Anesthesia triggers drug delivery to experimental glioma in mice by hijacking caveolar transport

  • Background Pharmaceutical intervention in the CNS is hampered by the shielding function of the blood–brain barrier (BBB). To induce clinical anesthesia, general anesthetics such as isoflurane readily penetrate the BBB. Here, we investigated whether isoflurane can be utilized for therapeutic drug delivery. Methods Barrier function in primary endothelial cells was evaluated by transepithelial/transendothelial electrical resistance, and nanoscale STED and SRRF microscopy. In mice, BBB permeability was quantified by extravasation of several fluorescent tracers. Mouse models including the GL261 glioma model were evaluated by MRI, immunohistochemistry, electron microscopy, western blot, and expression analysis. Results Isoflurane enhances BBB permeability in a time- and concentration-dependent manner. We demonstrate that, mechanistically, isoflurane disturbs the organization of membrane lipid nanodomains and triggers caveolar transport in brain endothelial cells. BBB tightnessBackground Pharmaceutical intervention in the CNS is hampered by the shielding function of the blood–brain barrier (BBB). To induce clinical anesthesia, general anesthetics such as isoflurane readily penetrate the BBB. Here, we investigated whether isoflurane can be utilized for therapeutic drug delivery. Methods Barrier function in primary endothelial cells was evaluated by transepithelial/transendothelial electrical resistance, and nanoscale STED and SRRF microscopy. In mice, BBB permeability was quantified by extravasation of several fluorescent tracers. Mouse models including the GL261 glioma model were evaluated by MRI, immunohistochemistry, electron microscopy, western blot, and expression analysis. Results Isoflurane enhances BBB permeability in a time- and concentration-dependent manner. We demonstrate that, mechanistically, isoflurane disturbs the organization of membrane lipid nanodomains and triggers caveolar transport in brain endothelial cells. BBB tightness re-establishes directly after termination of anesthesia, providing a defined window for drug delivery. In a therapeutic glioblastoma trial in mice, simultaneous exposure to isoflurane and cytotoxic agent improves efficacy of chemotherapy. Conclusions Combination therapy, involving isoflurane-mediated BBB permeation with drug administration has far-reaching thershow moreshow less

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Author:Lena Spieth, Stefan A. Berghoff, Sina K. Stumpf, Jan Winchenbach, Thomas Michaelis, Takashi Watanabe, Nina Gerndt, Tim Düking, Sabine Hofer, Torben Ruhwedel, Ali H. Shaib, Katrin WilligORCiDGND, Katharina Kronenberg, Uwe Karst, Jens Frahm, Jeong Seop Rhee, Susana Minguet, Wiebke Möbius, Niels Kruse, Christian von der Brelie, Peter Michels, Christine Stadelmann, Petra Hülper, Gesine Saher
URN:urn:nbn:de:bvb:384-opus4-1109518
Frontdoor URLhttps://opus.bibliothek.uni-augsburg.de/opus4/110951
ISSN:2632-2498OPAC
Parent Title (English):Neuro-Oncology Advances
Publisher:Oxford University Press (OUP)
Place of publication:Oxford
Type:Article
Language:English
Year of first Publication:2021
Publishing Institution:Universität Augsburg
Release Date:2024/01/22
Tag:General Medicine
Volume:3
Issue:1
First Page:vdab140
DOI:https://doi.org/10.1093/noajnl/vdab140
Institutes:Medizinische Fakultät
Medizinische Fakultät / Professur für Zelluläre und Molekulare Bildgebung in der Anatomie
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):CC-BY 4.0: Creative Commons: Namensnennung (mit Print on Demand)