<i>In Vitro</i>Assays for Assessing BBB Permeability

Avdeef, Alex; Deli, Mária A.; Neuhaus, Winfried

doi:10.1002/9781118788523.ch10

Cited by 13 publications

(3 citation statements)

References 188 publications

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“…This includes permeation through the BBB after, e.g., parenteral administration . Several sophisticated in vitro BBB models were developed in recent years to resemble the situation in vivo . − Apart from the cellular barrier, the in vivo situation is also complicated by flow, which has been taken into consideration by some recent models . One promising approach involves models based on human induced-pluripotent stem cells (hiPSCs)-derived BBB endothelial cells. , Using such a hiPSC-derived model, physiological characteristics like high transendothelial electrical resistances (TEER) up to 2500 Ω·cm 2 , distinct upregulation of typical BBB genes as well as the formation of an in vivo -like tight junction network could be achieved .…”

Section: Resultsmentioning

confidence: 99%

“…87 Several sophisticated in vitro BBB models were developed in recent years to resemble the situation in vivo. [88][89][90] Apart from the cellular barrier, the in vivo the situation is also complicated by flow, which has been taken into consideration by some recent models. 91 One promising approach are models based on human induced pluripotent stem cells (hiPSCs) derived BBB endothelial cells.…”

Section: Atv Permeability Through Artificial Blood-brain Barriermentioning

confidence: 99%

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In VitroBlood–Brain Barrier Permeability and Cytotoxicity of an Atorvastatin-Loaded Nanoformulation Against Glioblastoma in 2D and 3D Models

et al. 2020

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Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase of the family of statins have been suggested as therapeutic options in various tumors. Atorvastatin is a statin with potential to cross the blood-brain-barrier, however, the concentrations necessary for a cytotoxic effect against cancer cells exceeds the concentration achievable via oral administration, which made the development of a novel atorvastatin formulation necessary. We characterized the drug loading and basic physicochemical characteristics of micellar atorvastatin formulations and tested their cytotoxicity against a panel of different glioblastoma cell lines. In addition, activity against tumor spheroids formed from mouse glioma and mouse cancer stem cells, respectively, was evaluated. Our results show good activity of atorvastatin against all tested cell lines. Interestingly, in the 3D models, growth inhibition was more pronounced for the micellar formulation compared to free atorvastatin. Finally, atorvastatin penetration across a blood-brain-barrier model obtained from human induced-pluripotent stem cells was evaluated. Our results suggest that the presented micelles may enable much higher serum concentrations than possible by oral administration, however, if transport across the blood-brain-barrier is sufficient to reach therapeutic atorvastatin concentration for the treatment of glioblastoma via intravenous administration remains unclear.

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Section: Resultsmentioning

confidence: 99%

Section: Atv Permeability Through Artificial Blood-brain Barriermentioning

confidence: 99%

In VitroBlood–Brain Barrier Permeability and Cytotoxicity of an Atorvastatin-Loaded Nanoformulation Against Glioblastoma in 2D and 3D Models

et al. 2020

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“…Based on these calculations, analogues 16 , 20 , and 39 all are predicted to be CNS-inactive with values of −2 for each, while 38 has a predicted value of 0, indicating at least partial CNS activity. Alternatively, Madin–Darby canine kidney (MDCK) cells have been shown to be a viable surrogate to assess for BBB permeability. , This is captured in the QPPMDCK apparent permeability ( P app ) metric where a predicted P app > 500 nm/s is desired for CNS activity. Analogues 16 , 20 , and 39 all had QPPMDCK P app values around 140 nm/s, which would support the reduced CNS score, while 38 was predicted to have a value of 632 nm/s (Table ), indicating that it was the most likely of the cohort to reach the desired site of action.…”

Section: Resultsmentioning

confidence: 99%

Optimization of a Pyrimidinone Series for Selective Inhibition of Ca²⁺/Calmodulin-Stimulated Adenylyl Cyclase 1 Activity for the Treatment of Chronic Pain

et al. 2022

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Adenylyl cyclase type 1 (AC1) is involved in signaling for chronic pain sensitization in the central nervous system and is an emerging target for the treatment of chronic pain. AC1 and a closely related isoform AC8 are also implicated to have roles in learning and memory signaling processes. Our team has carried out cellular screening for inhibitors of AC1 yielding a pyrazolyl-pyrimidinone scaffold with low micromolar potency against AC1 and selectivity versus AC8. Structure–activity relationship (SAR) studies led to analogues with cellular IC50 values as low as 0.25 μM, selectivity versus AC8 and other AC isoforms as well as other common neurological targets. A representative analogue displayed modest antiallodynic effects in a mouse model of inflammatory pain. This series represents the most potent and selective inhibitors of Ca2+/calmodulin-stimulated AC1 activity to date with improved drug-like physicochemical properties making them potential lead compounds for the treatment of inflammatory pain.

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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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In VitroAssays for Assessing BBB Permeability

Cited by 13 publications

References 188 publications

In VitroBlood–Brain Barrier Permeability and Cytotoxicity of an Atorvastatin-Loaded Nanoformulation Against Glioblastoma in 2D and 3D Models

In VitroBlood–Brain Barrier Permeability and Cytotoxicity of an Atorvastatin-Loaded Nanoformulation Against Glioblastoma in 2D and 3D Models

Optimization of a Pyrimidinone Series for Selective Inhibition of Ca²⁺/Calmodulin-Stimulated Adenylyl Cyclase 1 Activity for the Treatment of Chronic Pain

A guide for blood–brain barrier models

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In VitroAssays for Assessing BBB Permeability

Cited by 13 publications

References 188 publications

In VitroBlood–Brain Barrier Permeability and Cytotoxicity of an Atorvastatin-Loaded Nanoformulation Against Glioblastoma in 2D and 3D Models

In VitroBlood–Brain Barrier Permeability and Cytotoxicity of an Atorvastatin-Loaded Nanoformulation Against Glioblastoma in 2D and 3D Models

Optimization of a Pyrimidinone Series for Selective Inhibition of Ca2+/Calmodulin-Stimulated Adenylyl Cyclase 1 Activity for the Treatment of Chronic Pain

A guide for blood–brain barrier models

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Product

Resources

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Optimization of a Pyrimidinone Series for Selective Inhibition of Ca²⁺/Calmodulin-Stimulated Adenylyl Cyclase 1 Activity for the Treatment of Chronic Pain