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系統識別號 U0026-0812200911420227
論文名稱(中文) 超順磁性奈米粒子在腫瘤表面分子診斷及作為治療用途之評估及應用
論文名稱(英文) The implications of superparamegnetic nano-particle in cancer diagnostics and therapeutics
校院名稱 成功大學
系所名稱(中) 分子醫學研究所
系所名稱(英) Institute of Molecular Medicine
學年度 93
學期 2
出版年 94
研究生(中文) 吳亞娜
研究生(英文) Ya-Na Wu
電子信箱 t1692105@mail.ncku.edu.tw
學號 t1692105
學位類別 碩士
語文別 英文
論文頁數 91頁
口試委員 召集委員-蘇五洲
指導教授-謝達斌
指導教授-葉晨聖
口試委員-陳東煌
中文關鍵字 氧化鐵  癌症  奈米粒子  抗體  核磁共振顯影  肝癌  腫瘤標記  鐵核金殼  選擇性毒殺  口腔癌  鐵離子  自由基  細胞週期 
英文關鍵字 iron core-gold shell  cytostatic  selective cytotoxicity  oral cancer  uptake  cell cycle  anti-cancer  redox  hepatoma  anti-Her2 antibody  MRI  Her2  iron oxide  nanoparticle  iron ion  free radical 
學科別分類
中文摘要   磁性奈米級粒子在癌症診斷及治療上具有很大的發展潛力。診斷方面,我們嘗試發展具特異分子親合性的氧化鐵奈米粒子,作為偵測Her2高表現腫瘤分子之磁共振顯影劑。我們合成表面修飾辨識Her2抗體的奈米粒子,並透過磁性分離及核磁共振顯影評估其在體外及體內試驗對Her2高表現腫瘤的標定能力。而經由磁性分離管柱、普魯士藍染色及穿透式電子顯微鏡的結果共同顯示,該抗體修飾的奈米粒子相較於對照組細胞NIH3T3能高度專一辨識並結合Her2高表現的細胞表面。而相較於對照組細胞NIH3T3細胞及修飾非辨識Her2抗體的奈米粒子之對照組,經表面修飾辨識Her2抗體的奈米粒子標記之GP7TB細胞在T2設定之核磁共振顯影下具有降低訊號強度之負顯影效果。而在大鼠模式動物實驗上,修飾辨識Her2抗體的奈米粒子能聚集在腫瘤邊緣及分佈在正常肝組織中的柯弗氏細胞。在活體核磁共振中則呈現非腫瘤區域訊號強度降低的顯影效果。進一步探討生物匿蹤避免柯佛氏細胞清除將對增加該奈米粒子對於Her2標記顯影之專一性。在利用奈米粒子作為癌症治療策略上,我們的研究發現核心(鐵)-外鞘(金)型奈米顆粒(Fe@Au)相較於正常口腔上皮細胞則能選擇性抑制癌細胞生長,為了更進一步瞭解其背後機轉,用直接細胞計數來評估Fe@Au對於細胞生長的動態發展,並分析Fe@Au影響細胞週期分佈及驅使細胞凋亡或壞死。結果顯示,低劑量Fe@Au(1, 5 μg/ml)抑制細胞生長速度並使得細胞有些微死亡增加的情形;高劑量Fe@Au(50 and 100 μg/ml)則使得細胞大量死亡。然而經分析發現癌細胞或正常細胞吞食奈米粒子的量上並沒有差異,而且二價及三價鐵離子相較於正常細胞對於癌細胞有比較明顯抑制的趨勢,此發現與先前發現之Fe@Au具緩釋鐵離子效應相互呼應。此外,在細胞活性氧化物質(ROS)的進一步評估中,我們發現在高劑量Fe@Au (50 μg/ml)處理後的OECM1相較於hNOK增加了超過三十倍的活性氧化物質。這意謂著Fe@Au可能藉由造成癌細胞及正常細胞活性氧化物質含量的差異性達成癌細胞選擇性傷害的效果,這可能藉由鐵離子本身或奈米粒子本身甚至是兩者共同達成增加活性氧化物質。我們需要更進一步評估其背後的詳細機轉,並發展其他抗癌藥物發展加成毒殺的抗癌應用。
英文摘要  Magnetic nanoparticles possess great potential in cancer diagnostic and therapeutic applications. For cancer diagnostics, we have explored the feasibility for affinity ligand tagged iron oxide nanoparticles as molecular MR imaging tool for Her-2 expressing cancer cells. The anti-Her2 antibody tagged iron oxide nanoparticles were synthesized and characterized and their in vitro and in vivo targeting for cancer cells were evaluated by magnetic column and MRI. The results showed specific targeting of the functionalized nanoparticles to the surface of Her2 expressing GP7TB cells compared to the control NIH3T3 cells as confirmed by magnetic cell separation column, iron stains and TEM. MR imaging of a phantom of ependorf tube array loaded with GP7TB or NIH3T3 cells labeled with anti-Her2 antibody tagged iron oxide nanoparticles or the control non-specific antibody tagged particles revealed specific enhanced reverse T2 weighed MR image signal only in the GP7TB cells incubated with anti-Her2 antibody labeled nanoparticles. In vivo study showed that anti-Her2 antibody tagged nanoparticles accumulate surround the Her2 expression tumor while could also be found to a less degree in the kupffer cells in normal hepatic tissues. Inversed contrast effect in the tumor nodule and the healthy liver tissue was observed under T2* weighed MR imaging sequence. Further study in the biological stealth may assist an improved Her-2 cancer specific molecular imaging. In cancer therapeutic strategy utilizing nanotechnology, we have continued our previous findings that iron core gold shell (Fe@Au) nanoparticle presented significant selective inhibition to the growth of oral squamous cell carcinoma while spare the normal oral keratinocytes. To further understand the underlying molecular mechanisms affected by Fe@Au nanoparticels, a series of functional evaluations were performed. The differential cell count for the dynamic cell growth and death as well as cell cycle analysis together with apoptosis and necrosis analysis were evaluated. Fe@Au exposure induced overall cell growth inhibition and cell cycle retardation at low treatment dose (1, 5 μg/ml), while only slightly increased cell death was observed. However, a strong cytotoxic effect was observed in high dose exposure (50 and 100 μg/ml). The cellular uptake of the nanoparticles was found to be no difference between the cancer and the normal cells. Both ferric and ferrous irons show a preferential growth inhibition to the of OECM1 cancer cells. We have further evaluated the cellular redox status after high dose treatment of Fe@Au (50 μg/ml). More than thirty times higher ROS was observed in OECM1 than hNOK. It is thus imply that Fe@Au may trigger the cytostatic effect through differential enhancement of basal level of the redox activity between cancer cell and normal cell. The altered redox activity could be derived through iron ion induced oxidative stress or the nanoparticle per se or even from both. Further study is required to further elucidate the selectivity for cancer cells and develop new chemotherapeutic and radiotherapy strategies with synergistic action with the nanoparticles.
論文目次 中文摘要................................................................................................i
Abstract..............................................................................................iii
誌謝....................................................................................................v

