Low-Intensity Ultrasound Facilitation of Intranasal Drug Delivery to Olfactory Bulb and Trigeminal Nerves

IF 2.4 3区医学 Q2 ACOUSTICS

Ultrasound in Medicine and Biology Pub Date : 2025-02-02 DOI:10.1016/j.ultrasmedbio.2025.01.003

Meng-Ting Lin , Tsai-Yun Chan , Wei-Hao Liao , Chueh-Hung Wu , Tai-Horng Young , Wen-Shiang Chen

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引用次数: 0

Abstract

Objective

Nasal-to-brain (NtoB) delivery is a noninvasive approach that uses the nasal cavity as a pathway to transport therapeutic agents directly to the brain. This approach bypasses systemic circulation and avoids the blood-brain barrier (BBB). Transcranial ultrasound, coupled with microbubbles (MB), is a technique used to oscillate and generate acoustic cavitation to open the capillary tight junctions of BBB temporarily. Its efficacy in facilitating NtoB delivery has been demonstrated in vivo. However, while opening the BBB, sonication with MB poses the risk of cerebral microhemorrhage or brain tissue damage due to sonication-induced physical injury. This study aimed to assess the effectiveness of low-intensity ultrasound treatment to facilitate NtoB delivery in a mouse model without using MB.

Methods

In this study, 10-kDa dextran was administered intranasally (IN), and transcranial planar US was applied to the entire mouse brain without MB assistance. Ex-vivo whole brain imaging via fluorescence macroscopy, brain slice analysis with fluorescence microscope, and quantification of dextran concentration in distinct brain regions were conducted to compare the IN-only, IN combined with US (IN+US), and sham groups. For the trigeminal nerves (TN), fluorescence macroscopy, microscopy, and TN concentration quantification were performed to compare the three groups.

Results

Whole brain imaging revealed that US facilitated the IN delivery of dextran to the olfactory bulb (OB) in the IN+US group compared with that in the IN-only and sham groups; however, this difference was not observed after a 24 h follow-up. Conversely, brain slice images showed that the tracer was delivered to the OB, cerebral cortex, striatum and brainstem in the IN+US group, but this finding was not observed in the IN-only group at the 4 h mark. The quantification of fluorescence intensity at two follow-up time points revealed no significant difference between the IN and IN+US groups in these specific regions. Dextran concentration analysis for distinct brain areas and TN showed that ultrasound significantly increased the tracer concentration delivered to the OB and TN in the IN+US group at the 4 h mark compared with that in the IN-only and sham groups; however, this effect was not sustained at 24 h. Confocal microscopy indicated that the dextran tracer accumulated in the perivascular space along the microvascular structures.

Conclusion

We demonstrated the efficacy of low-intensity ultrasound without using MB, in enhancing nose-to-OB and nose-to-TN drug delivery, and proposed the potential for future clinical application. Thus, we showed that this approach was safe, without evidence of microhemorrhage or brain tissue damage.

查看原文本刊更多论文

低强度超声促进鼻内给药对嗅球和三叉神经的作用。

目的：鼻到脑（NtoB）给药是一种无创的方法，它利用鼻腔作为通道将治疗剂直接输送到大脑。这种方法绕过体循环，避免血脑屏障（BBB）。经颅超声结合微泡（MB）是一种通过振荡产生声空化来暂时打开血脑屏障毛细血管紧密连接的技术。其促进NtoB递送的功效已在体内得到证实。然而，在打开血脑屏障的同时，用MB进行超声检查有因超声引起的物理损伤而导致脑出血或脑组织损伤的风险。本研究旨在评估低强度超声治疗在不使用MB的小鼠模型中促进NtoB递送的有效性。方法：在本研究中，10-kDa葡聚糖经鼻给药（in），经颅平面US在无MB辅助的情况下应用于小鼠全脑。采用荧光宏观离体全脑成像、荧光显微镜脑切片分析、不同脑区葡聚糖浓度定量比较in -only组、in联合US （in +US）组和sham组。对三叉神经（TN）进行荧光宏观、显微镜观察和TN浓度定量比较。结果：全脑成像显示，与IN组和假组相比，IN+US组的US促进了右旋糖酐向嗅球（OB）的传递；然而，在24小时的随访后没有观察到这种差异。相反，脑切片图像显示，在in +US组，示踪剂被递送到OB、大脑皮层、纹状体和脑干，但在in - US组，在4小时时没有观察到这一发现。两个随访时间点的荧光强度定量显示，IN组和IN+US组在这些特定区域无显著差异。不同脑区和TN的右旋糖酐浓度分析显示，超声在4 h时显著增加了in +US组OB和TN的示踪剂浓度，与in组和sham组相比；然而，这种作用在24小时后并没有持续。共聚焦显微镜显示，葡聚糖示踪剂沿着微血管结构在血管周围空间积累。结论：我们证明了不使用MB的低强度超声在增强鼻到ob和鼻到tn的药物传递方面的有效性，并提出了未来临床应用的潜力。因此，我们证明这种方法是安全的，没有微出血或脑组织损伤的证据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Ultrasound in Medicine and Biology 医学-核医学

CiteScore

6.20

自引率

6.90%

发文量

325

审稿时长

70 days

期刊介绍： Ultrasound in Medicine and Biology is the official journal of the World Federation for Ultrasound in Medicine and Biology. The journal publishes original contributions that demonstrate a novel application of an existing ultrasound technology in clinical diagnostic, interventional and therapeutic applications, new and improved clinical techniques, the physics, engineering and technology of ultrasound in medicine and biology, and the interactions between ultrasound and biological systems, including bioeffects. Papers that simply utilize standard diagnostic ultrasound as a measuring tool will be considered out of scope. Extended critical reviews of subjects of contemporary interest in the field are also published, in addition to occasional editorial articles, clinical and technical notes, book reviews, letters to the editor and a calendar of forthcoming meetings. It is the aim of the journal fully to meet the information and publication requirements of the clinicians, scientists, engineers and other professionals who constitute the biomedical ultrasonic community.