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Article ; Online: State of the art on microbubble cavitation monitoring and feedback control for blood-brain-barrier opening using focused ultrasound.

Mondou, Paul / Mériaux, Sébastien / Nageotte, Florent / Vappou, Jonathan / Novell, Anthony / Larrat, Benoit

2023 Volume 68, Issue 18

Abstract: Focused ultrasound (FUS) is a non-invasive and highly promising method for targeted and reversible blood-brain barrier permeabilization. Numerous preclinical studies aim to optimize the localized delivery of drugs using this method in rodents and non- ... ...

Abstract	Focused ultrasound (FUS) is a non-invasive and highly promising method for targeted and reversible blood-brain barrier permeabilization. Numerous preclinical studies aim to optimize the localized delivery of drugs using this method in rodents and non-human primates. Several clinical trials have been initiated to treat various brain diseases in humans using simultaneous BBB permeabilization and drug injection. This review presents the state of the art of
MeSH term(s)	Animals ; Humans ; Blood-Brain Barrier ; Feedback ; Microbubbles ; Ultrasonics/methods ; Brain Diseases ; Drug Delivery Systems/methods
Language	English
Publishing date	2023-09-08
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	208857-5
ISSN	1361-6560 ; 0031-9155
ISSN (online)	1361-6560
ISSN	0031-9155
DOI	10.1088/1361-6560/ace23e
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Article ; Online: Transcranial ultrasound simulations: A review.

Angla, Célestine / Larrat, Benoit / Gennisson, Jean-Luc / Chatillon, Sylvain

Medical physics

2022 Volume 50, Issue 2, Page(s) 1051–1072

Abstract: Transcranial ultrasound is more and more used for therapy and imaging of the brain. However, the skull is a highly attenuating and aberrating medium, with different structures and acoustic properties among samples and even within a sample. Thus, case- ... ...

Abstract	Transcranial ultrasound is more and more used for therapy and imaging of the brain. However, the skull is a highly attenuating and aberrating medium, with different structures and acoustic properties among samples and even within a sample. Thus, case-specific simulations are needed to perform transcranial focused ultrasound interventions safely. In this article, we provide a review of the different methods used to model the skull and to simulate ultrasound propagation through it.
MeSH term(s)	Computer Simulation ; Ultrasonography/methods ; Brain/diagnostic imaging ; Skull/diagnostic imaging ; Acoustics
Language	English
Publishing date	2022-09-12
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	188780-4
ISSN	2473-4209 ; 0094-2405
ISSN (online)	2473-4209
ISSN	0094-2405
DOI	10.1002/mp.15955
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Zs.A 1210: Show issues

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Soyer, Amélie / Goutal, Sébastien / Leterrier, Sarah / Marie, Solène / Larrat, Benoit / Selingue, Erwan / Winkeler, Alexandra / Sarazin, Marie / Bottlaender, Michel / Tournier, Nicolas

Annales pharmaceutiques francaises

2024

Abstract: Numerous studies suggest that blood-brain barrier (BBB) dysfunction may contribute to the progression of Alzheimer's disease (AD). Clinically available neuroimaging methods are needed for quantitative "scoring" of BBB permeability in AD patients. [ ...

Abstract	Numerous studies suggest that blood-brain barrier (BBB) dysfunction may contribute to the progression of Alzheimer's disease (AD). Clinically available neuroimaging methods are needed for quantitative "scoring" of BBB permeability in AD patients. [
Language	English
Publishing date	2024-04-22
Publishing country	France
Document type	Journal Article
ZDB-ID	307-4
ISSN	0003-4509
ISSN	0003-4509
DOI	10.1016/j.pharma.2024.04.004
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Article ; Online: Anticancer drug delivery by focused ultrasound-mediated blood-brain/tumor barrier disruption for glioma therapy: From benchside to bedside.

Bérard, Charlotte / Truillet, Charles / Larrat, Benoit / Dhermain, Frédéric / Estève, Marie-Anne / Correard, Florian / Novell, Anthony

Pharmacology & therapeutics

2023 Volume 250, Page(s) 108518

Abstract: The therapeutic management of gliomas remains particularly challenging. Brain tumors present multiple obstacles that make therapeutic innovation complex, mainly due to the presence of blood-tumor and blood-brain barriers (BTB and BBB, respectively) which ...

