Abstract：
Systemic drug administration provides convenience and non-invasive benefits for preventing and treating inner ear diseases. However, the blood-labyrinth barrier (BLB) restricts the transport of drugs to inner ear tissues. Ultrasound can stimulate specific areas and penetrate tissues, with the potential to overcome physiological barriers. We present a novel strategy based on low-pressure pulsed ultrasound assisted by microbubbles (USMB) to transiently open the BLB and deliver therapeutics into the inner ear. A pulsed ultrasound device with adjustable pressure was established; the generated ultrasound was transmitted through the external auditory canal into the guinea pig\'s inner ear. We observed that the application of microbubbles allowed the use of safe and efficient ultrasound conditions to penetrate the BLB. We found that USMB-mediated BLB opening seemed to be associated with a reduced expression of the tight junction proteins zonula occludens-1 and occludin. Following intravenous administration, hydrophilic dexamethasone sodium phosphate (DSP), hydrophobic curcumin (CUR), as well as drug-loaded nanoparticles (Fe3O4@CUR NPs) could be efficiently delivered into the inner ear. We observed better drug accumulation in the perilymph of the inner ear, resulting in less drug (cisplatin)-induced ototoxicity. Furthermore, physiological, hematological, and histological studies showed that the modulation of the BLB by low-pressure USMB was a safe process without significant adverse effects. We conclude that USMB could become a promising strategy for the systematic delivery of therapeutics in the treatment of inner ear diseases.
摘要：
全身给药提供了预防和治疗内耳疾病的便利和非侵入性益处。然而,血液迷宫屏障（BLB）限制药物向内耳组织的运输。超声波可以刺激特定区域并穿透组织，有可能克服生理障碍。我们提出了一种基于微泡（USMB）辅助的低压脉冲超声的新策略，以瞬时打开BLB并将治疗剂输送到内耳。建立了压力可调的脉冲超声装置；产生的超声波通过外耳道传输到豚鼠的内耳。我们观察到，微泡的应用允许使用安全有效的超声条件穿透BLB。我们发现USMB介导的BLB开放似乎与紧密连接蛋白zonulaoccludens-1和occludin的表达降低有关。静脉注射后，亲水性地塞米松磷酸钠（DSP），疏水性姜黄素（CUR），以及载药纳米粒子（Fe3O4@CURNP）可以有效地传递到内耳。我们观察到内耳外淋巴液中有更好的药物积累，导致更少的药物（顺铂）诱导的耳毒性。此外，生理,血液学,组织学研究表明，低压USMB对BLB的调节是一个安全的过程，没有明显的不良反应。我们得出结论，USMB可能成为治疗内耳疾病的系统疗法的有希望的策略。
