Impact of blood-brain barrier permeabilization induced by ultrasound associated to microbubbles on the brain delivery and kinetics of cetuximab: An immunoPET study using 89Zr-cetuximab

Tran, Vu Long; Novell, Anthony; Tournier, Nicolas; Gerstenmayer, Matthieu; Schweitzer-Chaput, Arnaud; Mateos, Claudia; Jego, Benoît; Bouleau, Alizée; Nozach, Hervé; Winkeler, Alexandra; Kühnast, Bertrand; Larrat, Benoît; Truillet, Charles

doi:10.1016/j.jconrel.2020.08.047

Cited by 41 publications

(35 citation statements)

References 42 publications

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“…In rodents, the use of FUS coupled with MB injection to increase the efficacy of gene therapy in the brain has mainly been used to target specific brain areas [ 30 ]. Here, we used an automated system to scan a large portion of the upper skull of young adult mice in order to target the whole brain [ 31 , 32 ], and our results showed that this protocol allowed efficient and safe BBB disruption in rodents. Concretely, the focal spot of the circular transducer had a 1 mm width, and it was moving over the head of the animal at a velocity of 10 mm·s −1 .…”

Section: Discussionmentioning

confidence: 99%

Ultrasound-Mediated Blood-Brain Barrier Opening Improves Whole Brain Gene Delivery in Mice

et al. 2021

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Gene therapy represents a powerful therapeutic tool to treat diseased tissues and provide a durable and effective correction. The central nervous system (CNS) is the target of many gene therapy protocols, but its high complexity makes it one of the most difficult organs to reach, in part due to the blood-brain barrier that protects it from external threats. Focused ultrasound (FUS) coupled with microbubbles appears as a technological breakthrough to deliver therapeutic agents into the CNS. While most studies focus on a specific targeted area of the brain, the present work proposes to permeabilize the entire brain for gene therapy in several pathologies. Our results show that, after i.v. administration and FUS sonication in a raster scan manner, a self-complementary AAV9-CMV-GFP vector strongly and safely infected the whole brain of mice. An increase in vector DNA (19.8 times), GFP mRNA (16.4 times), and GFP protein levels (17.4 times) was measured in whole brain extracts of FUS-treated GFP injected mice compared to non-FUS GFP injected mice. In addition to this increase in GFP levels, on average, a 7.3-fold increase of infected cells in the cortex, hippocampus, and striatum was observed. No side effects were detected in the brain of treated mice. The combining of FUS and AAV-based gene delivery represents a significant improvement in the treatment of neurological genetic diseases.

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Section: Discussionmentioning

confidence: 99%

Ultrasound-Mediated Blood-Brain Barrier Opening Improves Whole Brain Gene Delivery in Mice

et al. 2021

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“…To date, several immuno-PET imaging tracers have been designed to target glioblastoma and have already proven successful in detecting gliomas in multiple preclinical models. These tracers target membrane proteins whose expression is altered in glioblastoma (including the EGFR, DLL4, EPHA2, CD47, AC133 antigen, and MT1-MMP) [ 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 106 , 107 ]: several components of the tumor microenvironment including vessels, macrophages, and extracellular matrix proteins [ 104 , 105 , 108 , 109 , 110 , 114 ]. Notably, [ 89 Zr]Zr-DFO-fresolimumab, an immuno-PET tracer based on a monoclonal antibody that can neutralize all mammalian isoforms of TGF-β was assayed in humans, penetrated recurrent high-grade gliomas but did not result in clinical benefit [ 109 ].…”

