Research

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18 pages, 3158 KiB

Open AccessArticle

Endothelial-Derived Extracellular Vesicles Induce Cerebrovascular Dysfunction in Inflammation

by David Roig-Carles, Eduard Willms, Ruud D. Fontijn, Sarai Martinez-Pacheco, Imre Mäger, Helga E. de Vries, Mark Hirst, Basil Sharrack, David K. Male, Cheryl A. Hawkes and Ignacio A. Romero

Pharmaceutics 2021, 13(9), 1525; https://doi.org/10.3390/pharmaceutics13091525 - 21 Sep 2021

Cited by 16 | Viewed by 3385

Abstract

Blood–brain barrier (BBB) dysfunction is a key hallmark in the pathology of many neuroinflammatory disorders. Extracellular vesicles (EVs) are lipid membrane-enclosed carriers of molecular cargo that are involved in cell-to-cell communication. Circulating endothelial EVs are increased in the plasma of patients with neurological [...] Read more.

Blood–brain barrier (BBB) dysfunction is a key hallmark in the pathology of many neuroinflammatory disorders. Extracellular vesicles (EVs) are lipid membrane-enclosed carriers of molecular cargo that are involved in cell-to-cell communication. Circulating endothelial EVs are increased in the plasma of patients with neurological disorders, and immune cell-derived EVs are known to modulate cerebrovascular functions. However, little is known about whether brain endothelial cell (BEC)-derived EVs themselves contribute to BBB dysfunction. Human cerebral microvascular cells (hCMEC/D3) were treated with TNFα and IFNy, and the EVs were isolated and characterised. The effect of EVs on BBB transendothelial resistance (TEER) and leukocyte adhesion in hCMEC/D3 cells was measured by electric substrate cell-substrate impedance sensing and the flow-based T-cell adhesion assay. EV-induced molecular changes in recipient hCMEC/D3 cells were analysed by RT-qPCR and Western blotting. A stimulation of naïve hCMEC/D3 cells with small EVs (sEVs) reduced the TEER and increased the shear-resistant T-cell adhesion. The levels of microRNA-155, VCAM1 and ICAM1 were increased in sEV-treated hCMEC/D3 cells. Blocking the expression of VCAM1, but not of ICAM1, prevented sEV-mediated T-cell adhesion to brain endothelia. These results suggest that sEVs derived from inflamed BECs promote cerebrovascular dysfunction. These findings may provide new insights into the mechanisms involving neuroinflammatory disorders. Full article

(This article belongs to the Special Issue Biological Barriers in Health and Disease)

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18 pages, 4890 KiB

Open AccessArticle

Characterization of a Primate Blood-Brain Barrier Co-Culture Model Prepared from Primary Brain Endothelial Cells, Pericytes and Astrocytes

by Daisuke Watanabe, Shinsuke Nakagawa, Yoichi Morofuji, Andrea E. Tóth, Monika Vastag, Jun Aruga, Masami Niwa and Mária A. Deli

Pharmaceutics 2021, 13(9), 1484; https://doi.org/10.3390/pharmaceutics13091484 - 16 Sep 2021

Cited by 9 | Viewed by 3712

Abstract

Culture models of the blood-brain barrier (BBB) are important research tools. Their role in the preclinical phase of drug development to estimate the permeability for potential neuropharmaceuticals is especially relevant. Since species differences in BBB transport systems exist, primate models are considered as [...] Read more.

Culture models of the blood-brain barrier (BBB) are important research tools. Their role in the preclinical phase of drug development to estimate the permeability for potential neuropharmaceuticals is especially relevant. Since species differences in BBB transport systems exist, primate models are considered as predictive for drug transport to brain in humans. Based on our previous expertise we have developed and characterized a non-human primate co-culture BBB model using primary cultures of monkey brain endothelial cells, rat brain pericytes, and rat astrocytes. Monkey brain endothelial cells in the presence of both pericytes and astrocytes (EPA model) expressed enhanced barrier properties and increased levels of tight junction proteins occludin, claudin-5, and ZO-1. Co-culture conditions also elevated the expression of key BBB influx and efflux transporters, including glucose transporter-1, MFSD2A, ABCB1, and ABCG2. The correlation between the endothelial permeability coefficients of 10 well known drugs was higher (R² = 0.8788) when the monkey and rat BBB culture models were compared than when the monkey culture model was compared to mouse in vivo data (R² = 0.6619), hinting at transporter differences. The applicability of the new non-human primate model in drug discovery has been proven in several studies. Full article

