title: Development of a blood-brain barrier model in a membrane-based microchip for characterization of drug permeability and cytotoxicity for drug screening.
abstract: Since most of the central nervous system (CNS) drug candidates show poor permeability across the blood-brain barrier (BBB), development of a reliable platform for permeability assay will greatly accelerate drug discovery. Herein, we constructed a microfluidic BBB model to mimic drug delivery into the brain to induce cytotoxicity at target cells. To reconstitute the in vivo BBB properties, human cerebral microvessel endothelial cells (hCMEC/D3) were dynamically cultured in a membrane-based microchannel. Sunitinib, a model drug, was then delivered into the microchannel and forced to permeate through the BBB model. The permeated amount was directly quantified by an electrospray ionization quadrupole time-of-flight mass spectrometer (ESI-Q-TOF MS) after on-chip SPE (μSPE) pretreatment. Moreover, the permeated drug was incubated with glioma cells (U251) cultured inside agarose gel in the downstream to investigate drug-induced cytotoxicity. The resultant permeability of sunitinib was highly correlated with literature reported value, and it only required 30 min and 5 μL of sample solution for each permeation experiment. Moreover, after 48 h of treatment, the survival rate of U251 cells cultured in 3D scaffolds was nearly 6% higher than that in 2D, which was in accordance with the previously reported results. These results demonstrate that this platform provides a valid tool for drug permeability and cytotoxicity assays which have great value for the research and development of CNS drugs.
authors: State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Department of Chemistry, Tsinghua University, Beijing 100084, PR China.
authors: Xiaojian
authors: X
authors: Shao
authors: State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Key Laboratory of Metabolomics at Shenzhen, Shenzhen 518055, PR China. Electronic address: gao.dan@sz.tsinghua.edu.cn.
authors: Dan
authors: D
authors: Gao
authors: State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Key Laboratory of Metabolomics at Shenzhen, Shenzhen 518055, PR China.
authors: Yongli
authors: Y
authors: Chen
authors: State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Neptunus Pharmaceutical Technology Center, Shenzhen 518057, China.
authors: Feng
authors: F
authors: Jin
authors: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors: Guangnan
authors: G
authors: Hu
authors: State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; School of Medicine, Tsinghua University, Beijing 100084, PR China.
authors: Yuyang
authors: Y
authors: Jiang
authors: State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Department of Chemistry, Tsinghua University, Beijing 100084, PR China. Electronic address: liuhx@sz.tsinghua.edu.cn.
authors: Hongxia
authors: H
authors: Liu
mesh_terms: D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D046208:Microchip Analytical Procedures; D046210:Microfluidic Analytical Techniques / Q000295:instrumentation; D008954:Models, Biological; D010539:Permeability / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib
chemical_list: D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib
keywords: Blood-brain barrier; CNS drugs; Drug cytotoxicity; Drug permeability; Microfluidic device