Sound conditioning strategy promoting paracellular permeability of the blood-labyrinth-barrier benefits inner ear drug delivery.
Sound conditioning strategy promoting paracellular permeability of the blood-labyrinth-barrier benefits inner ear drug delivery.
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DOI：
10.1002/btm2.10596
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发表时间：
2024-01
影响因子：
7.4
通讯作者：
中科院分区：
文献类型：
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药物的治疗效果取决于其在耳蜗中的药物浓度。从体循环到内耳的有效药物递送受到血迷路屏障（BLB）的限制。本研究调查了一种新的非侵入性声音调节（SC）策略（90 dB SPL，8-16 kHz，2 h声音暴露），以可控的方式暂时增强BLB渗透性，有助于最大限度地提高药物从血液循环到耳蜗的渗透。异硫氰酸黄绿素结合的葡聚糖和牛血清白蛋白（FITC-葡聚糖和FITC-BSA）的运输表明，SC后BLB的细胞旁渗漏持续6 h，为全身给药提供了可控的时间窗。分别通过跨细胞途径和细胞旁途径转运的地塞米松（DEX）和磷酸地塞米松（DEX-P）的耳蜗浓度在SC后显示出后者的含量更高，进一步证实了细胞旁途径在SC诱导的高渗透性中的关键作用。高通量RNA测序的结果确定了一系列紧密连接（TJ）相关基因在SC后。TJ（ZO-1）的表达减少，并通过透射电子显微镜观察到SC后连接的不规则重排。我们进一步确定了Rab 13在ZO-1募集和随后调节细胞通透性中的抑制作用。同时，SC后内皮细胞小窝囊泡的数量没有显著变化，表明细胞转胞吞作用对SC后暂时性高通透性的影响很小。基于这些结果，SC在6 h内增强了BLB的通透性，并允许全身应用的药物易于通过细胞旁途径转运进入内耳，有助于指导听力损失的临床用药。
The therapeutic effects of pharmaceuticals depend on their drug concentrations in the cochlea. Efficient drug delivery from the systemic circulation into the inner ear is limited by the blood‐labyrinth‐barrier (BLB). This study investigated a novel noninvasive sound conditioning (SC) strategy (90 dB SPL, 8–16 kHz, 2 h sound exposure) to temporally enhance BLB permeability in a controllable way, contributing to maximizing the penetration of pharmaceuticals from blood circulation into the cochlea. Trafficking of Fluorescein Isothiocyanate conjugated dextran and bovine serum albumin (FITC‐dextran and FITC‐BSA) demonstrated that paracellular leakage of BLB sustained for 6 h after SC, providing a controllable time window for systemic administration. Cochlear concentrations of dexamethasone (DEX) and dexamethasone phosphate (DEX‐P), respectively transported by transcellular and paracellular pathways, showed a higher content of the latter one after SC, further confirming the key role of paracellular pathway in the SC‐induced hyperpermeability. Results of high‐throughput RNA‐sequencing identified a series of tight junction (TJ)‐associated genes after SC. The expressions of TJ (ZO‐1) were reduced and irregular rearrangements of the junction were observed by transmission electron microscopy after SC. We further determined the inhibiting role of Rab13 in the recruitment of ZO‐1 and later in the regulation of cellular permeability. Meanwhile, no significant change in the quantifications of endothelial caveolae vesicles after SC indicated that cellular transcytosis accounted little for the temporary hyperpermeability after SC. Based on these results, SC enhances the BLB permeability within 6 h and allows systemically applied drugs which tend to be transported by paracellular pathway to readily enter the inner ear, contributing to guiding the clinical medications on hearing loss.
DOI：
10.1083/jcb.200312118
发表时间：
2004-04-26
期刊：
The Journal of cell biology
影响因子：
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作者：
Köhler K;Louvard D;Zahraoui A
通讯作者：
Zahraoui A
DOI：
10.1083/jcb.124.1.101
发表时间：
1994-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Zahraoui A;Joberty G;Arpin M;Fontaine JJ;Hellio R;Tavitian A;Louvard D
通讯作者：
Louvard D