(This article belongs to the Special Issue Biological Barriers in Health and Disease)

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16 pages, 3688 KiB

Open AccessArticle

MAP Kinase Pathways in Brain Endothelial Cells and Crosstalk with Pericytes and Astrocytes Mediate Contrast-Induced Blood–Brain Barrier Disruption

by Yuki Matsunaga, Shinsuke Nakagawa, Yoichi Morofuji, Shinya Dohgu, Daisuke Watanabe, Nobutaka Horie, Tsuyoshi Izumo, Masami Niwa, Fruzsina R. Walter, Ana Raquel Santa-Maria, Maria A. Deli and Takayuki Matsuo

Pharmaceutics 2021, 13(8), 1272; https://doi.org/10.3390/pharmaceutics13081272 - 17 Aug 2021

Cited by 5 | Viewed by 3020

Abstract

Neurointervention with contrast media (CM) has rapidly increased, but the impact of CM extravasation and the related side effects remain controversial. This study investigated the effect of CM on blood–brain barrier (BBB) integrity. We established in vitro BBB models using primary cultures of [...] Read more.

Neurointervention with contrast media (CM) has rapidly increased, but the impact of CM extravasation and the related side effects remain controversial. This study investigated the effect of CM on blood–brain barrier (BBB) integrity. We established in vitro BBB models using primary cultures of rat BBB-related cells. To assess the effects of CM on BBB functions, we evaluated transendothelial electrical resistance, permeability, and tight junction (TJ) protein expression using immunohistochemistry (IHC) and Western blotting. To investigate the mechanism of iopamidol-induced barrier dysfunction, the role of mitogen-activated protein (MAP) kinases in brain endothelial cells was examined. We assessed the effect of conditioned medium derived from astrocytes and pericytes under iopamidol treatment. Short-term iopamidol exposure on the luminal side induced transient, while on the abluminal side caused persistent BBB dysfunction. IHC and immunoblotting revealed CM decreased the expression of TJ proteins. Iopamidol-induced barrier dysfunction was improved via the regulation of MAP kinase pathways. Conditioned medium from CM-exposed pericytes or astrocytes lacks the ability to enhance barrier function. CM may cause BBB dysfunction. MAP kinase pathways in brain endothelial cells and the interactions of astrocytes and pericytes mediate iopamidol-induced barrier dysfunction. CM extravasation may have negative effects on clinical outcomes in patients. Full article

(This article belongs to the Special Issue Biological Barriers in Health and Disease)

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19 pages, 6491 KiB

Open AccessArticle

Increased In Vitro Intercellular Barrier Function of Lung Epithelial Cells Using Adipose-Derived Mesenchymal Stem/Stromal Cells

by Mitsutoshi Ishii, Tomoshi Tsuchiya, Ryoichiro Doi, Yoichi Morofuji, Takashi Fujimoto, Hideki Muto, Takashi Suematsu, Ryoichi Mori, Keitaro Matsumoto, Takuro Miyazaki, Koichi Tomoshige, Hironosuke Watanabe, Mayumi Iwatake and Takeshi Nagayasu

Pharmaceutics 2021, 13(8), 1264; https://doi.org/10.3390/pharmaceutics13081264 - 16 Aug 2021

Cited by 4 | Viewed by 2379

Abstract

With the emergence of coronavirus disease-2019, researchers have gained interest in the therapeutic efficacy of mesenchymal stem/stromal cells (MSCs) in acute respiratory distress syndrome; however, the mechanisms of the therapeutic effects of MSCs are unclear. We have previously reported that adipose-derived MSCs (AD-MSCs) [...] Read more.

