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Anal Chim Acta. 2016 Aug 31;934:186-93. doi: 10.1016/j.aca.2016.06.028. Epub 2016 Jun 24.

Development of a blood-brain barrier model in a membrane-based microchip for characterization of drug permeability and cytotoxicity for drug screening.

Author information

1
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.
2
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.
3
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.
4
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.
5
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
6
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.
7
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.

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.

KEYWORDS:

Blood-brain barrier; CNS drugs; Drug cytotoxicity; Drug permeability; Microfluidic device

PMID:
27506359
DOI:
10.1016/j.aca.2016.06.028
[Indexed for MEDLINE]

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