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Blood-brain-barrier spheroids as an in vitro screening platform for brain-penetrating agents

Author

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  • Choi-Fong Cho

    (Harvey Cushing Neuro-Oncology Laboratories, Brigham and Women’s Hospital, Harvard Medical School
    Massachusetts Institute of Technology)

  • Justin M. Wolfe

    (Massachusetts Institute of Technology)

  • Colin M. Fadzen

    (Massachusetts Institute of Technology)

  • David Calligaris

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Kalvis Hornburg

    (Harvey Cushing Neuro-Oncology Laboratories, Brigham and Women’s Hospital, Harvard Medical School)

  • E. Antonio Chiocca

    (Harvey Cushing Neuro-Oncology Laboratories, Brigham and Women’s Hospital, Harvard Medical School)

  • Nathalie Y. R. Agar

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Bradley L. Pentelute

    (Massachusetts Institute of Technology)

  • Sean E. Lawler

    (Harvey Cushing Neuro-Oncology Laboratories, Brigham and Women’s Hospital, Harvard Medical School)

Abstract

Culture-based blood–brain barrier (BBB) models are crucial tools to enable rapid screening of brain-penetrating drugs. However, reproducibility of in vitro barrier properties and permeability remain as major challenges. Here, we report that self-assembling multicellular BBB spheroids display reproducible BBB features and functions. The spheroid core is comprised mainly of astrocytes, while brain endothelial cells and pericytes encase the surface, acting as a barrier that regulates transport of molecules. The spheroid surface exhibits high expression of tight junction proteins, VEGF-dependent permeability, efflux pump activity and receptor-mediated transcytosis of angiopep-2. In contrast, the transwell co-culture system displays comparatively low levels of BBB regulatory proteins, and is unable to discriminate between the transport of angiopep-2 and a control peptide. Finally, we have utilized the BBB spheroids to screen and identify BBB-penetrant cell-penetrating peptides (CPPs). This robust in vitro BBB model could serve as a valuable next-generation platform for expediting the development of CNS therapeutics.

Suggested Citation

  • Choi-Fong Cho & Justin M. Wolfe & Colin M. Fadzen & David Calligaris & Kalvis Hornburg & E. Antonio Chiocca & Nathalie Y. R. Agar & Bradley L. Pentelute & Sean E. Lawler, 2017. "Blood-brain-barrier spheroids as an in vitro screening platform for brain-penetrating agents," Nature Communications, Nature, vol. 8(1), pages 1-14, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15623
    DOI: 10.1038/ncomms15623
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    Cited by:

    1. Takeshi Hori & Hiroaki Okae & Shun Shibata & Norio Kobayashi & Eri H. Kobayashi & Akira Oike & Asato Sekiya & Takahiro Arima & Hirokazu Kaji, 2024. "Trophoblast stem cell-based organoid models of the human placental barrier," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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