Minimum Transendothelial Electrical Resistance Thresholds for the Study of Small and Large Molecule Drug Transport in a Human <i>in Vitro</i> Blood–Brain Barrier Model

Mantle, Jennifer L.; Min, Lie; Lee, Kelvin H.

doi:10.1021/acs.molpharmaceut.6b00818

Cited by 82 publications

(87 citation statements)

References 35 publications

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“…Previous work in our lab has shown that with a starting concentration of 10 mg/ml in the luminal compartment, 0.034% crosses into the abluminal compartment after 6 hr (Mantle et al, 2016). This figure falls between the widely accepted statistic of 0.1% of peripheral IgGs able to penetrate the brain (Banks et al, 2002) and 0.009% of peripherally administered IVIG measured in the murine brain (St-Amour et al, 2013).…”

Section: Discussionsupporting

confidence: 59%

“…Our previous work has shown that this iPSC-BBB model can be used to study small molecule therapeutics (Mantle et al, 2016), and here we demonstrate its utility in studying the transport of biologics, understanding transport events at the cellular level, and understanding changes to the BBB in disease. IgG transport in the model is saturable, consistent with in vivo IgG transport behavior.…”

Section: Discussionsupporting

confidence: 54%

“…While uptake experiments were performed with commercially available fluorescently labeled chimeric material, uptake with human antibodies could yield further insights into the transport of IgGs across the BBB. Our previous work has shown that this iPSC-BBB model can be used to study small molecule therapeutics (Mantle et al, 2016), and here we demonstrate its utility in studying the transport of biologics, understanding transport events at the cellular level, and understanding changes to the BBB in disease.…”

Section: Discussionsupporting

confidence: 54%

“…In vitro models are useful tools to study the transport of immunotherapies, as well as the effects of different aspects of the disease, at the BBB. Our previous work has shown that there are different transendothelial electrical resistance (TEER) thresholds required for studying small and large molecule drugs and demonstrated the utility of the model for assessing the permeability of small molecule therapeutics (Mantle, Min, & Lee, 2016…”

Section: Type Of Uptake Inhibitor Probe Characteristicsmentioning

confidence: 99%

“…2.3 | BMEC differentiation, culture, and disease models iPS(IMR90)-4 iPSCs (Yu et al, 2007) were maintained as previously described (Lippmann et al, 2014;Mantle et al, 2016). Briefly, iPSCs were grown in mTeSR-1 medium on six-well plates coated with growth factor-reduced Matrigel and passaged every 3-5 days using Versene and mechanical dissociation.…”

Section: Aβ 1-40 and Aβ 1-42 Preparationmentioning

confidence: 99%

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Immunoglobulin G transport increases in an in vitro blood–brain barrier model with amyloid‐β and with neuroinflammatory cytokines

Mantle

Lee

2019

Biotech & Bioengineering

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Immunotherapies are a promising strategy for the treatment of neurological diseases such as Alzheimer's disease (AD), however, transport of antibodies to the brain is severely restricted by the blood-brain barrier (BBB). Furthermore, molecular transport at the BBB is altered in disease, which may affect the mechanism and quantity of therapeutic antibody transport. To better understand the transport of immunotherapies at the BBB in disease, an in vitro BBB model derived from human induced pluripotent stem cells (iPSCs) was used to investigate the endocytic uptake route of immunoglobulin G (IgG). In this model, uptake of fluorescently labeled IgGs is a saturable process. Inhibition of clathrin-mediated endocytosis, caveolar endocytosis, and macropinocytosis demonstrated that macropinocytosis is a major transport route for IgGs at the BBB. IgG uptake and transport were increased after the addition of stimuli to mimic AD (Aβ₁₋₄₀ and Aβ₁₋₄₂) and neuroinflammation (tumor necrosis factor-α and interleukin-6). Lastly, caveolar endocytosis increased in the AD model, which may be responsible for the increase in IgG uptake in disease. This study presents an iPSC-derived BBB model that responds to disease stimuli with physiologically relevant changes to molecular transport and can be used to understand fundamental questions about transport mechanisms of immunotherapies in health and neurodegenerative disease.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionsupporting

confidence: 54%

Section: Discussionsupporting

confidence: 54%

Section: Type Of Uptake Inhibitor Probe Characteristicsmentioning

confidence: 99%

Section: Aβ 1-40 and Aβ 1-42 Preparationmentioning

confidence: 99%

See 3 more Smart Citations

Immunoglobulin G transport increases in an in vitro blood–brain barrier model with amyloid‐β and with neuroinflammatory cytokines

Mantle

Lee

2019

Biotech & Bioengineering

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A guide for blood–brain barrier models

Soliman,

Al‐khodor,

Yildirim Köken

et al. 2024

FEBS Letters

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Understanding the intricate mechanisms underlying brain‐related diseases hinges on unraveling the pivotal role of the blood–brain barrier (BBB), an essential dynamic interface crucial for maintaining brain equilibrium. This review offers a comprehensive analysis of BBB physiology, delving into its cellular and molecular components while exploring a wide range of in vivo and in vitro BBB models. Notably, recent advancements in 3D cell culture techniques are explicitly discussed, as they have significantly improved the fidelity of BBB modeling by enabling the replication of physiologically relevant environments under flow conditions. Special attention is given to the cellular aspects of in vitro BBB models, alongside discussions on advances in stem cell technologies, providing valuable insights into generating robust cellular systems for BBB modeling. The diverse array of cell types used in BBB modeling, depending on their sources, is meticulously examined in this comprehensive review, scrutinizing their respective derivation protocols and implications. By synthesizing diverse approaches, this review sheds light on the improvements of BBB models to capture physiological conditions, aiding in understanding BBB interactions in health and disease conditions to foster clinical developments.

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Progresses in the establishment, evaluation, and application of in vitro blood–brain barrier models

Yin,

Wang

2024

J of Neuroscience Research

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The blood–brain barrier (BBB) is a barrier between the circulatory system and the central nervous system (CNS), contributing to CNS protection and maintaining the brain homeostasis. Establishment of in vitro BBB models that are closer to the microenvironment of the human brain is helpful for evaluating the potential and efficiency of a drug penetrating BBB and thus the clinical application value of the drug. The in vitro BBB models not only provide great convenience for screening new drugs that can access to CNS but also help people to have a deeper study on the mechanism of substances entering and leaving the brain, which makes people have greater opportunities in the treatment of CNS diseases. Up to now, although much effort has been paid to the researches on the in vitro BBB models and many progresses have been achieved, no unified method has been described for establishing a BBB model and there is much work to do and many challenges to be faced with in the future. This review summarizes the research progresses in the establishment, evaluation, and application of in vitro BBB models.

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Minimum Transendothelial Electrical Resistance Thresholds for the Study of Small and Large Molecule Drug Transport in a Human in Vitro Blood–Brain Barrier Model

Cited by 82 publications

References 35 publications

Immunoglobulin G transport increases in an in vitro blood–brain barrier model with amyloid‐β and with neuroinflammatory cytokines

Immunoglobulin G transport increases in an in vitro blood–brain barrier model with amyloid‐β and with neuroinflammatory cytokines

A guide for blood–brain barrier models

Progresses in the establishment, evaluation, and application of in vitro blood–brain barrier models

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