Development of human multicellular spheroidal blood-brain barrier models for drug development studies

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07214
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: Furihata Tomomi 東京薬科大学, 薬学部, 教授 (80401008)
• Co-Investigator(Kenkyū-buntansha): 小島 伸彦 横浜市立大学, 理学部, 准教授 (90342956)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 血液脳関門 / 中枢創薬 / インビトロモデル / 脳

Outline of Final Research Achievements

We report on the development of a human conditionally immortalized cell-based multicellular spheroidal blood brain barrier (hiMCS-BBB) model. After being seeded into non-attachment culture wells, HASTR/ci35 and HBPC/ci37 cells self-assemble to form a spheroid core that is then covered with an outer monolayer of HBMEC/ci18 cells. hiMCS-BBB models exhibit physical, as well as biological, barrier functions. Furthermore, hiMCS-BBB models show receptor-mediated transcytosis functions at the levels enough to evaluate BBB permeability of antibodies. In addition, tumor necrosis factor-alpha treatment elicited an inflammatory response in HBMEC/ci18 cells. Therefore, hiMCS-BBB models can be expected to provide a useful and highly accessible experimental platform for accelerating various drug development studies, including development of brain drug delivery carriers as well as toxicological evaluations.

Free Research Field

薬物動態学

Academic Significance and Societal Importance of the Research Achievements

本研究では、３種のヒト不死化細胞を階層的に組み合わせることにより、新たなスフェロイド型ＢＢＢモデルを確立した。これまでに全てヒト不死化細胞から成るスフェロイド型ＢＢＢモデルの報告はなく、世界でも初めての成果となる。本モデルは、不死化細胞の汎用性と生体模倣による高機能性を兼ね備えており、高分子薬物のＢＢＢ透過性評価や種々の薬物に対するＢＢＢ障害評価を、迅速・経済的に、かつ高い精度で行うことを可能とすると期待される。本モデルが標準評価系として産・学で広く活用されれば、新たな薬物脳送達技術創出および薬物のヒト中枢毒性の的確な予測評価法の確立につながると期待される。