Low-intensity Pulsed Ultrasound-mediated Blood-brain Barrier Opening Increases Anti-programmed Death-ligand 1 Delivery and Efficacy in Gl261 Mouse Model

Mohammed H Ahmed; Emie Quissac; Nolwenn Lemaire; Isaias Hernández-Verdín; Noël Zahr; Charlotte Schmitt; Guillaume Bouchoux; Michael Canney; M.D. Santin; Alexandra Petiet; Laura Mouton; Coralie Guerin; Lea Guyonnet; Marc Sanson; Maïté Verreault; Alexandre Carpentier; Ahmed Idbaih

doi:10.20944/preprints202212.0170.v1

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preprints.org > medicine and pharmacology > pharmacology and toxicology > doi: 10.20944/preprints202212.0170.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Low-intensity Pulsed Ultrasound-mediated Blood-brain Barrier Opening Increases Anti-programmed Death-ligand 1 Delivery and Efficacy in Gl261 Mouse Model

Mohammed H Ahmed

^* ,

Emie Quissac

Nolwenn Lemaire

Isaias Hernández-Verdín

Version 1 : Received: 8 December 2022 / Approved: 9 December 2022 / Online: 9 December 2022 (02:59:28 CET)

A peer-reviewed article of this Preprint also exists.

Ahmed, M.H.; Hernández-Verdin, I.; Quissac, E.; Lemaire, N.; Guerin, C.; Guyonnet, L.; Zahr, N.; Mouton, L.; Santin, M.; Petiet, A.; Schmitt, C.; Bouchoux, G.; Canney, M.; Sanson, M.; Verreault, M.; Carpentier, A.; Idbaih, A. Low-Intensity Pulsed Ultrasound-Mediated Blood-Brain Barrier Opening Increases Anti-Programmed Death-Ligand 1 Delivery and Efficacy in Gl261 Mouse Model. Pharmaceutics 2023, 15, 455. Ahmed, M.H.; Hernández-Verdin, I.; Quissac, E.; Lemaire, N.; Guerin, C.; Guyonnet, L.; Zahr, N.; Mouton, L.; Santin, M.; Petiet, A.; Schmitt, C.; Bouchoux, G.; Canney, M.; Sanson, M.; Verreault, M.; Carpentier, A.; Idbaih, A. Low-Intensity Pulsed Ultrasound-Mediated Blood-Brain Barrier Opening Increases Anti-Programmed Death-Ligand 1 Delivery and Efficacy in Gl261 Mouse Model. Pharmaceutics 2023, 15, 455.

Abstract

Therapeutic antibodies targeting immune checkpoints have shown limited efficacy in clinical trials in glioblastoma (GBM) patients. Ultrasound-mediated blood-brain barrier opening (UMBO) using low-intensity pulsed ultrasound improved drug delivery to the brain. We explored the safety and the efficacy of UMBO plus immune checkpoint inhibitors in preclinical models of GBM. A Blood-brain barrier (BBB) opening was performed using a 1 MHz preclinical ultrasound system in combination with 10µl/g microbubbles. Brain penetration of immune checkpoint inhibitors was determined, and immune cell populations were evaluated using flow cytometry. The impact of repeated treatments on survival was determined. In syngeneic GL261-bearing immunocompetent mice, we showed that UMBO safely and repeatedly open the BBB. BBB opening was confirmed visually and microscopically using Evans’s blue dye and magnetic resonance imaging. UMBO plus anti-PDL-1 was associated with a significant improvement of the overall survival compared to anti-PD-L1 alone. Using mass spectroscopy, we showed that the penetration of therapeutic antibodies can be increased when delivered intravenously compared to non-sonicated brains. Furthermore, we observed an enhancement of activated microglia percentage when combined with anti-PD-L1. Here, we report that the combination of UMBO and anti-PD-L1 dramatically increases GL261-bearing mice's survival compared to their counterparts treated with anti-PD-L1 alone. Our study highlights the BBB as a limitation to overcome to increase the efficacy of anti-PD-L1 in GBM and supports clinical trials combining UMBO and in GBM patients.

Keywords

SonoCloud; GL261 mouse model; ultrasound-mediated drug delivery; glioblastoma; immune checkpoint inhibitors

Subject

Medicine and Pharmacology, Pharmacology and Toxicology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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