Section: Discussionmentioning

confidence: 99%

Diagnosis of Glioblastoma by Immuno-Positron Emission Tomography

Ruiz-López

Calatayud-Pérez

Castells-Yus

et al. 2021

Cancers

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Neuroimaging has transformed neuro-oncology and the way that glioblastoma is diagnosed and treated. Magnetic Resonance Imaging (MRI) is the most widely used non-invasive technique in the primary diagnosis of glioblastoma. Although MRI provides very powerful anatomical information, it has proven to be of limited value for diagnosing glioblastomas in some situations. The final diagnosis requires a brain biopsy that may not depict the high intratumoral heterogeneity present in this tumor type. The revolution in “cancer-omics” is transforming the molecular classification of gliomas. However, many of the clinically relevant alterations revealed by these studies have not yet been integrated into the clinical management of patients, in part due to the lack of non-invasive biomarker-based imaging tools. An innovative option for biomarker identification in vivo is termed “immunotargeted imaging”. By merging the high target specificity of antibodies with the high spatial resolution, sensitivity, and quantitative capabilities of positron emission tomography (PET), “Immuno-PET” allows us to conduct the non-invasive diagnosis and monitoring of patients over time using antibody-based probes as an in vivo, integrated, quantifiable, 3D, full-body “immunohistochemistry” in patients. This review provides the state of the art of immuno-PET applications and future perspectives on this imaging approach for glioblastoma.

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“…The method for spatially controlled BBB disruption was optimized from previous work [10] to induce reproducible BBB disruption in the right brain hemisphere only. Experiments were performed using female NMRI nu/nu mice.…”

Section: Focused Ultrasoundmentioning

confidence: 99%

“…Among these strategies, focused ultrasound in combination with microbubbles (FUS) is emerging as an effective means to locally and temporarily enhance BBB permeability, mainly through the "opening" of Pharmaceutics 2021, 13, 1752 2 of 15 the paracellular route by disruption of the tight junctions [6]. A large body of preclinical research has convincingly shown that FUS enhanced the brain exposure of small molecules, biologics or gene therapy [7][8][9][10][11]. More than 30 clinical trials using FUS-induced BBB disruption are ongoing and assessed the translational potential and clinical safety of the technique [12][13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

[18F]2-Fluoro-2-deoxy-sorbitol PET Imaging for Quantitative Monitoring of Enhanced Blood-Brain Barrier Permeability Induced by Focused Ultrasound

et al. 2021

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Focused ultrasound in combination with microbubbles (FUS) provides an effective means to locally enhance the delivery of therapeutics to the brain. Translational and quantitative imaging techniques are needed to noninvasively monitor and optimize the impact of FUS on blood–brain barrier (BBB) permeability in vivo. Positron-emission tomography (PET) imaging using [18F]2-fluoro-2-deoxy-sorbitol ([18F]FDS) was evaluated as a small-molecule (paracellular) marker of blood–brain barrier (BBB) integrity. [18F]FDS was straightforwardly produced from chemical reduction of commercial [18F]2-deoxy-2-fluoro-D-glucose. [18F]FDS and the invasive BBB integrity marker Evan’s blue (EB) were i.v. injected in mice after an optimized FUS protocol designed to generate controlled hemispheric BBB disruption. Quantitative determination of the impact of FUS on the BBB permeability was determined using kinetic modeling. A 2.2 ± 0.5-fold higher PET signal (n = 5; p < 0.01) was obtained in the sonicated hemisphere and colocalized with EB staining observed post mortem. FUS significantly increased the blood-to-brain distribution of [18F]FDS by 2.4 ± 0.8-fold (VT; p < 0.01). Low variability (=10.1%) of VT values in the sonicated hemisphere suggests reproducibility of the estimation of BBB permeability and FUS method. [18F]FDS PET provides a readily available, sensitive and reproducible marker of BBB permeability to noninvasively monitor the extent of BBB disruption induced by FUS in vivo.

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Impact of blood-brain barrier permeabilization induced by ultrasound associated to microbubbles on the brain delivery and kinetics of cetuximab: An immunoPET study using 89Zr-cetuximab

Cited by 41 publications

References 42 publications

Ultrasound-Mediated Blood-Brain Barrier Opening Improves Whole Brain Gene Delivery in Mice

Ultrasound-Mediated Blood-Brain Barrier Opening Improves Whole Brain Gene Delivery in Mice

Diagnosis of Glioblastoma by Immuno-Positron Emission Tomography

[18F]2-Fluoro-2-deoxy-sorbitol PET Imaging for Quantitative Monitoring of Enhanced Blood-Brain Barrier Permeability Induced by Focused Ultrasound

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