With the emergence of coronavirus disease-2019, researchers have gained interest in the therapeutic efficacy of mesenchymal stem/stromal cells (MSCs) in acute respiratory distress syndrome; however, the mechanisms of the therapeutic effects of MSCs are unclear. We have previously reported that adipose-derived MSCs (AD-MSCs) strengthen the barrier function of the pulmonary vessels in scaffold-based bioengineered rat lungs. In this study, we evaluated whether AD-MSCs could enhance the intercellular barrier function of lung epithelial cells in vitro using a transwell coculture system. Transepithelial electrical resistance (TEER) measurements revealed that the peak TEER value was significantly higher in the AD-MSC coculture group than in the AD-MSC non-coculture group. Similarly, the permeability coefficient was significantly decreased in the AD-MSC coculture group compared to that in the AD-MSC non-coculture group. Immunostaining of insert membranes showed that zonula occuldens-1 expression was significantly high at cell junctions in the AD-MSC coculture group. Moreover, cell junction-related gene profiling showed that the expression of some claudin genes, including claudin-4, was upregulated in the AD-MSC coculture group. Taken together, these results showed that AD-MSCs enhanced the barrier function between lung epithelial cells, suggesting that both direct adhesion and indirect paracrine effects strengthened the barrier function of lung alveolar epithelium in vitro. Full article

(This article belongs to the Special Issue Biological Barriers in Health and Disease)

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12 pages, 1894 KiB

Open AccessArticle

Detection of Microplastic in Human Placenta and Meconium in a Clinical Setting

by Thorsten Braun, Loreen Ehrlich, Wolfgang Henrich, Sebastian Koeppel, Ievgeniia Lomako, Philipp Schwabl and Bettina Liebmann

Pharmaceutics 2021, 13(7), 921; https://doi.org/10.3390/pharmaceutics13070921 - 22 Jun 2021

Cited by 147 | Viewed by 18102

Abstract

Environmental pollution with microplastics (MPs) is a major and worldwide concern. Involuntary exposure to MPs by ingestion or inhalation is unavoidable. The effects on human health are still under debate, while in animals, cellular MP translocation and subsequent deleterious effects were shown. First [...] Read more.

Environmental pollution with microplastics (MPs) is a major and worldwide concern. Involuntary exposure to MPs by ingestion or inhalation is unavoidable. The effects on human health are still under debate, while in animals, cellular MP translocation and subsequent deleterious effects were shown. First reports indicate a potential intrauterine exposure with MPs, yet readouts are prone to contamination. Method: To establish a thorough protocol for the detection of MPs in human placenta and fetal meconium in a real-life clinical setting, a pilot study was set up to screen for MPs > 50 µm in placental tissue and meconium sampled during two cesarean sections for breech deliveries. After chemical digestion of non-plastic material, Fourier-transform infrared (FTIR) microspectroscopy was used to analyze the presence of 10 common types of microplastic in placenta and stool samples. Results: Human placenta and meconium samples were screened positive for polyethylene, polypropylene, polystyrene, and polyurethane, of which only the latter one was also detected as airborne fallout in the operating room—thus representing potential contamination. Conclusion: We found MPs > 50 µm in placenta and meconium acquired from cesarean delivery. Critical evaluation of potential contamination sources is pivotal and may guide future clinical studies to improve the correct detection of MPs in organ tissue. Studies investigating nano-sized plastics in human tissue are warranted. Full article

(This article belongs to the Special Issue Biological Barriers in Health and Disease)

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21 pages, 4738 KiB

Open AccessArticle

Miniaturization and Automation of a Human In Vitro Blood–Brain Barrier Model for the High-Throughput Screening of Compounds in the Early Stage of Drug Discovery

by Elisa L. J. Moya, Elodie Vandenhaute, Eleonora Rizzi, Marie-Christine Boucau, Johan Hachani, Nathalie Maubon, Fabien Gosselet and Marie-Pierre Dehouck

Pharmaceutics 2021, 13(6), 892; https://doi.org/10.3390/pharmaceutics13060892 - 16 Jun 2021

Cited by 10 | Viewed by 3803

Abstract

Central nervous system (CNS) diseases are one of the top causes of death worldwide. As there is a difficulty of drug penetration into the brain due to the blood–brain barrier (BBB), many CNS drugs treatments fail in clinical trials. Hence, there is a [...] Read more.

