Blood–Brain Barrier Drug Targeting: The Future of Brain Drug Development

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (10 March 2022) | Viewed by 37301

Special Issue Editor

Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA
Interests: blood–brain barrier; pain therapeutics; drug delivery; drug development; CNS targeting
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neurological disorders have been a challenge to target therapeutically given the presence of the blood–brain barrier (BBB). Blood–brain barrier (BBB)/Neurovascular unit (NVU) integrity is vital to the health of the central nervous system (CNS) and serves as the gateway for CNS drug delivery. However, the influence of pathological changes on BBB dynamics and ultimately on brain drug development is oft overlooked. Thus, it is important to the clinical success of new CNS-targeting agents to account for pathological changes, as well as those resulting from aging and sex differences, to fully understand BBB integrity, its impact on drug delivery, and how these issues will be addressed in the future.

The aim of this Special Issue of Pharmaceutics is to collect research and review papers on targeting the CNS during disease by understanding the role of the BBB in drug discovery and development. We welcome articles dealing with any aspect of BBB dynamics during physiological and pathophysiological states on CNS drug delivery and invite researchers and drug developers to publish their original research or review articles with expert opinions and perspectives in the area of therapeutics.

Dr. Tally M. Largent-Milnes
Guest Editor

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Keywords

  • blood–brain barrier
  • drug delivery
  • CNS targeting
  • drug development
  • pathologic influence on the neurovascular unit

Published Papers (10 papers)

