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研究生：	楊雅涵 Yang, Ya-Han
論文名稱：	製備磁性奈米粒子作為藥物載體 Preparation of Magnetic Nanoparticles as Drug Carriers
指導教授：	蕭世裕 none
學位類別：	碩士 Master
系所名稱：	生物科學與科技學院 - 生物科技研究所 Institute of Biotechnology
論文出版年：	2007
畢業學年度：	95
語文別：	中文
論文頁數：	116
中文關鍵詞：	尿激酶、磁性奈米粒子、紫杉醇
外文關鍵詞：	Magnetic nanoparticles, Paclitaxel, Urokinase
相關次數：	點閱：101 下載：12
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本篇論文主要的研究方向是利用磁性奈米顆粒作為藥物載體之應用，分為兩部份探討，其一是將磁性奈米粒子作為抗血栓藥物之載體(MN-UK)，另外則是將磁性奈米粒子作為紫杉醇藥物載體之應用。
在磁性奈米粒子之抗血栓藥物載體(MN-UK)研究方面，由多種儀器鑑定我們所製備出之磁性奈米載體其平均直徑為45 nm，為四氧化三鐵之尖晶石構型，具有超順磁特性，以及表面帶有maleimide修飾之官能基。將基因重組人類尿激酶(UK)以thiol ether鍵結方式與磁性奈米粒子(MN)結合，製備出一種新型的抗血栓藥物(MN-UK)，在酵素活性試驗中，發現與MN-UK其Km=1.2 mM，Kcat=203 sec-1。在細胞毒性測試發現MN-UK對於3T3細胞沒有明顯的細胞毒性。於體外血栓穿透實驗與體內血栓溶解實驗結果顯示，MN-UK可藉由外加磁場引導至血栓堵塞處並有效的溶解血栓，證明MN-UK在活體內確實可以達到較快速溶解血栓之效果。
在紫杉醇磁性奈米粒子研究方面，因磁性載體具有高的比表面積，所以只需微量之磁性載體即可乘載大量的紫杉醇藥物，由MTT試驗中證明磁性載體本身對於腫瘤細胞不具有毒性，一旦乘載紫杉醇藥物後之磁性奈米粒子可對腫瘤細胞產生毒性，並可藉由磁場引導至特定腫瘤細胞區域做局部毒殺。

The goal of this research is to prepare magnetic nanoparticles as drug carriers. Two kinds of drug were used in this study. The first one is human urokinase (UK) and the second one is Paclitaxel. UK was immobilized to magnetic nanoparticles via a thiol ether linkage while Paclitaxel was adsorbed to the magnetic nanoparticles through hydrophobic interaction. Magnetic nanoparticles Fe3O4 coated with 1,6 hexane diamine were prepared
by polyol reduction method and they were further reacted with
N-succinimidyl- 3-maleimidopropionate (NSMP) to obtain maleimide coated magnetic particle. A recombinant thrombin-activable human prourokinase was activated with thrombin to obtain urokinase (UK), and it was subsequently reduced with a reducing agent (TCEP) and immobilized onto maleimide coated magnetic nanoparticles through a thiol ether linkage to obtain the magnetic nanoparticles bound UK (MN-UK).
Transmission electron microscopy (TEM) showed that the particles were with a mean diameter of 45 nm. X-ray diffraction patterns indicated that both the particles with or without UK were pure Fe3O4. Fourier transform infrared (FTIR) spectroscopy patterns confirmed the maleimide functional group bound to the particles. Measurement of the protein content revealed that the weight ratio of UK to the particles was 0.129 which was about 300 UK molecules per particle. The enzyme activity analysis results showed that the immobilized UK retained 67 % of its original activity. The kinetic constants of the MN-UK was Km=1.2 mM and Kcat=203 min-1. In an in vitro thrombolysis experiment using external magnet to guide MN-UK, the lysis rate of MN-UK was seven fold faster than that of free UK. Cytotoxicity assay reveals that MN-UK is non-cytotoxic to 3T3 cells. An experimental rat model of arterial thrombosis was induced by ferric chloride and thrombolysis was induced by MN-UK or UK. The pathological sections were performed for observation of the occlusion and thrombolysis of the blood vessel. The result demonstrated that MN-UK lysed the thrombus more efficient than UK alone. In conclusion, we have prepared a novel thrombolytic agent (MN-UK) that can be concentrated and localized to a thrombus site by an external magnet and perform efficient lysis of a thrombus.
Paclitaxel-loaded MN was prepared by adsorption of Paclitaxel into MN in an optimum condition (in 20% ethanol and at room temperature for two days). High performance liquid chromatography was used to measure the drug encapsulation efficiency and in vitro drug release profile. Average of 2,674 Paclitaxel molecules was adsorbed to each MN particle and 50% of adsorbed Paclitaxel was released into saline phosphate buffer in 3 days. Paclitaxel-loaded MN can be targeted by external magnet and release Paclitaxel on site to kill MBT-3 tumor cells. This result is the first report to use magnetic nanoparticles to deliver Paclitaxel.