Central nervous system (CNS) diseases are one of the top causes of death worldwide. As there is a difficulty of drug penetration into the brain due to the blood–brain barrier (BBB), many CNS drugs treatments fail in clinical trials. Hence, there is a need to develop effective CNS drugs following strategies for delivery to the brain by better selecting them as early as possible during the drug discovery process. The use of in vitro BBB models has proved useful to evaluate the impact of drugs/compounds toxicity, BBB permeation rates and molecular transport mechanisms within the brain cells in academic research and early-stage drug discovery. However, these studies that require biological material (animal brain or human cells) are time-consuming and involve costly amounts of materials and plastic wastes due to the format of the models. Hence, to adapt to the high yields needed in early-stage drug discoveries for compound screenings, a patented well-established human in vitro BBB model was miniaturized and automated into a 96-well format. This replicate met all the BBB model reliability criteria to get predictive results, allowing a significant reduction in biological materials, waste and a higher screening capacity for being extensively used during early-stage drug discovery studies. Full article

(This article belongs to the Special Issue Biological Barriers in Health and Disease)

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24 pages, 4712 KiB

Open AccessArticle

Endothelial Iron Homeostasis Regulates Blood-Brain Barrier Integrity via the HIF2α—Ve-Cadherin Pathway

by Daniel Rand, Orly Ravid, Dana Atrakchi, Hila Israelov, Yael Bresler, Chen Shemesh, Liora Omesi, Sigal Liraz-Zaltsman, Fabien Gosselet, Taber S. Maskrey, Michal Schnaider Beeri, Peter Wipf and Itzik Cooper

Pharmaceutics 2021, 13(3), 311; https://doi.org/10.3390/pharmaceutics13030311 - 28 Feb 2021

Cited by 16 | Viewed by 4551

Abstract

The objective of this study was to investigate the molecular response to damage at the blood-brain barrier (BBB) and to elucidate critical pathways that might lead to effective treatment in central nervous system (CNS) pathologies in which the BBB is compromised. We have [...] Read more.

The objective of this study was to investigate the molecular response to damage at the blood-brain barrier (BBB) and to elucidate critical pathways that might lead to effective treatment in central nervous system (CNS) pathologies in which the BBB is compromised. We have used a human, stem-cell derived in-vitro BBB injury model to gain a better understanding of the mechanisms controlling BBB integrity. Chemical injury induced by exposure to an organophosphate resulted in rapid lipid peroxidation, initiating a ferroptosis-like process. Additionally, mitochondrial ROS formation (MRF) and increase in mitochondrial membrane permeability were induced, leading to apoptotic cell death. Yet, these processes did not directly result in damage to barrier functionality, since blocking them did not reverse the increased permeability. We found that the iron chelator, Desferal© significantly decreased MRF and apoptosis subsequent to barrier insult, while also rescuing barrier integrity by inhibiting the labile iron pool increase, inducing HIF2α expression and preventing the degradation of Ve-cadherin specifically on the endothelial cell surface. Moreover, the novel nitroxide JP4-039 significantly rescued both injury-induced endothelium cell toxicity and barrier functionality. Elucidating a regulatory pathway that maintains BBB integrity illuminates a potential therapeutic approach to protect the BBB degradation that is evident in many neurological diseases. Full article

(This article belongs to the Special Issue Biological Barriers in Health and Disease)

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17 pages, 1666 KiB

Open AccessArticle

Directed Transport of CRP Across In Vitro Models of the Blood-Saliva Barrier Strengthens the Feasibility of Salivary CRP as Biomarker for Neonatal Sepsis

by Grace C. Lin, Erik Küng, Merima Smajlhodzic, Sandra Domazet, Heinz P. Friedl, Joachim Angerer, Lukas Wisgrill, Angelika Berger, Lynne Bingle, Johannes R. Peham and Winfried Neuhaus

Pharmaceutics 2021, 13(2), 256; https://doi.org/10.3390/pharmaceutics13020256 - 12 Feb 2021

Cited by 11 | Viewed by 3059

Abstract

C-reactive protein (CRP) is a commonly used serum biomarker for detecting sepsis in neonates. After the onset of sepsis, serial measurements are necessary to monitor disease progression; therefore, a non-invasive detection method is beneficial for neonatal well-being. While some studies have shown a [...] Read more.