Abstract	The therapeutic management of gliomas remains particularly challenging. Brain tumors present multiple obstacles that make therapeutic innovation complex, mainly due to the presence of blood-tumor and blood-brain barriers (BTB and BBB, respectively) which prevent penetration of anticancer agents into the brain parenchyma. Focused ultrasound-mediated BBB disruption (FUS-BBBD) provides a physical method for non-invasive, local, and reversible BBB disruption. The safety of this technique has been demonstrated in small and large animal models. This approach promises to enhance drug delivery into the brain tumor and therefore to improve survival outcomes by repurposing existing drugs. Several clinical trials continue to be initiated in the last decade. In this review, we provide an overview of the rationale behind the use of FUS-BBBD in gliomas and summarize the preclinical studies investigating different approaches (free drugs, drug-loaded microbubbles and drug-loaded nanocarriers) in combination with this technology in in vivo glioma models. Furthermore, we discuss the current state of clinical trials and devices developed and review the challenges to overcome for clinical use of FUS-BBBD in glioma therapy.
Language	English
Publishing date	2023-08-22
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	194735-7
ISSN	1879-016X ; 0163-7258
ISSN (online)	1879-016X
ISSN	0163-7258
DOI	10.1016/j.pharmthera.2023.108518
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Zs.A 1183: Show issues

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Article ; Online: Imaging the impact of blood-brain barrier disruption induced by focused ultrasound on P-glycoprotein function

Goutal, Sébastien / Novell, Anthony / Leterrier, Sarah / Breuil, Louise / Selingue, Erwan / Gerstenmayer, Matthieu / Marie, Solène / Saubaméa, Bruno / Caillé, Fabien / Langer, Oliver / Truillet, Charles / Larrat, Benoît / Tournier, Nicolas

Journal of Controlled Release.

2023

Abstract: The P-glycoprotein (P-gp/ABCB1) is a major efflux transporter which impedes the brain delivery of many drugs across the blood-brain barrier (BBB). Focused ultrasound with microbubbles (FUS) enables BBB disruption, which immediate and delayed impact on P- ... ...

Abstract	The P-glycoprotein (P-gp/ABCB1) is a major efflux transporter which impedes the brain delivery of many drugs across the blood-brain barrier (BBB). Focused ultrasound with microbubbles (FUS) enables BBB disruption, which immediate and delayed impact on P-gp function remains unclear. Positron emission tomography (PET) imaging using the radiolabeled substrate [¹¹C]metoclopramide provides a sensitive and translational method to study P-gp function at the living BBB. A FUS protocol was devised in rats to induce a substantial and targeted disruption of the BBB in the left hemisphere. BBB disruption was confirmed by the Evan's Blue extravasation test or the minimally-invasive contrast-enhanced MRI. The expression of P-gp was measured 24 h or 48 h after FUS using immunostaining and fluorescence microscopy. The brain kinetics of [¹¹C]metoclopramide was studied by PET at baseline, and both immediately or 24 h after FUS, with or without half-maximum P-gp inhibition (tariquidar 1 mg/kg). In each condition (n = 4-5 rats per group), brain exposure of [¹¹C]metoclopramide was estimated as the area-under-the-curve (AUC) in regions corresponding to the sonicated volume in the left hemisphere, and the contralateral volume. Kinetic modeling was performed to estimate the uptake clearance ratio (R₁) of [¹¹C]metoclopramide in the sonicated volume relative to the contralateral volume. In the absence of FUS, half-maximum P-gp inhibition increased brain exposure (+135.0 ± 12.9%, p < 0.05) but did not impact R₁ (p > 0.05). Immediately after FUS, BBB integrity was selectively disrupted in the left hemisphere without any detectable impact on the brain kinetics of [¹¹C]metoclopramide compared with the baseline group (p > 0.05) or the contralateral volume (p > 0.05). 24 h after FUS, BBB integrity was fully restored while P-gp expression was maximally down-regulated (−45.0 ± 4.5%, p < 0.001) in the sonicated volume. This neither impacted AUC nor R₁ in the FUS + 24 h group (p > 0.05). Only when P-gp was inhibited with tariquidar were the brain exposure (+130 ± 70%) and R₁(+29.1 ± 15.4%) significantly increased in the FUS + 24 h/tariquidar group, relative to the baseline group (p < 0.001). We conclude that the brain kinetics of [¹¹C]metoclopramide specifically depends on P-gp function rather than BBB integrity. Delayed FUS-induced down-regulation of P-gp function can be detected. Our results suggest that almost complete down-regulation is required to substantially enhance the brain delivery of P-gp substrates.
Keywords	P-glycoproteins ; blood-brain barrier ; brain ; fluorescence microscopy ; metoclopramide ; microbubbles ; positron-emission tomography ; radiolabeling ; ultrasonics ; Blood-brain barrier integrity ; Brain delivery ; Efflux transporter ; Membrane transporters ; Therapeutic ultrasound
Language	English
Publishing place	Elsevier B.V.
Document type	Article ; Online
Note	Pre-press version
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2023.08.012
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: About the Marty model of blood-brain barrier closure after its disruption using focused ultrasound.