目錄
中文摘要----------------------------------------------------Ⅰ
英文摘要----------------------------------------------------Ⅱ
誌謝--------------------------------------------------------Ⅴ
目錄--------------------------------------------------------Ⅵ
表目錄------------------------------------------------------Ⅹ
圖目錄----------------------------------------------------ⅩⅠ
附錄------------------------------------------------------ⅩⅢ



第一章	  緒論-------------------------------------------------1
第二章　磁性奈米粒子之抗血栓藥物載體製備與應用--------------27
一. 研究動機------------------------------------------------27
二. 實驗方法------------------------------------------------27
    2.1 化學藥品--------------------------------------------27
    2.2 實驗儀器--------------------------------------------29
2.3 製備磁性奈米粒子------------------------------------31
2.4 磁性奈米粒子之性質鑑定------------------------------31
2.5 製備表面帶有maleimide官能基之磁性奈米粒子----------34
2.6  NSMP（N-succinimidyl-3-maleimidopropionate）之鑑定-36
    2.7 磁性奈米粒子表面胺基檢測----------------------------37
    2.8 蛋白質定量方法--------------------------------------39
    2.9 以Throbinm與TCEP還原UK之十二烷基硫酸鈉
-聚丙烯酰胺凝膠電泳分析-----------------------------40
    2.10  MN-UK固定化效率分析-------------------------------42
    2.11  MN-UK比活性測定-----------------------------------43
    2.12  MN-UK酵素動力學-----------------------------------45
    2.13  MN-UK溶解血纖維蛋白Fibrinogen之測定--------------45
    2.14  MN-UK溶解血栓之測定-------------------------------46
    2.15  MN-UK之生物相容性(MTT assay)----------------------46
    2.16  MN-UK之血栓動物模型評估---------------------------47
三. 結果與討論----------------------------------------------48
　　3.1 磁性奈米粒子之大小、型態鑑定------------------------48
3.2 磁性奈米粒子之內部晶型結構鑑定----------------------48
3.3 磁性奈米粒子之磁性鑑定------------------------------49
3.4 磁性奈米粒子之密度量測(Density Measurement)---------50
3.5 NSMP（N-succinimidyl-3-maleimidopropionate）之鑑定--51
3.6 磁性奈米粒子表面成分鑑定----------------------------51
3.7 磁性奈米粒子表面胺基的檢測--------------------------52
3.8 以Throbinm與TCEP還原UK之十二烷基硫酸鈉
-聚丙烯酰胺凝膠電泳分析-----------------------------52
3.9 固定化效率分析--------------------------------------53
3.10 MN-UK比活性分析------------------------------------54
3.11 MN-UK酵素動力學------------------------------------54
3.12 MN-UK溶解血纖維蛋白Fibrinogen之測定---------------54
3.13 MN-UK溶解血栓之測定--------------------------------55
3.14 MN-UK之生物相容性(MTT assay)-----------------------55
3.15 MN-UK之血栓動物模型評估----------------------------56
四. 結論----------------------------------------------------57
第三章  紫杉醇磁性奈米粒子之製備與應用----------------------58
一. 研究動機------------------------------------------------58
二. 實驗方法------------------------------------------------58
    2.1 化學藥品--------------------------------------------58
    2.2 實驗儀器--------------------------------------------58
2.3 製備磁性奈米粒子包覆紫杉醇藥物----------------------59
2.4 紫杉醇定量------------------------------------------59
2.5 細胞毒性試驗----------------------------------------60
2.6 細胞型態觀察----------------------------------------60
三. 結果與討論----------------------------------------------61
3.1 磁性奈米粒子之大小、型態鑑定------------------------61
3.2 紫杉醇磁性奈米粒子製備------------------------------61
3.3 紫杉醇磁性奈米粒子藥物釋放動力學--------------------62
3.4 紫杉醇磁性奈米粒子細胞毒性試驗----------------------62
3.5 紫杉醇磁性奈米粒子針對特定區域細胞毒殺之型態觀察----62
四. 結論----------------------------------------------------63
第四章  總結------------------------------------------------65
參考文獻----------------------------------------------------67