C-reactive protein (CRP) is a commonly used serum biomarker for detecting sepsis in neonates. After the onset of sepsis, serial measurements are necessary to monitor disease progression; therefore, a non-invasive detection method is beneficial for neonatal well-being. While some studies have shown a correlation between serum and salivary CRP levels in septic neonates, the causal link behind this correlation remains unclear. To investigate this relationship, CRP was examined in serum and saliva samples from 18 septic neonates and compared with saliva samples from 22 healthy neonates. While the measured blood and saliva concentrations of the septic neonates varied individually, a correlation of CRP levels between serum and saliva samples was observed over time. To clarify the presence of active transport of CRP across the blood–salivary barrier (BSB), transport studies were performed with CRP using in vitro models of oral mucosa and submandibular salivary gland epithelium. The results showed enhanced transport toward saliva in both models, supporting the clinical relevance for salivary CRP as a biomarker. Furthermore, CRP regulated the expression of the receptor for advanced glycation end products (RAGE) and the addition of soluble RAGE during the transport studies indicated a RAGE-dependent transport process for CRP from blood to saliva. Full article

(This article belongs to the Special Issue Biological Barriers in Health and Disease)

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Review

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13 pages, 1089 KiB

Open AccessReview

Biological Models of the Lower Human Airways—Challenges and Special Requirements of Human 3D Barrier Models for Biomedical Research

by Cornelia Wiese-Rischke, Rasika S. Murkar and Heike Walles

Pharmaceutics 2021, 13(12), 2115; https://doi.org/10.3390/pharmaceutics13122115 - 08 Dec 2021

Cited by 7 | Viewed by 2841

Abstract

In our review, we want to summarize the current status of the development of airway models and their application in biomedical research. We start with the very well characterized models composed of cell lines and end with the use of organoids. An important [...] Read more.

In our review, we want to summarize the current status of the development of airway models and their application in biomedical research. We start with the very well characterized models composed of cell lines and end with the use of organoids. An important aspect is the function of the mucus as a component of the barrier, especially for infection research. Finally, we will explain the need for a nondestructive characterization of the barrier models using TEER measurements and live cell imaging. Here, organ-on-a-chip technology offers a great opportunity for the culture of complex airway models. Full article

(This article belongs to the Special Issue Biological Barriers in Health and Disease)

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36 pages, 30113 KiB

Open AccessReview

Blood-Brain Barrier Dysfunction in CNS Disorders and Putative Therapeutic Targets: An Overview

by Sabrina Rahman Archie, Abdullah Al Shoyaib and Luca Cucullo

Pharmaceutics 2021, 13(11), 1779; https://doi.org/10.3390/pharmaceutics13111779 - 26 Oct 2021

Cited by 56 | Viewed by 8521

Abstract

The blood-brain barrier (BBB) is a fundamental component of the central nervous system (CNS). Its functional and structural integrity is vital to maintain the homeostasis of the brain microenvironment by controlling the passage of substances and regulating the trafficking of immune cells between [...] Read more.

The blood-brain barrier (BBB) is a fundamental component of the central nervous system (CNS). Its functional and structural integrity is vital to maintain the homeostasis of the brain microenvironment by controlling the passage of substances and regulating the trafficking of immune cells between the blood and the brain. The BBB is primarily composed of highly specialized microvascular endothelial cells. These cells’ special features and physiological properties are acquired and maintained through the concerted effort of hemodynamic and cellular cues from the surrounding environment. This complex multicellular system, comprising endothelial cells, astrocytes, pericytes, and neurons, is known as the neurovascular unit (NVU). The BBB strictly controls the transport of nutrients and metabolites into brain parenchyma through a tightly regulated transport system while limiting the access of potentially harmful substances via efflux transcytosis and metabolic mechanisms. Not surprisingly, a disruption of the BBB has been associated with the onset and/or progression of major neurological disorders. Although the association between disease and BBB disruption is clear, its nature is not always evident, specifically with regard to whether an impaired BBB function results from the pathological condition or whether the BBB damage is the primary pathogenic factor prodromal to the onset of the disease. In either case, repairing the barrier could be a viable option for treating and/or reducing the effects of CNS disorders. In this review, we describe the fundamental structure and function of the BBB in both healthy and altered/diseased conditions. Additionally, we provide an overview of the potential therapeutic targets that could be leveraged to restore the integrity of the BBB concomitant to the treatment of these brain disorders. Full article