Conti, Allegra / Mériaux, Sébastien / Larrat, Benoit

Physics in medicine and biology

2019 Volume 64, Issue 14, Page(s) 14NT02

Abstract: Many studies have demonstrated that pulsed ultrasound combined with circulating microbubbles can permeate the blood-brain barrier in a reversible manner. In 2012, our group demonstrated that the BBB remains permeable to small MRI contrast agents up to 24 ...

Abstract	Many studies have demonstrated that pulsed ultrasound combined with circulating microbubbles can permeate the blood-brain barrier in a reversible manner. In 2012, our group demonstrated that the BBB remains permeable to small MRI contrast agents up to 24 h after ultrasound application and also that this duration was dependent on nanoparticle size. We derived a simple theoretical model explaining these observations (Marty et al 2012 J. Cereb. Blood Flow Metab. 32 1948-58). However, in this original paper the expression of the BBB closure time (t
MeSH term(s)	Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Blood-Brain Barrier/radiation effects ; Brain/drug effects ; Brain/metabolism ; Brain/radiation effects ; Contrast Media/metabolism ; Drug Delivery Systems/methods ; Humans ; Magnetic Resonance Imaging/methods ; Microbubbles ; Models, Statistical ; Sonication/methods ; Ultrasonic Waves
Chemical Substances	Contrast Media
Language	English
Publishing date	2019-07-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	208857-5
ISSN	1361-6560 ; 0031-9155
ISSN (online)	1361-6560
ISSN	0031-9155
DOI	10.1088/1361-6560/ab259d
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Zs.A 199: Show issues

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Article: Amphiphilic and Perfluorinated Poly(3-Hydroxyalkanoate) Nanocapsules for

Le Gal, Marion / Renard, Estelle / Simon-Colin, Christelle / Larrat, Benoit / Langlois, Valérie

Bioengineering (Basel, Switzerland)

2021 Volume 8, Issue 9

Abstract: Nanoparticles have recently emerged as valuable tools in biomedical imaging techniques. Here PEGylated and fluorinated nanocapsules based on poly(3-hydroxyalkanoate) containing a liquid core of perfluorooctyl bromide PFOB were formulated by an emulsion- ... ...

Abstract	Nanoparticles have recently emerged as valuable tools in biomedical imaging techniques. Here PEGylated and fluorinated nanocapsules based on poly(3-hydroxyalkanoate) containing a liquid core of perfluorooctyl bromide PFOB were formulated by an emulsion-evaporation process as potential
Language	English
Publishing date	2021-09-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2746191-9
ISSN	2306-5354
ISSN	2306-5354
DOI	10.3390/bioengineering8090121
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Article: Molecular Imaging of Ultrasound-Mediated Blood-Brain Barrier Disruption in a Mouse Orthotopic Glioblastoma Model.

Bastiancich, Chiara / Fernandez, Samantha / Correard, Florian / Novell, Anthony / Larrat, Benoit / Guillet, Benjamin / Estève, Marie-Anne

Pharmaceutics

2022 Volume 14, Issue 10

Abstract: Glioblastoma (GBM) is an aggressive and malignant primary brain tumor. The blood-brain barrier (BBB) limits the therapeutic options available to tackle this incurable tumor. Transient disruption of the BBB by focused ultrasound (FUS) is a promising and ... ...

