidates for receptor-mediated transcytosis across the blood–brain barrier (BBB). Here, we comprehensively screened endocytic cell-surface proteins in hCMEC/D3 cells, a model of human brain microvascular endothelial cells, using surface biotinylation [...] Read more.

Cell-surface proteins that can endocytose into brain microvascular endothelial cells serve as promising candidates for receptor-mediated transcytosis across the blood–brain barrier (BBB). Here, we comprehensively screened endocytic cell-surface proteins in hCMEC/D3 cells, a model of human brain microvascular endothelial cells, using surface biotinylation methodology and sequential window acquisition of all theoretical fragment-ion spectra-mass spectrometry (SWATH-MS)-based quantitative proteomics. Using this method, we identified 125 endocytic cell-surface proteins from hCMEC/D3 cells. Of these, 34 cell-surface proteins were selectively internalized into human brain microvascular endothelial cells, but not into human umbilical vein endothelial cells (HUVECs), a model of human peripheral microvascular endothelial cells. Two cell-surface proteins, intercellular adhesion molecule-1 (ICAM1) and podocalyxin (PODXL), were identified as BBB-localized endocytic cell-surface proteins in humans, using open mRNA and protein databases. Immunohistochemical evaluation confirmed PODXL expression in the plasma membrane of hCMEC/D3 cells and revealed that anti-PODXL antibody-labeled cell-surface PODXL internalized into hCMEC/D3 cells. Immunohistochemistry further revealed that PODXL is localized at the luminal side of human brain microvessels, supporting its potential suitability for translational applications. In conclusion, our findings highlight novel endocytic cell-surface proteins capable of internalizing into human brain microvascular endothelial cells. ICAM1 or PODXL targeted antibody or ligand-labeled biopharmaceuticals and nanocarriers may provide effective targeted delivery to the brain across the BBB for the treatment of central nervous system (CNS) diseases. Full article

(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)

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12 pages, 1386 KiB

Open AccessArticle

L-Type Amino Acid Transporter 1-Utilizing Prodrugs of Ketoprofen Can Efficiently Reduce Brain Prostaglandin Levels

by Ahmed Montaser, Marko Lehtonen, Mikko Gynther and Kristiina M. Huttunen

Pharmaceutics 2020, 12(4), 344; https://doi.org/10.3390/pharmaceutics12040344 - 11 Apr 2020

Cited by 7 | Viewed by 3331

Abstract

In order to efficiently combat neuroinflammation, it is essential to deliver the anti-inflammatory drugs to their target sites in the brain. Pro-drugs utilizing the L-type amino acid transporter 1 (LAT1) can be transported across the blood-brain barrier (BBB) and the cellular barriers of [...] Read more.

In order to efficiently combat neuroinflammation, it is essential to deliver the anti-inflammatory drugs to their target sites in the brain. Pro-drugs utilizing the L-type amino acid transporter 1 (LAT1) can be transported across the blood-brain barrier (BBB) and the cellular barriers of the brain’s parenchymal cells. In this study, we evaluated, for the first time, the efficacy of LAT1-utilizing prodrugs of ketoprofen (KPF) on cyclooxygenase (COX) enzymes in vitro and prostaglandin E2 production in vivo by using an enzymatic assay and liquid chromatography- tandem mass spectrometry method, respectively. Aliphatic amino acid-conjugated pro-drugs inhibited the peroxidase activity of COX in vitro in their intact form (85% inhibition, IC50 ≈ 1.1 µM and 79%, IC50 ≈ 2.3 µM), which was comparable to KPF (90%, IC50 ≈ 0.9). Thus, these compounds acted more as KPF derivatives rather than pro-drugs. In turn, aromatic amino acid-conjugated pro-drugs behaved differently. The ester pro-drug inhibited the COX peroxidase activity in vitro (90%, IC50 ≈ 0.6 µM) due to its bioconversion to KPF, whereas the amide pro-drug was inactive toward COX enzymes in vitro. However, the amide pro-drug released KPF in the mouse brain in sufficient and effective amounts measured as reduced PGE2 levels. Full article

(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)

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17 pages, 2882 KiB

Open AccessArticle

An Interspecies Molecular and Functional Study of Organic Cation Transporters at the Blood-Brain Barrier: From Rodents to Humans

by Catarina Chaves, Federica Campanelli, Hélène Chapy, David Gomez-Zepeda, Fabienne Glacial, Maria Smirnova, Meryam Taghi, Johan Pallud, Nicolas Perrière, Xavier Declèves, Marie-Claude Menet and Salvatore Cisternino

Pharmaceutics 2020, 12(4), 308; https://doi.org/10.3390/pharmaceutics12040308 - 28 Mar 2020

Cited by 20 | Viewed by 3564

Abstract

Organic cation transporters (OCTs) participate in the handling of compounds in kidneys and at the synaptic cleft. Their role at the blood-brain barrier (BBB) in brain drug delivery is still unclear. The presence of OCT1,2,3 (SLC22A1-3) in mouse, rat and human isolated brain [...] Read more.

