title: Minimum Transendothelial Electrical Resistance Thresholds for the Study of Small and Large Molecule Drug Transport in a Human in Vitro Blood-Brain Barrier Model.
abstract: A human cell-based in vitro model that can accurately predict drug penetration into the brain as well as metrics to assess these in vitro models are valuable for the development of new therapeutics. Here, human induced pluripotent stem cells (hPSCs) are differentiated into a polarized monolayer that express blood-brain barrier (BBB)-specific proteins and have transendothelial electrical resistance (TEER) values greater than 2500 Ω·cm2. By assessing the permeabilities of several known drugs, a benchmarking system to evaluate brain permeability of drugs was established. Furthermore, relationships between TEER and permeability to both small and large molecules were established, demonstrating that different minimum TEER thresholds must be achieved to study the brain transport of these two classes of drugs. This work demonstrates that this hPSC-derived BBB model exhibits an in vivo-like phenotype, and the benchmarks established here are useful for assessing functionality of other in vitro BBB models.
authors.affiliation: Department of Chemical and Biomolecular Engineering and Delaware Biotechnology Institute, University of Delaware , 15 Innovation Way, Newark, Delaware 19711, United States.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Mantle
authors.affiliation: Department of Chemical and Biomolecular Engineering and Delaware Biotechnology Institute, University of Delaware , 15 Innovation Way, Newark, Delaware 19711, United States.
authors.forename: Lie
authors.initials: L
authors.lastname: Min
authors.affiliation: Department of Chemical and Biomolecular Engineering and Delaware Biotechnology Institute, University of Delaware , 15 Innovation Way, Newark, Delaware 19711, United States.
authors.forename: Kelvin H
authors.initials: KH
authors.lastname: Lee
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000493:pharmacokinetics*; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D017097:Electric Impedance; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations
keywords: Alzheimer’s disease; IgG transport; blood−brain barrier; drug transport; human brain microvascular endothelial cells; human induced pluripotent stem cells