Imagerie Moléculaire In Vivo, IMIV, Institut des sciences du vivant Frédéric Joliot, Direction de la Recherche Fondamentale, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France; Molecular Imaging Research Center, MIRCen, Institut de Biologie François Jacob, Direction de la Recherche Fondamentale, CEA, Fontenay-Aux-Roses, France.
Neurospin, Institut des sciences du vivant Frédéric Joliot, Direction de la Recherche Fondamentale, CEA, Université Paris Saclay, Gif sur Yvette, France.
J Control Release. 2018 Dec 28;292:210-220. doi: 10.1016/j.jconrel.2018.11.009. Epub 2018 Nov 8.
Overcoming the efflux mediated by ATP-binding cassette (ABC) transporters at the blood-brain barrier (BBB) remains a challenge for the delivery of small molecule tyrosine kinase inhibitors (TKIs) such as erlotinib to the brain. Inhibition of ABCB1 and ABCG2 at the mouse BBB improved the BBB permeation of erlotinib but could not be achieved in humans. BBB disruption induced by focused ultrasound (FUS) was investigated as a strategy to overcome the efflux transport of erlotinib in vivo. In rats, FUS combined with microbubbles allowed for a large and spatially controlled disruption of the BBB in the left hemisphere. ABCB1/ABCG2 inhibition was performed using elacridar (10 mg/kg i.v). The brain kinetics of erlotinib was studied using C-erlotinib Positron Emission Tomography (PET) imaging in 5 groups (n = 4-5 rats per group) including a baseline group, immediately after sonication (FUS), 48 h after FUS (FUS + 48 h), elacridar (ELA) and their combination (FUS + ELA). BBB integrity was assessed using the Evan's Blue (EB) extravasation test. Brain exposure to C-erlotinib was measured as the area under the curve (AUC) of the brain kinetics (% injected dose (%ID) versus time (min)) in volumes corresponding to the disrupted (left) and the intact (right) hemispheres, respectively. EB extravasation highlighted BBB disruption in the left hemisphere of animals of the FUS and FUS + ELA groups but not in the control and ELA groups. EB extravasation was not observed 48 h after FUS suggesting recovery of BBB integrity. Compared with the control group (AUC = 1.4 ± 0.5%ID.min), physical BBB disruption did not impact the brain kinetics of C-erlotinib in the left hemisphere (p > .05) either immediately (AUC = 1.2 ± 0.1%ID.min) or 48 h after FUS (AUC = 1.1 ± 0.3%ID.min). Elacridar similarly increased C-erlotinib brain exposure to the left hemisphere in the absence (AUC = 2.2 ± 0.5%ID.min, p < .001) and in the presence of BBB disruption (AUC = 2.1 ± 0.5%ID.min, p < .001). AUC was never significantly different from AUC (p > .05), in any of the tested conditions. BBB integrity is not the rate limiting step for erlotinib delivery to the brain which is mainly governed by ABC-mediated efflux. Efflux transport of erlotinib persisted despite BBB disruption.
克服血脑屏障 (BBB) 中 ATP 结合盒 (ABC) 转运体介导的外排作用仍然是将小分子酪氨酸激酶抑制剂 (TKI) 如厄洛替尼递送至大脑的挑战。在小鼠 BBB 中抑制 ABCB1 和 ABCG2 可提高厄洛替尼的 BBB 通透性，但在人类中无法实现。聚焦超声 (FUS) 诱导的 BBB 破坏被研究为克服体内厄洛替尼外排转运的策略。在大鼠中，FUS 联合微泡允许在左侧大脑半球中进行大的、空间受控的 BBB 破坏。使用埃拉西达 (10 mg/kg 静脉内) 进行 ABCB1/ABCG2 抑制。使用 C-厄洛替尼正电子发射断层扫描 (PET) 成像在 5 组 (每组 n = 4-5 只大鼠) 中研究厄洛替尼的脑动力学，包括基线组、超声后立即 (FUS)、FUS 后 48 小时 (FUS+48 小时)、埃拉西达 (ELA) 及其组合 (FUS+ELA)。通过 Evans 蓝 (EB) 渗出试验评估 BBB 完整性。通过曲线下面积 (AUC) 测量 C-厄洛替尼在大脑动力学中的脑暴露 (以大脑中的注射剂量百分比 (%ID) 与时间 (分钟) 的关系表示)，分别对应于破坏 (左侧) 和完整 (右侧) 半球。EB 外渗突出显示 FUS 和 FUS+ELA 组动物左侧半球的 BBB 破坏，但在对照和 ELA 组中没有。FUS 后 48 小时未观察到 EB 外渗，表明 BBB 完整性恢复。与对照组 (AUC = 1.4±0.5%ID.min) 相比，物理 BBB 破坏对左侧半球 C-厄洛替尼的脑动力学没有影响，无论是立即 (AUC = 1.2±0.1%ID.min) 还是 FUS 后 48 小时 (AUC = 1.1±0.3%ID.min)。埃拉西达同样增加了 C-厄洛替尼在左侧半球的脑暴露，无论是在不存在 BBB 破坏的情况下 (AUC = 2.2±0.5%ID.min，p < 0.001) 还是在存在 BBB 破坏的情况下 (AUC = 2.1±0.5%ID.min，p < 0.001)。在任何测试条件下，AUC 从未与 AUC 显著不同 (p > 0.05)。厄洛替尼向大脑的递送至脑不是由 ABC 介导的外排作用限制的，而是主要由 ABC 介导的外排作用限制的。尽管 BBB 被破坏，但厄洛替尼的外排转运仍在继续。