Organic cation transporters (OCTs) participate in the handling of compounds in kidneys and at the synaptic cleft. Their role at the blood-brain barrier (BBB) in brain drug delivery is still unclear. The presence of OCT1,2,3 (SLC22A1-3) in mouse, rat and human isolated brain microvessels was investigated by either qRT-PCR, quantitative proteomics and/or functional studies. BBB transport of the prototypical substrate [³H]-1-methyl-4-phenylpyridinium ([³H]-MPP⁺) was measured by in situ brain perfusion in six mouse strains and in Sprague Dawley rats, in primary human brain microvascular endothelial cells seeded on inserts, in the presence or absence of OCTs and a MATE1 (SLC49A1) inhibitor. The results show negligible OCT1 (SLC22A1) and OCT2 (SLC22A2) expression in either mice, rat or human brain microvessels, while OCT3 expression was identified in rat microvessels by qRT-PCR. The in vitro human cellular uptake of [³H]-MPP⁺ was not modified by OCTs/MATE-inhibitor. Brain transport of [³H]-MPP⁺ remains unchanged between 2- and 6-month old mice, and no alteration was observed in mice and rats with inhibitors. In conclusion, the evidenced lack of expression and/or functional OCTs and MATE at the BBB allows the maintenance of the brain homeostasis and function as it prevents an easy access of their neurotoxicant substrates to the brain parenchyma. Full article

(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)

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Review

Jump to: Research

19 pages, 1839 KiB

Open AccessReview

Tight Junction Modulating Bioprobes for Drug Delivery System to the Brain: A Review

by Keisuke Tachibana, Yumi Iwashita, Erika Wakayama, Itsuki Nishino, Taiki Nishikaji and Masuo Kondoh

Pharmaceutics 2020, 12(12), 1236; https://doi.org/10.3390/pharmaceutics12121236 - 19 Dec 2020

Cited by 10 | Viewed by 3435

Abstract

The blood-brain barrier (BBB), which is composed of endothelial cells, pericytes, astrocytes, and neurons, separates the brain extracellular fluid from the circulating blood, and maintains the homeostasis of the central nervous system (CNS). The BBB endothelial cells have well-developed tight junctions (TJs) and [...] Read more.

The blood-brain barrier (BBB), which is composed of endothelial cells, pericytes, astrocytes, and neurons, separates the brain extracellular fluid from the circulating blood, and maintains the homeostasis of the central nervous system (CNS). The BBB endothelial cells have well-developed tight junctions (TJs) and express specific polarized transport systems to tightly control the paracellular movements of solutes, ions, and water. There are two types of TJs: bicellular TJs (bTJs), which is a structure at the contact of two cells, and tricellular TJs (tTJs), which is a structure at the contact of three cells. Claudin-5 and angulin-1 are important components of bTJs and tTJs in the brain, respectively. Here, we review TJ-modulating bioprobes that enable drug delivery to the brain across the BBB, focusing on claudin-5 and angulin-1. Full article

(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)

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39 pages, 2069 KiB

Open AccessReview

Bypassing the Blood–Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

by Manuela Gernert and Malte Feja

Pharmaceutics 2020, 12(12), 1134; https://doi.org/10.3390/pharmaceutics12121134 - 24 Nov 2020

Cited by 34 | Viewed by 3803

Abstract

Epilepsies are common chronic neurological diseases characterized by recurrent unprovoked seizures of central origin. The mainstay of treatment involves symptomatic suppression of seizures with systemically applied antiseizure drugs (ASDs). Systemic pharmacotherapies for epilepsies are facing two main challenges. First, adverse effects from (often [...] Read more.

