Hugon Gaëlle, Goutal Sébastien, Dauba Ambre, Breuil Louise, Larrat Benoit, Winkeler Alexandra, Novell Anthony, Tournier Nicolas
CEA, CNRS, Inserm, BioMaps, Université Paris-Saclay, 91401 Orsay, France.
CNRS, CEA, DRF/JOLIOT/NEUROSPIN/BAOBAB, Université Paris-Saclay, 91191 Gif-sur-Yvette, France.
Pharmaceutics. 2021 Oct 20;13(11):1752. doi: 10.3390/pharmaceutics13111752.
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 [F]2-fluoro-2-deoxy-sorbitol ([F]FDS) was evaluated as a small-molecule (paracellular) marker of blood-brain barrier (BBB) integrity. [F]FDS was straightforwardly produced from chemical reduction of commercial [F]2-deoxy-2-fluoro-D-glucose. [F]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 ( = 5; < 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 [F]FDS by 2.4 ± 0.8-fold (; < 0.01). Low variability (=10.1%) of values in the sonicated hemisphere suggests reproducibility of the estimation of BBB permeability and FUS method. [F]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.
聚焦超声联合微泡（FUS）为局部增强治疗药物向脑内的递送提供了一种有效手段。需要采用转化和定量成像技术来无创监测和优化FUS对体内血脑屏障（BBB）通透性的影响。使用[F]2-氟-2-脱氧山梨醇（[F]FDS）的正电子发射断层扫描（PET）成像被评估为血脑屏障（BBB）完整性的小分子（细胞旁）标志物。[F]FDS可通过对市售[F]2-脱氧-2-氟-D-葡萄糖进行化学还原直接制得。在设计用于产生可控的半球形血脑屏障破坏的优化FUS方案后，将[F]FDS和侵入性血脑屏障完整性标志物伊文思蓝（EB）静脉注射到小鼠体内。使用动力学模型定量测定FUS对血脑屏障通透性的影响。在超声处理的半球中获得了比PET信号高2.2±0.5倍（ = 5； < 0.01）的信号，并且与死后观察到的EB染色共定位。FUS使[F]FDS的血脑分布显著增加了2.4±0.8倍（； < 0.01）。超声处理半球中 值的低变异性（=10.1%）表明血脑屏障通透性估计和FUS方法具有可重复性。[F]FDS PET提供了一种易于获得、敏感且可重复的血脑屏障通透性标志物，用于无创监测FUS在体内诱导的血脑屏障破坏程度。