表目錄

表一、磁性奈米粒子的各種磁性數據----------------------------50
表二、磁性奈米粒子密度量測結果------------------------------50














圖目錄

圖一、(a)溶劑熱還原法磁性奈米粒子、(b)MN-UK磁性奈米粒子之SEM   
      照片-------------------------------------------------78
圖二、溶劑熱還原法磁性奈米粒子之TEM照片和粒徑分布圖-------79
圖三、(a) 溶劑熱還原法磁性奈米粒子、(b)MN-UK磁性奈米粒子之XRD 圖形---------------------------------------------------80
圖四、(a)溶劑熱還原法磁性奈米粒子、(b)MN-UK磁性奈米粒子之磁滯曲線---------------------------------------------------81
圖五、NSMP之1H-NMR圖譜------------------------------------82
圖六、NSMP 之HPLC圖譜--------------------------------------83
圖七、(a) 溶劑熱還原法磁性奈米粒子、(b)帶有maleimide官能基之磁性奈米粒子之傅立葉紅外光光譜儀 (FTIR)圖譜------------84

圖八、蛋白質電泳圖。探討Thrombin切割pro-UK之最佳條件-----85
圖九、蛋白質電泳圖。探討TCEP還原UK之最佳條件-------------86
圖十、UK固定化效率與時間之關係圖---------------------------87
圖十一、UK濃度與固定化效率之關係圖-------------------------88
圖十二、MN-UK溶解血纖維蛋白Fibrinogen之測定---------------89
圖十三、不同時間下(a)UK、(b)MN-UK、(c)MN及(d)MN with UK在外
        加磁場(底部)穿透血栓之照片-------------------------90
圖十四、不同濃度的UK、MN、及MN-UK對3T3細胞之毒性測試驗--92
圖十五、大鼠血管栓塞及溶解之組織切片圖---------------------93
圖十六、紫杉醇磁性奈米粒子之SEM照片-----------------------94
圖十七、紫杉醇在不同酒精濃度條件吸附至磁性奈米粒子之吸附效率圖
        ---------------------------------------------------95
圖十八、在生理食鹽水中紫杉醇磁性奈米粒子藥物釋放出紫杉醇之速率圖-------------------------------------------------96
圖十九、不同濃度之紫杉醇毒殺老鼠膀胱腫瘤細胞之關係圖-------97
圖二十、不同濃度紫杉醇磁性奈米粒子毒殺老鼠膀胱腫瘤細胞之關係圖
        ---------------------------------------------------97
圖二十一、不同濃度磁性奈米粒子毒殺老鼠膀胱腫瘤細胞之關係圖-97
圖二十二、利用光學顯微鏡觀察紫杉醇磁性奈米粒子定點毒殺MBT-2細胞
          -------------------------------------------------98
圖二十三、利用螢光顯微鏡觀察紫杉醇磁性奈米粒子定點毒殺MBT-2細胞之細胞核-----------------------------------------99
圖二十四、尿激酶磁性奈米粒子圖示--------------------------100

附錄

附表一、奈米粒子製造技術------------------------------------101
附表二、以液相法製造奈米粒子之分類	-------------------------102
附表三、製備鐵奈米粒子方法之比較----------------------------103
附表四、體內參與血栓溶解的成分「24」----------------------------104
附表五、抗凝血劑依作用機轉不同可以分為以下三類--------------105
附圖一、磁滯曲線--------------------------------------------106
附圖二、血栓形成的過程--------------------------------------107
附圖三、體內溶解血栓機制------------------------------------108
附圖四、t-PA與u-PA溶解血栓機制-----------------------------109
附圖五、proUK與proUK-MU結構之差異---------------------------110
附圖六、藥物通過細胞膜的方式--------------------------------111
附圖七、奈米材料與生物組織間可能發生的機制------------------112
附圖八、Paclitaxel化學結構式--------------------------------113
附圖九、Bragg 繞射原理圖------------------------------------114
附圖十、s-2444結構圖---------------------------------------115
附圖十一、Fe3O4尖晶石( spinel structure )的構形-------------116
                                    

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