Epilepsies are common chronic neurological diseases characterized by recurrent unprovoked seizures of central origin. The mainstay of treatment involves symptomatic suppression of seizures with systemically applied antiseizure drugs (ASDs). Systemic pharmacotherapies for epilepsies are facing two main challenges. First, adverse effects from (often life-long) systemic drug treatment are common, and second, about one-third of patients with epilepsy have seizures refractory to systemic pharmacotherapy. Especially the drug resistance in epilepsies remains an unmet clinical need despite the recent introduction of new ASDs. Apart from other hypotheses, epilepsy-induced alterations of the blood–brain barrier (BBB) are thought to prevent ASDs from entering the brain parenchyma in necessary amounts, thereby being involved in causing drug-resistant epilepsy. Although an invasive procedure, bypassing the BBB by targeted intracranial drug delivery is an attractive approach to circumvent BBB-associated drug resistance mechanisms and to lower the risk of systemic and neurologic adverse effects. Additionally, it offers the possibility of reaching higher local drug concentrations in appropriate target regions while minimizing them in other brain or peripheral areas, as well as using otherwise toxic drugs not suitable for systemic administration. In our review, we give an overview of experimental and clinical studies conducted on direct intracranial drug delivery in epilepsies. We also discuss challenges associated with intracranial pharmacotherapy for epilepsies. Full article

(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)

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21 pages, 1301 KiB

Open AccessReview

Blood–Brain Barrier Modulation to Improve Glioma Drug Delivery

by Huilong Luo and Eric V. Shusta

Pharmaceutics 2020, 12(11), 1085; https://doi.org/10.3390/pharmaceutics12111085 - 12 Nov 2020

Cited by 55 | Viewed by 4043

Abstract

The blood–brain barrier (BBB) is formed by brain microvascular endothelial cells that are sealed by tight junctions, making it a significant obstacle for most brain therapeutics. The poor BBB penetration of newly developed therapeutics has therefore played a major role in limiting their [...] Read more.

The blood–brain barrier (BBB) is formed by brain microvascular endothelial cells that are sealed by tight junctions, making it a significant obstacle for most brain therapeutics. The poor BBB penetration of newly developed therapeutics has therefore played a major role in limiting their clinical success. A particularly challenging therapeutic target is glioma, which is the most frequently occurring malignant brain tumor. Thus, to enhance therapeutic uptake in tumors, researchers have been developing strategies to modulate BBB permeability. However, most conventional BBB opening strategies are difficult to apply in the clinical setting due to their broad, non-specific modulation of the BBB, which can result in damage to normal brain tissue. In this review, we have summarized strategies that could potentially be used to selectively and efficiently modulate the tumor BBB for more effective glioma treatment. Full article

(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)

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32 pages, 6925 KiB

Open AccessReview

Novel Intrinsic Mechanisms of Active Drug Extrusion at the Blood-Brain Barrier: Potential Targets for Enhancing Drug Delivery to the Brain?

by Wolfgang Löscher and Birthe Gericke

Pharmaceutics 2020, 12(10), 966; https://doi.org/10.3390/pharmaceutics12100966 - 14 Oct 2020

Cited by 14 | Viewed by 3868

Abstract

The blood-brain barrier (BBB) limits the pharmacotherapy of several brain disorders. In addition to the structural and metabolic characteristics of the BBB, the ATP-driven, drug efflux transporter P-glycoprotein (Pgp) is a selective gatekeeper of the BBB; thus, it is a primary hindrance to [...] Read more.

The blood-brain barrier (BBB) limits the pharmacotherapy of several brain disorders. In addition to the structural and metabolic characteristics of the BBB, the ATP-driven, drug efflux transporter P-glycoprotein (Pgp) is a selective gatekeeper of the BBB; thus, it is a primary hindrance to drug delivery into the brain. Here, we review the complex regulation of Pgp expression and functional activity at the BBB with an emphasis on recent studies from our laboratory. In addition to traditional processes such as transcriptional regulation and posttranscriptional or posttranslational modification of Pgp expression and functionality, novel mechanisms such as intra- and intercellular Pgp trafficking and intracellular Pgp-mediated lysosomal sequestration in BBB endothelial cells with subsequent disposal by blood neutrophils are discussed. These intrinsic mechanisms of active drug extrusion at the BBB are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the treatment of brain diseases and enhance drug delivery to the brain. Full article

(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)

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34 pages, 2163 KiB

Open AccessReview

Targeting the Choroid Plexuses for Protein Drug Delivery

by Mark A. Bryniarski, Tianjing Ren, Abbas R. Rizvi, Anthony M. Snyder and Marilyn E. Morris

Pharmaceutics 2020, 12(10), 963; https://doi.org/10.3390/pharmaceutics12100963 - 14 Oct 2020

Cited by 14 | Viewed by 5957

Abstract

Delivery of therapeutic agents to the central nervous system is challenged by the barriers in place to regulate brain homeostasis. This is especially true for protein therapeutics. Targeting the barrier formed by the choroid plexuses at the interfaces of the systemic circulation and [...] Read more.