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Research

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15 pages, 1948 KiB  
Article
Inhibition of HSP90 Preserves Blood–Brain Barrier Integrity after Cortical Spreading Depression
by Seph M. Palomino, Aidan A. Levine, Jared Wahl, Erika Liktor-Busa, John M. Streicher and Tally M. Largent-Milnes
Pharmaceutics 2022, 14(8), 1665; https://doi.org/10.3390/pharmaceutics14081665 - 10 Aug 2022
Cited by 1 | Viewed by 1818
Abstract
Cortical spreading depression (CSD) is a pathophysiological mechanism underlying headache disorders, including migraine. Blood–brain barrier (BBB) permeability is increased during CSD. Recent papers have suggested that heat shock proteins (HSP) contribute to the integrity of the blood–brain barrier. In this study, the possible [...] Read more.
Cortical spreading depression (CSD) is a pathophysiological mechanism underlying headache disorders, including migraine. Blood–brain barrier (BBB) permeability is increased during CSD. Recent papers have suggested that heat shock proteins (HSP) contribute to the integrity of the blood–brain barrier. In this study, the possible role of HSP90 in CSD-associated blood–brain barrier leak at the endothelial cell was investigated using an in vitro model, for the blood–endothelial barrier (BEB), and an in vivo model with an intact BBB. We measured barrier integrity using trans endothelial electric resistance (TEER) across a monolayer of rodent brain endothelial cells (bEnd.3), a sucrose uptake assay, and in situ brain perfusion using female Sprague Dawley rats. CSD was induced by application of 60 mM KCl for 5 min in in vitro experiments or cortical injection of KCl (1 M, 0.5 µL) through a dural cannula in vivo. HSP90 was selectively blocked by 17-AAG. Our data showed that preincubation with 17-AAG (1 µM) prevented the reduction of TEER values caused by the KCl pulse on the monolayer of bEnd.3 cells. The elevated uptake of 14C-sucrose across the same endothelial monolayer induced by the KCl pulse was significantly reduced after preincubation with HSP90 inhibitor. Pre-exposure to 17-AAG significantly mitigated the transient BBB leak after CSD induced by cortical KCl injection as determined by in situ brain perfusion in female rats. Our results demonstrated that inhibition of HSP90 with the selective agent 17-AAG reduced CSD-associated BEB/BBB paracellular leak. Overall, this novel observation supports HSP90 inhibition mitigates KCl-induced BBB permeability and suggests the development of new therapeutic approaches targeting HSP90 in headache disorders. Full article
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29 pages, 15026 KiB  
Article
Extracellular Alterations in pH and K+ Modify the Murine Brain Endothelial Cell Total and Phospho-Proteome
by Jared R. Wahl, Anjali Vivek, Seph M. Palomino, Moyad Almuslim, Karissa E. Cottier, Paul R. Langlais, John M. Streicher, Todd W. Vanderah, Erika Liktor-Busa and Tally M. Largent-Milnes
Pharmaceutics 2022, 14(7), 1469; https://doi.org/10.3390/pharmaceutics14071469 - 15 Jul 2022
Cited by 2 | Viewed by 1668
Abstract
Pathologies of the blood–brain barrier (BBB) have been linked to a multitude of central nervous system (CNS) disorders whose pathology is poorly understood. Cortical spreading depression (CSD) has long been postulated to be involved in the underlying mechanisms of these disease states, yet [...] Read more.
Pathologies of the blood–brain barrier (BBB) have been linked to a multitude of central nervous system (CNS) disorders whose pathology is poorly understood. Cortical spreading depression (CSD) has long been postulated to be involved in the underlying mechanisms of these disease states, yet a complete understanding remains elusive. This study seeks to utilize an in vitro model of the blood–brain barrier (BBB) with brain endothelial cell (b.End3) murine endothelioma cells to investigate the role of CSD in BBB pathology by characterizing effects of the release of major pronociceptive substances into the extracellular space of the CNS. The application of trans-endothelial electrical resistance (TEER) screening, transcellular uptake, and immunoreactive methods were used in concert with global proteome and phospho-proteomic approaches to assess the effect of modeled CSD events on the modeled BBB in vitro. The findings demonstrate relocalization and functional alteration to proteins associated with the actin cytoskeleton and endothelial tight junctions. Additionally, unique pathologic mechanisms induced by individual substances released during CSD were found to have unique phosphorylation signatures in phospho-proteome analysis, identifying Zona Occludins 1 (ZO-1) as a possible pathologic “checkpoint” of the BBB. By utilizing these phosphorylation signatures, possible novel diagnostic methods may be developed for CSD and warrants further investigation. Full article
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14 pages, 3140 KiB  
Article
Large-Scale Evaluation of Collision Cross Sections to Investigate Blood-Brain Barrier Permeation of Drugs
by Armin Sebastian Guntner, Thomas Bögl, Franz Mlynek and Wolfgang Buchberger
Pharmaceutics 2021, 13(12), 2141; https://doi.org/10.3390/pharmaceutics13122141 - 13 Dec 2021
Cited by 2 | Viewed by 2005
Abstract
Successful drug administration to the central nervous system requires accurate adjustment of the drugs’ molecular properties. Therefore, structure-derived descriptors of potential brain therapeutic agents are essential for an early evaluation of pharmacokinetics during drug development. The collision cross section (CCS) of molecules was [...] Read more.