I.INTRODUCTION..........................................................................................1
1.Nanotechnology........................................................................................1
1.1.The development of Nano era.........................................................................1
1.2.The general characteristics of metallic nanoparticles...............................................2
1.2.1.Surface effect....................................................................................2
1.2.2.Superparamagnetism................................................................................3
1.2.3.Catalytic property................................................................................4
1.2.4.Optical property..................................................................................4
1.3.Nanobiotechnology & bionanotechnology...............................................................5
2.Cancer medicine.......................................................................................7
2.1Cancer...............................................................................................7
2.2Cancer Diagnosis.....................................................................................8
2.2Cancer Therapy.......................................................................................8
2.3The challenges for current tumor diagnosis and therapy...............................................9
2.3.1.The challenges for cancer diagnosis...............................................................9
2.3.2.The challenges for cancer therapy................................................................10
2.4The chance to remedy by nanotechnology..............................................................11
2.4.1.Nanoparticles in MRI.............................................................................11
2.4.2.The Ligand-directed targeting of nanoparticles...................................................12
2.4.3.Development of noninvasive molecular diagnostic tool by MRI......................................13
2.4.4.A novel anticancer drug: nanoparticle per se kills the cancer without further modification.......14

II.Materials and Methods...............................................................................17
Culture of normal oral keratinocytes...................................................................17
Cell lines culture.....................................................................................17
Anti-Her2 antibody production from mice ascites........................................................18
Preparation of iron oxide nanoparticles and antibody conjugation.......................................19
Preparation of superparamagnetic Fe@Au nanoparticles...................................................20
The immunochemistry method to characterize the antibody conjugation on the iron oxide nanoparticles....21
Magnetic column separation of iron oxide conjugated cells..............................................21
Iron stain by Prussian blue staining...................................................................22
The MRI contrast effect of in vitro nanoparticle targeting.............................................22
Hepatoma induction in Rat..............................................................................23
In vivo targeting and imaging..........................................................................24
Cell cycle synchronization.............................................................................24
Cell cycle analysis....................................................................................25
Cell viability assay...................................................................................25
Reactive oxygen species (ROS) analysis.................................................................26

III.Results............................................................................................28
1.Anti-Her2 antibody tagged nanoparticles as MR imaging contrast agent.................................28
1.1.Characterization of the modified nanoparticles.....................................................28
1.2.The in vitro targeting assay by MR imaging.........................................................30
1.3.Rat hepatoma model.................................................................................31
1.4.The in vivo targeting and tracing by MR imaging....................................................31
1.5.Histochemical observation of the in vivo targeting.................................................32
2.Fe@Au Nanoparticles in cancer therapy................................................................33
2.1.The trypan blue exclusion analysis of cell growth..................................................33
2.2.The cancer growth inhibition by Fe@Au nanoparticles................................................33
2.3.The nanoparticle uptake by cancer vs. normal cells.................................................34
2.4.The cytotoxic effect of iron ion to cancer and normal cells........................................35
2.5.The redox status of cell after Fe@Au treatment.....................................................36

IV.Discussion..........................................................................................37

V.References...........................................................................................67

VI.Appendix............................................................................................73

VII.About the author...................................................................................78
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