以磁場控制包覆尿激酶之四氧化三鐵奈米粒子應用於血栓清除之研究

本研究是以共價鍵結法(Covalent bonding)將尿激酶鍵結在包附瓊脂之四氧化三鐵奈米粒子表面，形成具有溶血栓功能之磁控奈米粒子，控制一固定磁場及交變磁場相互作用使奈米粒子沿磁力線方向團聚成微米粒子並作旋轉運動，微米粒子作旋轉運動時對環境之流場產生渦流，利用此渦流破壞血栓結構，增加血栓與尿激酶反應之表面積，進而達到快速清除血栓之效果。因四氧化三鐵奈米粒子有高生物相容性、高表面積以及超順磁性等特性，加上磁力控制為一種非侵入式的力量，近年常將四氧化三鐵奈米粒子應用在藥物傳遞。本研究以化學共沉澱法制作包覆瓊脂的四氧化三鐵粒子，其粒徑分布為189 nm，接著使用共價鍵結合法將瓊脂活化後使尿激酶與瓊脂之間產生共價鍵進而固定，經由FTIR的檢測證實尿激酶確實鍵結在磁性奈米粒子上。在磁性粒子控制實驗中，透過永久磁鐵產生靜態磁場將四氧化三鐵磁性奈米粒子磁化後，奈米微粒會團聚並產生平移運動，電磁線圈通以交流電源產生交變磁場環境，使得奈米微粒沿著磁力線作旋轉運動，產生一強制渦流，此強制渦流接觸到血栓表面時因渦流產生之拖曳力將表面的血栓結構破壞。在靜態溶解血栓實驗中，將血栓置於密封樣本瓶內，分別投入尿激酶粉末與包覆尿激酶之磁性奈米粒子，後者另以磁場控制其運動，並針對不同重量之血栓進行溶解速率比較，以磁場控制溶血栓磁性奈米粒子與僅具尿激酶粉末之試體相較，實驗顯示其血栓溶解效率提升了46.6%～51.3%，其原因為能透過磁場控制方式導引溶血栓磁性奈米粒子靠近血栓部位，進而提升血栓附近的藥物濃度加速血栓溶解。在清除血管栓塞之體外模擬實驗中，將血栓放置於寬度800 m之微流管內，使用微幫浦間歇式的注射溶血栓磁性奈米粒子，最高流速為5 l/sec，奈米粒子注入的同時施與交變磁場，固定磁場強度及磁場梯度分別為624 A/m及3.2 T/m，在藥物注入180秒後，約溶解了10.32 mg的血栓，此結果初步證實利用本研究之溶血栓磁性奈米粒子配合磁場控制技術能夠達到快速血栓清除之功能。

關鍵字

四氧化三鐵奈米材料；磁性操控；瓊脂；材料包覆；尿激酶；酵素固定化；血栓清除

並列摘要

This study is develop a magnetic nano-drugs (MND) for thrombus removal. Fe3O4 nanoparticles were prepared by co-precipitation method and coating agarose-gel on the surface. Characterization of synthesized agar@Fe3O4 nanoparticles were analyzed by TEM, VSM and XRD. The agar@Fe3O4 particle size distribution is 16-30 nm. Urokinase was immobilized onto the agar@Fe3O4 nanoparticles by covalent bonding via EDC and Sulfo-NHS. The motion of MND is controlled by a magnetic manipulation system (MMS). The MMS is composed of permanent magnets and an electromagnetic coil. The static magnetic field generated by the permanent magnets will magnetize the nanoparticles to form microparticles, which move in a liquid suspension through a gradient field. The electromagnetic coil connects to an alternating current source thereby producing an oscillating field to rotate the microparticles. The rotation of microparticles can create vortex and shear stress which move nearby micro objects in vortex region. The rotating microparticles will destroy the thrombus surface, which increase the thrombus surface area to react with urokinase. It will increase the thrombolytic rate. In static thrombolytic experiment, the magnetic nano-drugs efficiency of is higher than urokinase about 50%. Because the magnetic nano-drugs can be attract to thrombus by magnet and thus enhance drug concentration near the thrombus. In dynamic thrombolytic experiment, the thrombus placed in the 800 m diameter microchannel. By injecting the nanoparticles on one side of the microchannel and controlling the motion towards the thrombus, maximum flow rate is 5 l/sec. The thrombus was been removed 10.32 mg in 180 sec.

並列關鍵字

Iron oxide ； nanoparticles ； magnetic manipulation ； urokinase ； immobilized enzyme ； thrombus removal

參考文獻

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以磁場控制包覆尿激酶之四氧化三鐵奈米粒子應用於血栓清除之研究

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