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研究生:林曉蘋
研究生(外文):Hsiao Pin Lin
論文名稱:磁導組織型胞漿素原活化劑於大鼠缺血性中風模型溶解血栓之效價
論文名稱(外文):Magnetically Guided Recombinant Tissue Plasminogen Activator for Target Thrombolysis in a Rat Ischemic Stroke Model
指導教授:馬蘊華
指導教授(外文):Y. H. Ma
學位類別:碩士
校院名稱:長庚大學
系所名稱:生物醫學研究所
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
論文頁數:100
中文關鍵詞:栓塞磁性奈米粒子血栓溶解
外文關鍵詞:emoblicmagnetic nanoparticlethrombolysis
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重組型組織性胞漿素原活化劑(rtPA)為急性缺血性中風之臨床治療藥物,但具有出血的風險。以磁性奈米粒子(MNP)作為攜藥分子可在外部磁場的導引下達到標靶給藥的目的,以增加局部藥物濃度。然而,此治療方針尚未與rtPA結合應用於中風模型。在此,我們以大鼠栓塞性中風模型測試以磁導給予rtPA是否能夠以較低劑量達到血栓溶解效果。利用共價鍵結將rtPA固定於表面包覆聚丙烯酸(PAA)的MNP後,形成粒徑366 nm的複合物並仍保有原活性之91%。我們將一個混合靛氰綠(ICG)的血栓(1×1 mm)經由大鼠右側外頸動脈注入血管,並在遠紅外線攝影機追蹤下嵌入內頸動脈,此時以雷射都卜勒血流計(laser doppler flowmetry)測得右腦表層血流下降至基準值之32 ± 7%且可穩定維持三小時,而左側腦血流則相對穩定,其差別在雷射都卜勒血流影像及磁振造影中亦能顯現。利用此動物模型,在注入血栓5分鐘後於外頸動脈給予rtPA 1 mg/kg,則能於55及175分鐘後使右側腦血流回復至基準值之66 ± 14%及 89 ± 12% (n=7)。在1.58 kG的磁鐵於內頸動脈來回往復導引下,給予攜有等同於0.1 mg/kg rtPA劑量的MNP,則可使右側腦血流於35及175分鐘後回復至基準值之66 ± 21% 及70 ± 18% (n=7)。上述結果顯示,磁導標靶給藥的方式能夠以小於常規劑量10%的rtPA使血栓溶解並改善腦部灌流。
Recombinant tissue plasminogen activator (rtPA) is used for acute ischemic stroke therapy with high incidence of hemorrhagic side effect. Magnetic nanoparticles (MNP) may serve as drug carriers for target therapeutics under the guidance of an external magnetic field to increase local drug concentration and reduce systemic distribution. However, the strategy has never been tested with rtPA in a stroke model. We asked whether magnetic target delivery of rtPA allows less drug administered with similar efficacy in a rat embolic stroke model. The rtPA was immobilized to polyacrylic acid-coated MNP (95 nm) by covalent binding with 91% of its amidolytic activity reserved. In anesthetized rat, right internal carotid artery (ICA) was occluded by injection of a 1×1 mm whole blood clot containing indocyanine green (ICG), allowing visualization of the clot lodging in the artery. Right cerebral blood flow (CBF) was then reduced to 32 ± 7% of basal and remained stable for 3 hr, as revealed by laser Doppler flowmetry; the difference in perfusion of left and right hemispheres was also observed with laser Doppler imaging and magnetic resonance imaging. Free rtPA of 1 mg/kg administrated 5 min after introducing the clot restored right CBF to 66 ± 14% and 89 ± 12% of basal at 55 and 175 min after administration. (n=7). With a 1.58 kG magnet moving back and forth along ICA, MNP-rtPA with rtPA equivalent to 0.1 mg/kg restored right CBF to 66 ± 21% and 70 ± 18% of basal at 35 and 175 min after administration. (n=7). Target delivery of rtPA with MNP may achieve reproducible and effective thrombolysis with <10% of a regular dose of rtPA.
一、 緒論(Introduction)
1.1缺血性中風...............................................1
1.2.血栓的形成與溶解.........................................................2
1.2.1血栓形成之機制.........................................................2
1.2.2 血栓溶解之機制........................................5
1.2.3 胞漿素原的活化.........................................................6
1.3 缺血性中風的血栓溶解藥物-rtPA.............................8
1.4. 栓塞性中風之動物模型........................................................10
1.5. 奈米粒子的醫學應用........................................................11
1.5.1 不同種類之奈米粒子....................................12
1.5.2 MRI診斷............................................14
1.5.3 腫瘤熱治療...........................................16
1.5.4 標靶給藥.............................................17
二、 實驗目的 (Specifice aims) .........................21
三、 實驗材料與方法(Materials and Methods)..............22
實驗材料..................................................22
實驗方法..................................................23
3.1磁性奈米粒子結合血栓溶解藥物..............................23
3.1.1 固定化酵素...........................................23
3.1.2 蛋白質分析...........................................23
3.1.3 活性分析.............................................24
3.1.4 Toluidine Blue O (TBO)分析..........................24
3.1.5粒徑分析..............................................25
3.2動物模型與血管模擬系統...................................25
3.2.1血管模擬系統..........................................25
3.2.2 大鼠的預備及手術......................................25
3.2.3雷射都卜勒及絕對血流血流偵測............................28
3.2.4 雷射都卜勒血流影像....................................30
3.3 磁振造影...............................................30
3.4 分析及統計方法.........................................32
四、 實驗結果...........................................34
4.1磁性奈米粒子表面之羧基量..................................34
4.2 rtPA於磁性奈米粒子上之固定量............................34
4.3 rtPA於磁性奈米粒子固定後之酵素活性......................35
4.4 磁性奈米粒子之粒徑分析.................................35
4.5 血管模擬系統..........................................35
4.6 建立大鼠栓塞中風模型...................................36
4.7 rtPA於大鼠栓塞中風模型中之血栓溶解效果...................37
4.8 磁導給藥於大鼠栓塞中風模型中之血栓溶解效果................39
4.9 磁性奈米粒子於腦中之分布................................42
五、討論...................................................43
5.1磁性奈米粒子之特性.......................................43
5.2 大鼠缺血性中風模型.....................................44
5.3 rtPA於大鼠栓塞中風模型之血栓溶解效果.....................47
5.4 磁導給藥於大鼠栓塞中風模型之血栓溶解效果..................48
5.5 磁性奈米粒子於腦中之分布................................49
六、結論 (Conclusion)…………………………………………………54
參考文獻 (Reference)………………………………………………55
表格……………………………………………………………………...66
圖表說明 (Figure legends)……………………………………………..67
圖表 (Figures)…………………………………………………………..70
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