Successful drug administration to the central nervous system requires accurate adjustment of the drugs’ molecular properties. Therefore, structure-derived descriptors of potential brain therapeutic agents are essential for an early evaluation of pharmacokinetics during drug development. The collision cross section (CCS) of molecules was recently introduced as a novel measurable parameter to describe blood-brain barrier (BBB) permeation. This descriptor combines molecular information about mass, structure, volume, branching and flexibility. As these chemical properties are known to influence cerebral pharmacokinetics, CCS determination of new drug candidates may provide important additional spatial information to support existing models of BBB penetration of drugs. Besides measuring CCS, calculation is also possible; but however, the reliability of computed CCS values for an evaluation of BBB permeation has not yet been fully investigated. In this work, prediction tools based on machine learning were used to compute CCS values of a large number of compounds listed in drug libraries as negative or positive with respect to brain penetration (BBB+ and BBB compounds). Statistical evaluation of computed CCS and several other descriptors could prove the high value of CCS. Further, CCS-deduced maximum molecular size of BBB+ drugs matched the dimensions of BBB pores. A threshold for transcellular penetration and possible permeation through pore-like openings of cellular tight-junctions is suggested. In sum, CCS evaluation with modern in silico tools shows high potential for its use in the drug development process. Full article
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17 pages, 4047 KiB  
Article
Blood–Brain Barrier Permeability: Is 5-Hydroxytryptamine Receptor Type 4 a Game Changer?
by Guillaume Becker, Sylvia Da Silva, Amelia-Naomi Sabo, Maria Cristina Antal, Véronique Kemmel and Laurent Monassier
Pharmaceutics 2021, 13(11), 1856; https://doi.org/10.3390/pharmaceutics13111856 - 03 Nov 2021
Cited by 4 | Viewed by 2288
Abstract
Serotonin affects many functions in the body, both in the central nervous system (CNS) and the periphery. However, its effect on the blood–brain barrier (BBB) in separating these two worlds has been scarcely investigated. The aim of this work was to characterize the [...] Read more.
Serotonin affects many functions in the body, both in the central nervous system (CNS) and the periphery. However, its effect on the blood–brain barrier (BBB) in separating these two worlds has been scarcely investigated. The aim of this work was to characterize the serotonin receptor 5-HT4 in the hCMEC/D3 cell line, in the rat and the human BBB. We also examined the effect of prucalopride, a 5-HT4 receptor agonist, on the permeability of the hCMEC/D3 in an in vitro model of BBB. We then confirmed our observations by in vivo experiments. In this work, we show that the 5-HT4 receptor is expressed by hCMEC/D3 cells and in the capillaries of rat and human brains. Prucalopride increases the BBB permeability by downregulating the expression of the tight junction protein, occludin. This effect is prevented by GR113808, a 5-HT4 receptor antagonist, and is mediated by the Src/ERK1/2 signaling pathway. The canonical G-protein-dependent pathway does not appear to be involved in this phenomenon. Finally, the administration of prucalopride increases the diffusion of Evans blue in the rat brain parenchyma, which is synonymous with BBB permeabilization. All these data indicate that the 5-HT4 receptor contributes to the regulation of BBB permeability. Full article
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15 pages, 2625 KiB  
Article
Physiologically Based Pharmacokinetic (PBPK) Modeling for Predicting Brain Levels of Drug in Rat
by Bárbara Sánchez-Dengra, Isabel Gonzalez-Alvarez, Marival Bermejo and Marta Gonzalez-Alvarez
Pharmaceutics 2021, 13(9), 1402; https://doi.org/10.3390/pharmaceutics13091402 - 03 Sep 2021
Cited by 4 | Viewed by 2517
Abstract
One of the main obstacles in neurological disease treatment is the presence of the blood–brain barrier. New predictive high-throughput screening tools are essential to avoid costly failures in the advanced phases of development and to contribute to the 3 Rs policy. The objective [...] Read more.
One of the main obstacles in neurological disease treatment is the presence of the blood–brain barrier. New predictive high-throughput screening tools are essential to avoid costly failures in the advanced phases of development and to contribute to the 3 Rs policy. The objective of this work was to jointly develop a new in vitro system coupled with a physiological-based pharmacokinetic (PBPK) model able to predict brain concentration levels of different drugs in rats. Data from in vitro tests with three different cells lines (MDCK, MDCK-MDR1 and hCMEC/D3) were used together with PK parameters and three scaling factors for adjusting the model predictions to the brain and plasma profiles of six model drugs. Later, preliminary quantitative structure–property relationships (QSPRs) were constructed between the scaling factors and the lipophilicity of drugs. The predictability of the model was evaluated by internal validation. It was concluded that the PBPK model, incorporating the barrier resistance to transport, the disposition within the brain and the drug–brain binding combined with MDCK data, provided the best predictions for passive diffusion and carrier-mediated transported drugs, while in the other cell lines, active transport influence can bias predictions. Full article
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Review