Delivery of therapeutic agents to the central nervous system is challenged by the barriers in place to regulate brain homeostasis. This is especially true for protein therapeutics. Targeting the barrier formed by the choroid plexuses at the interfaces of the systemic circulation and ventricular system may be a surrogate brain delivery strategy to circumvent the blood-brain barrier. Heterogenous cell populations located at the choroid plexuses provide diverse functions in regulating the exchange of material within the ventricular space. Receptor-mediated transcytosis may be a promising mechanism to deliver protein therapeutics across the tight junctions formed by choroid plexus epithelial cells. However, cerebrospinal fluid flow and other barriers formed by ependymal cells and perivascular spaces should also be considered for evaluation of protein therapeutic disposition. Various preclinical methods have been applied to delineate protein transport across the choroid plexuses, including imaging strategies, ventriculocisternal perfusions, and primary choroid plexus epithelial cell models. When used in combination with simultaneous measures of cerebrospinal fluid dynamics, they can yield important insight into pharmacokinetic properties within the brain. This review aims to provide an overview of the choroid plexuses and ventricular system to address their function as a barrier to pharmaceutical interventions and relevance for central nervous system drug delivery of protein therapeutics. Protein therapeutics targeting the ventricular system may provide new approaches in treating central nervous system diseases. Full article

(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)

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16 pages, 681 KiB

Open AccessReview

Brain Delivery of Single-Domain Antibodies: A Focus on VHH and VNAR

by Elodie Pothin, Dominique Lesuisse and Pierre Lafaye

Pharmaceutics 2020, 12(10), 937; https://doi.org/10.3390/pharmaceutics12100937 - 30 Sep 2020

Cited by 41 | Viewed by 6125

Abstract

Passive immunotherapy, i.e., treatment with therapeutic antibodies, has been increasingly used over the last decade in several diseases such as cancers or inflammation. However, these proteins have some limitations that single-domain antibodies could potentially solve. One of the main issues of conventional antibodies [...] Read more.

Passive immunotherapy, i.e., treatment with therapeutic antibodies, has been increasingly used over the last decade in several diseases such as cancers or inflammation. However, these proteins have some limitations that single-domain antibodies could potentially solve. One of the main issues of conventional antibodies is their limited brain penetration because of the blood–brain barrier (BBB). In this review, we aim at exploring the different options single-domain antibodies (sDAbs) such as variable domain of heavy-chain antibodies (VHHs) and variable new antigen receptors (VNARs) have already taken to reach the brain allowing them to be used as therapeutic, diagnosis or transporter tools. Full article

(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)

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18 pages, 2848 KiB

Open AccessReview

Drugs Modulating CD4+ T Cells Blood–Brain Barrier Interaction in Alzheimer’s Disease

by Norwin Kubick, Patrick C. Henckell Flournoy, Ana-Maria Enciu, Gina Manda and Michel-Edwar Mickael

Pharmaceutics 2020, 12(9), 880; https://doi.org/10.3390/pharmaceutics12090880 - 16 Sep 2020

Cited by 27 | Viewed by 4363

Abstract

The effect of Alzheimer’s disease (AD) medications on CD4+ T cells homing has not been thoroughly investigated. CD4+ T cells could both exacerbate and reduce AD symptoms based on their infiltrating subpopulations. Proinflammatory subpopulations such as Th1 and Th17 constitute a major source [...] Read more.

The effect of Alzheimer’s disease (AD) medications on CD4+ T cells homing has not been thoroughly investigated. CD4+ T cells could both exacerbate and reduce AD symptoms based on their infiltrating subpopulations. Proinflammatory subpopulations such as Th1 and Th17 constitute a major source of proinflammatory cytokines that reduce endothelial integrity and stimulate astrocytes, resulting in the production of amyloid β. Anti-inflammatory subpopulations such as Th2 and Tregs reduce inflammation and regulate the function of Th1 and Th17. Recently, pathogenic Th17 has been shown to have a superior infiltrating capacity compared to other major CD4+ T cell subpopulations. Alzheimer’s drugs such as donepezil (Aricept), rivastigmine (Exelon), galantamine (Razadyne), and memantine (Namenda) are known to play an important part in regulating the mechanisms of the neurotransmitters. However, little is known about the effect of these drugs on CD4+ T cell subpopulations’ infiltration of the brain during AD. In this review, we focus on understanding the influence of AD drugs on CD4+ T cell subpopulation interactions with the BBB in AD. While current AD therapies improve endothelial integrity and reduce astrocytes activations, they vary according to their influence on various CD4+ T cell subpopulations. Donepezil reduces the numbers of Th1 but not Th2, Rivastigmine inhibits Th1 and Th17 but not Th2, and memantine reduces Th1 but not Treg. However, none of the current AD drugs is specifically designed to target the dysregulated balance in the Th17/Treg axis. Future drug design approaches should specifically consider inhibiting CD4+ Th17 to improve AD prognosis. Full article

(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)

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