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

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.