Abstract	Glioblastoma (GBM) is an aggressive and malignant primary brain tumor. The blood-brain barrier (BBB) limits the therapeutic options available to tackle this incurable tumor. Transient disruption of the BBB by focused ultrasound (FUS) is a promising and safe approach to increase the brain and tumor concentration of drugs administered systemically. Non-invasive, sensitive, and reliable imaging approaches are required to better understand the impact of FUS on the BBB and brain microenvironment. In this study, nuclear imaging (SPECT/CT and PET/CT) was used to quantify neuroinflammation 48 h post-FUS and estimate the influence of FUS on BBB opening and tumor growth in vivo. BBB disruptions were performed on healthy and GBM-bearing mice (U-87 MG xenograft orthotopic model). The BBB recovery kinetics were followed and quantified by [99mTc]Tc-DTPA SPECT/CT imaging at 0.5 h, 3 h and 24 h post-FUS. The absence of neuroinflammation was confirmed by [18F]FDG PET/CT imaging 48 h post-FUS. The presence of the tumor and its growth were evaluated by [68Ga]Ga-RGD
Language	English
Publishing date	2022-10-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics14102227
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Article ; Online: Regulation of P-glycoprotein and Breast Cancer Resistance Protein Expression Induced by Focused Ultrasound-Mediated Blood-Brain Barrier Disruption: A Pilot Study.

Conti, Allegra / Geffroy, Francoise / Kamimura, Hermes A S / Novell, Anthony / Tournier, Nicolas / Mériaux, Sébastien / Larrat, Benoit

International journal of molecular sciences

2022 Volume 23, Issue 24

Abstract: The blood-brain barrier (BBB) controls brain homeostasis; it is formed by vascular endothelial cells that are physically connected by tight junctions (TJs). The BBB expresses efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance ... ...

Abstract	The blood-brain barrier (BBB) controls brain homeostasis; it is formed by vascular endothelial cells that are physically connected by tight junctions (TJs). The BBB expresses efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which limit the passage of substrate molecules from blood circulation to the brain. Focused ultrasound (FUS) with microbubbles can create a local and reversible detachment of the TJs. However, very little is known about the effect of FUS on the expression of efflux transporters. We investigated the in vivo effects of moderate acoustic pressures on both P-gp and BCRP expression for up to two weeks after sonication. Magnetic resonance-guided FUS was applied in the striatum of 12 rats. P-gp and BCRP expression were determined by immunohistochemistry at 1, 3, 7, and 14 days postFUS. Our results indicate that FUS-induced BBB opening is capable of (i) decreasing P-gp expression up to 3 days after sonication in both the treated and in the contralateral brain regions and is capable of (ii) overexpressing BCRP up to 7 days after FUS in the sonicated regions only. Our findings may help improve FUS-aided drug delivery strategies by considering both the mechanical effect on the TJs and the regulation of P-gp and BCRP.
Language	English
Publishing date	2022-12-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms232415488
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Article ; Online: Planning Framework for Robot-assisted Blood-Brain Barrier Opening with Focused Ultrasound.

Thomas, Gaelle / Barbe, Laurent / Larrat, Benoit / Agou, Pauline / Vappou, Jonathan / Nageotte, Florent

Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference

2020 Volume 2020, Page(s) 5033–5036

Abstract: This article presents a method to plan BloodBrain Barrier (BBB) disruption with Focused Ultrasound, under neuronavigated robotic assistance. Robotic and acoustic constraints are defined to estimate brain target accessibility. The relevance of the ... ...

Abstract	This article presents a method to plan BloodBrain Barrier (BBB) disruption with Focused Ultrasound, under neuronavigated robotic assistance. Robotic and acoustic constraints are defined to estimate brain target accessibility. The relevance of the proposed framework is illustrated in specific brain target examples.
MeSH term(s)	Biological Transport ; Blood-Brain Barrier/diagnostic imaging ; Brain/diagnostic imaging ; Robotics ; Ultrasonography
Language	English
Publishing date	2020-10-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2694-0604
ISSN (online)	2694-0604
DOI	10.1109/EMBC44109.2020.9175849
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