(This article belongs to the Special Issue Biological Barriers in Health and Disease)

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24 pages, 1950 KiB

Open AccessReview

Aberrant Neurogliovascular Unit Dynamics in Cerebral Small Vessel Disease: A Rheological Clue to Vascular Parkinsonism

by Che Mohd Nasril Che Mohd Nassir, Thenmoly Damodaran, Siti R. Yusof, Anwar Norazit, Geetha Chilla, Isaac Huen, Bhanu Prakash K. N., Norlinah Mohamed Ibrahim and Muzaimi Mustapha

Pharmaceutics 2021, 13(8), 1207; https://doi.org/10.3390/pharmaceutics13081207 - 05 Aug 2021

Cited by 8 | Viewed by 5254

Abstract

The distinctive anatomical assemble and functionally discrete multicellular cerebrovasculature dynamics confer varying rheological and blood–brain barrier permeabilities to preserve the integrity of cerebral white matter and its neural microenvironment. This homeostasis intricately involves the glymphatic system that manages the flow of interstitial solutes, [...] Read more.

The distinctive anatomical assemble and functionally discrete multicellular cerebrovasculature dynamics confer varying rheological and blood–brain barrier permeabilities to preserve the integrity of cerebral white matter and its neural microenvironment. This homeostasis intricately involves the glymphatic system that manages the flow of interstitial solutes, metabolic waste, and clearance through the venous circulation. As a physiologically integrated neurogliovascular unit (NGVU) serving a particularly vulnerable cerebral white matter (from hypoxia, metabolic insults, infection, and inflammation), a likely insidious process over a lifetime could inflict microenvironment damages that may lead to pathological conditions. Two such conditions, cerebral small vessel disease (CSVD) and vascular parkinsonism (VaP), with poorly understood pathomechanisms, are frequently linked to this brain-wide NGVU. VaP is widely regarded as an atypical parkinsonism, described by cardinal motor manifestations and the presence of cerebrovascular disease, particularly white matter hyperintensities (WMHs) in the basal ganglia and subcortical region. WMHs, in turn, are a recognised imaging spectrum of CSVD manifestations, and in relation to disrupted NGVU, also include enlarged perivascular spaces. Here, in this narrative review, we present and discuss on recent findings that argue for plausible clues between CSVD and VaP by focusing on aberrant multicellular dynamics of a unique integrated NGVU—a crossroad of the immune–vascular–nervous system—which may also extend fresher insights into the elusive interplay between cerebral microvasculature and neurodegeneration, and the potential therapeutic targets. Full article

(This article belongs to the Special Issue Biological Barriers in Health and Disease)

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14 pages, 4263 KiB

Open AccessReview

Microfluidic and Lab-on-a-Chip Systems for Cutaneous Wound Healing Studies

by Ghazal Shabestani Monfared, Peter Ertl and Mario Rothbauer

Pharmaceutics 2021, 13(6), 793; https://doi.org/10.3390/pharmaceutics13060793 - 26 May 2021

Cited by 17 | Viewed by 5603

Abstract

Cutaneous wound healing is a complex, multi-stage process involving direct and indirect cell communication events with the aim of efficiently restoring the barrier function of the skin. One key aspect in cutaneous wound healing is associated with cell movement and migration into the [...] Read more.

