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

Abstract

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.

Perfluorocarbon Nanodroplets as Potential Nanocarriers for Brain Delivery Assisted by Focused Ultrasound-Mediated Blood–Brain Barrier Disruption

“…A raster scan (X Y -axis, velocity: 10 mm s −1 ) was synchronized to the generator output in order to induce a hemispheric brain BBB opening of 6 mm (anterior-posterior) × 3.6 mm (lateral right hemisphere). The sequence was repeated 20 times for a total exposure of 112 s. Safe and efficient BBB disruptions in mice were demonstrated in previous studies using scanning patterns combined with high-DC US [ 35 , 36 ]. The left hemisphere was not sonicated and was used as control.…”

Molecular Imaging of Ultrasound-Mediated Blood-Brain Barrier Disruption in a Mouse Orthotopic Glioblastoma Model

“…Eight days following tumor grafting, mice were anesthetized by the intraperitoneal injection of ketamine/xylazine (100 and 10 mg/kg, respectively) and placed in a dedicated stereotactic frame positioned below the BBB opening set up as previously explained. For this experiment the mice were divided in three groups ( n = 4–5 per group): Group “GBM + FUS”: tumor-bearing animals undergoing FUS-mediated hemispheric BBB permeabilization (3.6 × 3.6 mm trajectory covering the whole right hemisphere; quasi-continuous sonication—duty cycle 71%—repeated 36 times and paused between each execution and a moving speed of 10 mm/s; the total sonication time of 115 s [ 28 ]); Group “GBM only”: tumor-bearing animals undergoing the same procedure as group “GBM + FUS“ (anesthesia, surgical procedure, microbubbles injections, SPECT/PET imaging protocols) but without launching the mechanical scan and BBB permeabilization sequence (tumor growth control); Group “FUS only”: healthy animals undergoing FUS-mediated hemispheric BBB permeabilization (BBB opening control). Groups “GBM + FUS” and “GBM only” were imaged for [99mTc]Tc-DTPA, [18F]FDG and [68Ga]Ga-RGD 2 .…”

Low-Intensity Focused Ultrasound Technique in Glioblastoma Multiforme Treatment

“…Trypan Blue ( 74 ), Sodium Fluorescein ( 58 , 73 ), and Nile Blue ( 44 ) are other alternatives that can be used instead of EB. As far as image tracers are concerned there is a variety of them, namely Gd-DTPA (diethylenetriamine penta-acetic acid), superparamagnetic iron-oxide (SPIO) NPs, horseradish peroxidase, lanthanum chloride, ionic manganese, Alexa Fluor 488, Texas-Red-tagged dextran, GFP-tagged dextran, gold nanorods, and 99m Tc-DTPA ( 31 , 83 , 85 ). These tracers can be visualized either by in vivo imaging or other different ways of imaging techniques under the microscope ( 31 ).…”

“…These tracers can be visualized either by in vivo imaging or other different ways of imaging techniques under the microscope ( 31 ). Other emerging techniques include diffusion tensor imaging ( 86 ), bioluminescent imaging for drug uptake (refer to Table 5 ), and PET imaging ( 39 , 60 , 61 , 77 , 83 ). Recently, apart from the existing glucose, mannitol, and inulin derivatives, [ 18 F]2-fluoro-2-deoxy-sorbitol (18FDS) has also been proposed for PET imaging ( 83 ).…”

“…Other emerging techniques include diffusion tensor imaging ( 86 ), bioluminescent imaging for drug uptake (refer to Table 5 ), and PET imaging ( 39 , 60 , 61 , 77 , 83 ). Recently, apart from the existing glucose, mannitol, and inulin derivatives, [ 18 F]2-fluoro-2-deoxy-sorbitol (18FDS) has also been proposed for PET imaging ( 83 ). Another newly used technique in preclinical studies is the change in K trans values, which is short for transfer coefficient from blood to brain extravascular space ( 87 ).…”