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

Spieth, L.; Berghoff, S. A.; Stumpf, S. K.; Winchenbach, J.; Michaelis, T.; Watanabe, T.; Gerndt, N.; Düking, T.; Hofer, S.; Ruhwedel, T.; Shaib, A. H.; Willig, K. I.; Kronenberg, K.; Karst, U.; Frahm, J.; Rhee, J. S.; Minguet, S.; Möbius, W.; Kruse, N.; von der Brelie, C.; Michels, P.; Stadelmann, C.; Hülper, P.; Saher, G.

doi:10.1093/noajnl/vdab140

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

MPG-Autoren

/persons/resource/persons213399

Spieth, L.
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons202532

Berghoff, S. A.
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182438

Stumpf, S. K.
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons202528

Winchenbach, J.
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons15525

Michaelis, T.
Biomedical NMR Research GmbH, MPI for biophysical chemistry, Max Planck Society;

/persons/resource/persons15994

Watanabe, T.
Biomedical NMR Research GmbH, MPI for biophysical chemistry, Max Planck Society;

/persons/resource/persons202941

Gerndt, N.
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons202530

Düking, T.
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons15241

Hofer, S.
Biomedical NMR Research GmbH, MPI for biophysical chemistry, Max Planck Society;

/persons/resource/persons182382

Ruhwedel, T.
Electron microscopy, Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons226430

Shaib, A. H.
Molecular neurobiology, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons16030

Willig, K. I.
Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons15082

Frahm, J.
Biomedical NMR Research GmbH, MPI for biophysical chemistry, Max Planck Society;

/persons/resource/persons182371

Rhee, J. S.
Molecular neurobiology, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182306

Möbius, W.
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

/persons/resource/persons182386

Saher, G.
Neurogenetics, Max Planck Institute of Experimental Medicine, Max Planck Society;

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Zitation

Spieth, L., Berghoff, S. A., Stumpf, S. K., Winchenbach, J., Michaelis, T., Watanabe, T., et al. (2021). Anesthesia triggers drug delivery to experimental glioma in mice by hijacking caveolar transport. Neuro-Oncology Advances, 3(1): vdab140. doi:10.1093/noajnl/vdab140.

Zitierlink: https://hdl.handle.net/21.11116/0000-000A-B951-A

Zusammenfassung

Abstract

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 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 therapeutic implications for CNS malignancies.