Cutaneous wound healing is a complex, multi-stage process involving direct and indirect cell communication events with the aim of efficiently restoring the barrier function of the skin. One key aspect in cutaneous wound healing is associated with cell movement and migration into the physically, chemically, and biologically injured area, resulting in wound closure. Understanding the conditions under which cell migration is impaired and elucidating the cellular and molecular mechanisms that improve healing dynamics are therefore crucial in devising novel therapeutic strategies to elevate patient suffering, reduce scaring, and eliminate chronic wounds. Following the global trend towards the automation, miniaturization, and integration of cell-based assays into microphysiological systems, conventional wound healing assays such as the scratch assay and cell exclusion assay have recently been translated and improved using microfluidics and lab-on-a-chip technologies. These miniaturized cell analysis systems allow for precise spatial and temporal control over a range of dynamic microenvironmental factors including shear stress, biochemical and oxygen gradients to create more reliable in vitro models that resemble the in vivo microenvironment of a wound more closely on a molecular, cellular, and tissue level. The current review provides (a) an overview on the main molecular and cellular processes that take place during wound healing, (b) a brief introduction into conventional in vitro wound healing assays, and (c) a perspective on future cutaneous and vascular wound healing research using microfluidic technology. Full article

(This article belongs to the Special Issue Biological Barriers in Health and Disease)

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19 pages, 1852 KiB

Open AccessReview

Delivery of Therapeutic Agents to the Central Nervous System and the Promise of Extracellular Vesicles

by Charlotte A. René and Robin J. Parks

Pharmaceutics 2021, 13(4), 492; https://doi.org/10.3390/pharmaceutics13040492 - 03 Apr 2021

Cited by 22 | Viewed by 3222

Abstract

The central nervous system (CNS) is surrounded by the blood–brain barrier (BBB), a semipermeable border of endothelial cells that prevents pathogens, solutes and most molecules from non-selectively crossing into the CNS. Thus, the BBB acts to protect the CNS from potentially deleterious insults. [...] Read more.

The central nervous system (CNS) is surrounded by the blood–brain barrier (BBB), a semipermeable border of endothelial cells that prevents pathogens, solutes and most molecules from non-selectively crossing into the CNS. Thus, the BBB acts to protect the CNS from potentially deleterious insults. Unfortunately, the BBB also frequently presents a significant barrier to therapies, impeding passage of drugs and biologicals to target cells within the CNS. This review provides an overview of different approaches to deliver therapeutics across the BBB, with an emphasis in extracellular vesicles as delivery vehicles to the CNS. Full article

(This article belongs to the Special Issue Biological Barriers in Health and Disease)

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38 pages, 2763 KiB

Open AccessReview

Delivery Systems for Nucleic Acids and Proteins: Barriers, Cell Capture Pathways and Nanocarriers

by Julian D. Torres-Vanegas, Juan C. Cruz and Luis H. Reyes

Pharmaceutics 2021, 13(3), 428; https://doi.org/10.3390/pharmaceutics13030428 - 22 Mar 2021

Cited by 55 | Viewed by 5697

Abstract

Gene therapy has been used as a potential approach to address the diagnosis and treatment of genetic diseases and inherited disorders. In this line, non-viral systems have been exploited as promising alternatives for delivering therapeutic transgenes and proteins. In this review, we explored [...] Read more.

Gene therapy has been used as a potential approach to address the diagnosis and treatment of genetic diseases and inherited disorders. In this line, non-viral systems have been exploited as promising alternatives for delivering therapeutic transgenes and proteins. In this review, we explored how biological barriers are effectively overcome by non-viral systems, usually nanoparticles, to reach an efficient delivery of cargoes. Furthermore, this review contributes to the understanding of several mechanisms of cellular internalization taken by nanoparticles. Because a critical factor for nanoparticles to do this relies on the ability to escape endosomes, researchers have dedicated much effort to address this issue using different nanocarriers. Here, we present an overview of the diversity of nanovehicles explored to reach an efficient and effective delivery of both nucleic acids and proteins. Finally, we introduced recent advances in the development of successful strategies to deliver cargoes. Full article

(This article belongs to the Special Issue Biological Barriers in Health and Disease)