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30 pages, 4284 KiB  
Review
Current Strategies to Enhance Delivery of Drugs across the Blood–Brain Barrier
by Raluca Ioana Teleanu, Manuela Daniela Preda, Adelina-Gabriela Niculescu, Oana Vladâcenco, Crina Ioana Radu, Alexandru Mihai Grumezescu and Daniel Mihai Teleanu
Pharmaceutics 2022, 14(5), 987; https://doi.org/10.3390/pharmaceutics14050987 - 04 May 2022
Cited by 40 | Viewed by 5396
Abstract
The blood–brain barrier (BBB) has shown to be a significant obstacle to brain medication delivery. The BBB in a healthy brain is a diffusion barrier that prevents most substances from passing from the blood to the brain; only tiny molecules can pass across [...] Read more.
The blood–brain barrier (BBB) has shown to be a significant obstacle to brain medication delivery. The BBB in a healthy brain is a diffusion barrier that prevents most substances from passing from the blood to the brain; only tiny molecules can pass across the BBB. The BBB is disturbed in specific pathological illnesses such as stroke, diabetes, seizures, multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. The goal of this study is to offer a general overview of current brain medication delivery techniques and associated topics from the last five years. It is anticipated that this review will stimulate readers to look into new ways to deliver medications to the brain. Following an introduction of the construction and function of the BBB in both healthy and pathological conditions, this review revisits certain contested questions, such as whether nanoparticles may cross the BBB on their own and if medications are selectively delivered to the brain by deliberately targeted nanoparticles. Current non-nanoparticle options are also discussed, including drug delivery via the permeable BBB under pathological circumstances and the use of non-invasive approaches to improve brain medication absorption. Full article
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16 pages, 1356 KiB  
Review
Current and Emerging Strategies for Enhancing Antibody Delivery to the Brain
by Rinie Bajracharya, Alayna C. Caruso, Laura J. Vella and Rebecca M. Nisbet
Pharmaceutics 2021, 13(12), 2014; https://doi.org/10.3390/pharmaceutics13122014 - 26 Nov 2021
Cited by 13 | Viewed by 4813
Abstract
For the treatment of neurological diseases, achieving sufficient exposure to the brain parenchyma is a critical determinant of drug efficacy. The blood–brain barrier (BBB) functions to tightly control the passage of substances between the bloodstream and the central nervous system, and as such [...] Read more.
For the treatment of neurological diseases, achieving sufficient exposure to the brain parenchyma is a critical determinant of drug efficacy. The blood–brain barrier (BBB) functions to tightly control the passage of substances between the bloodstream and the central nervous system, and as such poses a major obstacle that must be overcome for therapeutics to enter the brain. Monoclonal antibodies have emerged as one of the best-selling treatment modalities available in the pharmaceutical market owing to their high target specificity. However, it has been estimated that only 0.1% of peripherally administered antibodies can cross the BBB, contributing to the low success rate of immunotherapy seen in clinical trials for the treatment of neurological diseases. The development of new strategies for antibody delivery across the BBB is thereby crucial to improve immunotherapeutic efficacy. Here, we discuss the current strategies that have been employed to enhance antibody delivery across the BBB. These include (i) focused ultrasound in combination with microbubbles, (ii) engineered bi-specific antibodies, and (iii) nanoparticles. Furthermore, we discuss emerging strategies such as extracellular vesicles with BBB-crossing properties and vectored antibody genes capable of being encapsulated within a BBB delivery vehicle. Full article
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54 pages, 24568 KiB  
Review
Modulating the Blood–Brain Barrier: A Comprehensive Review
by Rory Whelan, Grainne C. Hargaden and Andrew J. S. Knox
Pharmaceutics 2021, 13(11), 1980; https://doi.org/10.3390/pharmaceutics13111980 - 22 Nov 2021
Cited by 21 | Viewed by 6235
Abstract
The highly secure blood–brain barrier (BBB) restricts drug access to the brain, limiting the molecular toolkit for treating central nervous system (CNS) diseases to small, lipophilic drugs. Development of a safe and effective BBB modulator would revolutionise the treatment of CNS diseases and [...] Read more.
