非侵入式聚焦超音波結合超音波顯影劑應用於中樞神經系統藥物傳輸之強化與監控

Enhancement and Monitoring of Drug Delivery for CNS with Noninvasive Focused Ultrasound and Ultrasound Contrast Agent

李咏馨(Yung-Shin Lee)

指導教授 ： 林文澧

國立臺灣大學/工學院/醫學工程學研究所/碩士(2009年)

https://doi.org/10.6342/NTU.2009.00480

摘要

根據過去研究指出，利用聚焦式超音波結合超音波顯影劑可以非侵入地開啟特定區域的血腦屏障，達到增加藥物輸送的效果。本研究探討以頻率為1MHz的聚焦型超音波配合超音波顯影劑局部開啟血腦屏障後，在相同位置加入第二次的超音波震盪，其強化Evans Blue (EB)和Self-assemble Iron Oxide Nanocarriers (about 60 nm)輸送的影響。
本研究使用平均380克重的大鼠來進行實驗。將1MHz的聚焦式超音波探頭置於僅經剃毛後的大鼠頭上，參數設定為1Hz重複頻率，50 ms脈衝長度，每次震盪持續時間為60s; 超音波顯影劑劑量為200μl/kg; 壓力場分佈狀態由水診器測量可得，最大值為1.2 MPa。暫時性開啟血腦屏障以及等待超音波顯影劑清除後，注射EB或iron oxide nanocarrier，並且在相同定位點加入第二次的超音波震盪。所有大鼠皆在4小時後犧牲，並將鼠腦取出，以便進行EB/nanocarrier extravasation分析。
在強化組中，Evans Blue的萃取結果為每單位重量腦組織中98.43±35.48 μg，相較於非強化組9.46±2.94 μg有明顯差異。另一方面，也觀察到經強化輸送作用後， Evans Blue和奈米粒子在目標區中的分佈範圍較廣且深。
由實驗結果得知，增加第二次超音波震盪而沒有超音波顯影劑的情況下，確實是可有效地強化Evans Blue和Self-assemble Iron Oxide Nanocarrier 在血腦屏障暫時性開啟之特定區域的滲出量。此研究結果證明，在血腦屏障開啟的有限時間內，經由上述的治療策略，有助於強化藥物輸送，達到有效治療的目的。

關鍵字

聚焦式超音波 ； 超音波顯影劑 ； 血腦屏障 ； 強化藥物輸送 ； 奈米粒子

並列摘要

Previous studies showed that focused ultrasound (FUS) with ultrasound contrast agent (UCA) could non-invasively open blood-brain barrier of targeted region to do local drug delivery. In this study, we investigated the effects of ultrasound sonication on the delivery enhancement of Evans Blue (EB) and iron oxide nanocarriers (about 60 nm) into rat brain after the blood-brain barrier was temporarily opened by FUS with UCA. Wistar rats averaging about 380g were used in this study and the hair on their heads was removed thoroughly. After an intravenous injection of microbubbles (200μl/kg, Artison, Artison Corp., Inola, USA), 1.0 MHz focused ultrasound was immediately sonicated through the skull to the target region at 1.2 MPa pressure, 50ms burst length, 1 Hz repetition frequency, and 60s duration, to disrupt the blood-brain barrier. Ten minutes later, EB and/or iron oxide nanocarrier were injected, and then a second sonication was exposed at the same location. All rats were sacrificed about 4 hrs after the second sonication. The brains were removed and sectioned for extraction and detection of EB/nanocarrier extravasation and distribution. The results of EB extraction showed that the density of EB in the brains with a second sonication is 98.43±35.48μg/ (g of brain tissue) compared to 9.46±2.94μg/g for those without a second sonication. The spatial distributions of EB stain and fluorescent dye (Fluorescein isothiocyanate, FITC) for nanocarrier in the sonicated regions showed that a larger and much deeper region was produced for the cases with a second sonication. A second sonication without the injection of microbubbles can effectively enhance the delivery of molecules (EB) and nanoparticles (iron oxide nanocarrier) into the region with BBB temporarily disrupted. It indicated that this sonication strategy is potentially employed to improve the drug delivery within a limited duration.

並列關鍵字

focused ultrasound ； ultrasound contrast agent ； blood-brain barrier ； enhanced drug delivery ； nanoparrticles

參考文獻

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