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22 pages, 927 KiB

Open AccessReview

Transient Receptor Potential Vanilloid in the Brain Gliovascular Unit: Prospective Targets in Therapy

by Huilong Luo, Xavier Declèves and Salvatore Cisternino

Pharmaceutics 2021, 13(3), 334; https://doi.org/10.3390/pharmaceutics13030334 - 04 Mar 2021

Cited by 2 | Viewed by 2639

Abstract

The gliovascular unit (GVU) is composed of the brain microvascular endothelial cells forming blood–brain barrier and the neighboring surrounding “mural” cells (e.g., pericytes) and astrocytes. Modulation of the GVU/BBB features could be observed in a variety of vascular, immunologic, neuro-psychiatric diseases, and cancers, [...] Read more.

The gliovascular unit (GVU) is composed of the brain microvascular endothelial cells forming blood–brain barrier and the neighboring surrounding “mural” cells (e.g., pericytes) and astrocytes. Modulation of the GVU/BBB features could be observed in a variety of vascular, immunologic, neuro-psychiatric diseases, and cancers, which can disrupt the brain homeostasis. Ca²⁺ dynamics have been regarded as a major factor in determining BBB/GVU properties, and previous studies have demonstrated the role of transient receptor potential vanilloid (TRPV) channels in modulating Ca²⁺ and BBB/GVU properties. The physiological role of thermosensitive TRPV channels in the BBB/GVU, as well as their possible therapeutic potential as targets in treating brain diseases via preserving the BBB are reviewed. TRPV2 and TRPV4 are the most abundant isoforms in the human BBB, and TRPV2 was evidenced to play a main role in regulating human BBB integrity. Interspecies differences in TRPV2 and TRPV4 BBB expression complicate further preclinical validation. More studies are still needed to better establish the physiopathological TRPV roles such as in astrocytes, vascular smooth muscle cells, and pericytes. The effect of the chronic TRPV modulation should also deserve further studies to evaluate their benefit and innocuity in vivo. Full article

(This article belongs to the Special Issue Biological Barriers in Health and Disease)

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20 pages, 1173 KiB

Open AccessReview

Unlocking the Power of Exosomes for Crossing Biological Barriers in Drug Delivery

by Rebekah Omarkhail Elliott and Mei He

Pharmaceutics 2021, 13(1), 122; https://doi.org/10.3390/pharmaceutics13010122 - 19 Jan 2021

Cited by 115 | Viewed by 10051

Abstract

Since the 2013 Nobel Prize was awarded for the discovery of vesicle trafficking, a subgroup of nanovesicles called exosomes has been driving the research field to a new regime for understanding cellular communication. This exosome-dominated traffic control system has increased understanding of many [...] Read more.

Since the 2013 Nobel Prize was awarded for the discovery of vesicle trafficking, a subgroup of nanovesicles called exosomes has been driving the research field to a new regime for understanding cellular communication. This exosome-dominated traffic control system has increased understanding of many diseases, including cancer metastasis, diabetes, and HIV. In addition to the important diagnostic role, exosomes are particularly attractive for drug delivery, due to their distinctive properties in cellular information transfer and uptake. Compared to viral and non-viral synthetic systems, the natural, cell-derived exosomes exhibit intrinsic payload and bioavailability. Most importantly, exosomes easily cross biological barriers, obstacles that continue to challenge other drug delivery nanoparticle systems. Recent emerging studies have shown numerous critical roles of exosomes in many biological barriers, including the blood–brain barrier (BBB), blood–cerebrospinal fluid barrier (BCSFB), blood–lymph barrier (BlyB), blood–air barrier (BAB), stromal barrier (SB), blood–labyrinth barrier (BLaB), blood–retinal barrier (BRB), and placental barrier (PB), which opens exciting new possibilities for using exosomes as the delivery platform. However, the systematic reviews summarizing such discoveries are still limited. This review covers state-of-the-art exosome research on crossing several important biological barriers with a focus on the current, accepted models used to explain the mechanisms of barrier crossing, including tight junctions. The potential to design and engineer exosomes to enhance delivery efficacy, leading to future applications in precision medicine and immunotherapy, is discussed. Full article

(This article belongs to the Special Issue Biological Barriers in Health and Disease)

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