The highly secure blood–brain barrier (BBB) restricts drug access to the brain, limiting the molecular toolkit for treating central nervous system (CNS) diseases to small, lipophilic drugs. Development of a safe and effective BBB modulator would revolutionise the treatment of CNS diseases and future drug development in the area. Naturally, the field has garnered a great deal of attention, leading to a vast and diverse range of BBB modulators. In this review, we summarise and compare the various classes of BBB modulators developed over the last five decades—their recent advancements, advantages and disadvantages, while providing some insight into their future as BBB modulators. Full article
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58 pages, 4708 KiB  
Review
Nanoparticle-Guided Brain Drug Delivery: Expanding the Therapeutic Approach to Neurodegenerative Diseases
by Claudia Riccardi, Filomena Napolitano, Daniela Montesarchio, Simone Sampaolo and Mariarosa Anna Beatrice Melone
Pharmaceutics 2021, 13(11), 1897; https://doi.org/10.3390/pharmaceutics13111897 - 08 Nov 2021
Cited by 23 | Viewed by 5521
Abstract
Neurodegenerative diseases (NDs) represent a heterogeneous group of aging-related disorders featured by progressive impairment of motor and/or cognitive functions, often accompanied by psychiatric disorders. NDs are denoted as ‘protein misfolding’ diseases or proteinopathies, and are classified according to their known genetic mechanisms and/or [...] Read more.
Neurodegenerative diseases (NDs) represent a heterogeneous group of aging-related disorders featured by progressive impairment of motor and/or cognitive functions, often accompanied by psychiatric disorders. NDs are denoted as ‘protein misfolding’ diseases or proteinopathies, and are classified according to their known genetic mechanisms and/or the main protein involved in disease onset and progression. Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD) are included under this nosographic umbrella, sharing histopathologically salient features, including deposition of insoluble proteins, activation of glial cells, loss of neuronal cells and synaptic connectivity. To date, there are no effective cures or disease-modifying therapies for these NDs. Several compounds have not shown efficacy in clinical trials, since they generally fail to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells that greatly limits the brain internalization of endogenous substances. By engineering materials of a size usually within 1–100 nm, nanotechnology offers an alternative approach for promising and innovative therapeutic solutions in NDs. Nanoparticles can cross the BBB and release active molecules at target sites in the brain, minimizing side effects. This review focuses on the state-of-the-art of nanoengineered delivery systems for brain targeting in the treatment of AD, PD and HD. Full article
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25 pages, 2048 KiB  
Review
Emerging Nano-Carrier Strategies for Brain Tumor Drug Delivery and Considerations for Clinical Translation
by David J. Lundy, Helen Nguyễn and Patrick C. H. Hsieh
Pharmaceutics 2021, 13(8), 1193; https://doi.org/10.3390/pharmaceutics13081193 - 03 Aug 2021
Cited by 18 | Viewed by 3638
Abstract
Treatment of brain tumors is challenging since the blood–brain tumor barrier prevents chemotherapy drugs from reaching the tumor site in sufficient concentrations. Nanomedicines have great potential for therapy of brain disorders but are still uncommon in clinical use despite decades of research and [...] Read more.
Treatment of brain tumors is challenging since the blood–brain tumor barrier prevents chemotherapy drugs from reaching the tumor site in sufficient concentrations. Nanomedicines have great potential for therapy of brain disorders but are still uncommon in clinical use despite decades of research and development. Here, we provide an update on nano-carrier strategies for improving brain drug delivery for treatment of brain tumors, focusing on liposomes, extracellular vesicles and biomimetic strategies as the most clinically feasible strategies. Finally, we describe the obstacles in translation of these technologies including pre-clinical models, analytical methods and regulatory issues. Full article
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