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博碩士論文 etd-0612114-005137 詳細資訊
Title page for etd-0612114-005137
論文名稱
Title
使用寡核苷酸及奈米材料開發高靈敏度及高選擇性的螢光感測器
Development of oligonucleotides and nanoparticles-based fluorescent sensor for highly sensitive and selective detection of target analyte
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
130
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2014-07-08
繳交日期
Date of Submission
2014-07-12
關鍵字
Keywords
Tween-20金奈米粒子、腺苷、Fe3O4奈米粒子、鹼性磷酸酶、BODIPY-ATP、肝素、Coralyne、Polyadenosine
BODIPY-ATP, Heparin, Adenosine, Fe3O4 nanoparticles, Tween 20-gold nanoparticles, Alkaline Phosphatase, Coralyne, Polyadenosine
統計
Statistics
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中文摘要
(一) 以Polyadenosine-Coralyne錯合物作為螢光探針偵測人類血漿中的肝素
  肝素(Heparin)是一種具有多負電荷的多醣體分子,在臨床上常作為心血管手術中的抗凝血劑,或者用於治療急性冠心症和預防靜脈血栓塞的發生。在心血管手術中所使用的劑量大約為17~67 μM;而治療用的劑量大約為1.7~10 μM,若使用過量會造成出血或是血小板減少的症狀,因此開發一個準確的偵測方法來監控肝素含量是相當重要的。本實驗藉由A20-coralyne錯合物並透過螢光消光的方式對Heparin進行偵測。在含有A20的溶液中,Coralyne會誘導A(Adenine)與A之間形成穩定的A2-corlayne-A2錯合物,導致Coralyne在中性環境下產生螢光增強的現象,若溶液中存在Heparin時,由於它具有多負電荷,因此可藉由靜電作用力使帶有正電荷的Coralyne從A20-coralyne錯合物結構中置換出來並形成二聚體,當Coralyne形成二聚體時會產生消光現象,藉由此螢光下降值來對Heparin進行定量分析,此探針具有高靈敏性、選擇性並且成功應用於血漿樣品中Heparin的定量。
(二) 以BODIPY-ATP結合Fe3O4奈米粒子作為螢光探針偵測鹼性磷酸酶
  鹼性磷酸酶(Alkaline phosphatase,ALP)是一種可透過其磷酸單脂的水解,將受質分子上的磷酸基團去除的酵素,大量存在於生物體中,目前主要應用在分子生物學、免疫分析或是在工業上作為檢驗牛奶中巴斯滅菌的標誌,因為其在自然界的豐富性,ALP的活性已是在生物系統中最為普遍的酵素測試。本實驗以BODIPY-ATP螢光分子結合Fe3O4奈米粒子為基礎並透過螢光回復的方式對ALP進行偵測,當溶液存在Fe3O4奈米粒子時,BODIPY-ATP上的三磷酸結構會與奈米粒子表面上的Fe2+與Fe3+進行共價性鍵結,藉由光誘導電子轉移(PET)產生消光現象。若溶液中含有ALP,會將BODIPY-ATP結構中的三磷酸基團進行水解,使BODIPY-ATP無法與Fe3O4奈米粒子進行鍵結,因此隨著ALP的酵素活性增加,溶液中自由的BODIPY量變多,螢光訊號也會隨之回復,因此藉由螢光回復值來對ALP的活性進行定量分析。
(三) 以BODIPY-ATP結合Tween-20金奈米粒子偵測人類尿液中的腺苷
  腺苷(Adenosine)分別由核醣與腺嘌呤的一部分所組成,在生物學上扮演其重要角色,包括信號傳遞及神經系統調節劑,最近更發現有刺激大腦的作用,可緩解帕金森氏症及其他腦病患者的症狀,因此檢測腺苷是十分具有意義的。本實驗是以Tween-20金奈米粒子與BODIPY-ATP為基礎並透過螢光消光的方式,對Adenosine進行偵測。當Tween-20金奈米粒子與BODIPY-ATP反應時,會因為奈米粒子表面能量轉移(NSET)消光機制,使BODIPY-ATP產生消光現象。由於BODIPY-ATP結構中的磷酸基團與Tween-20金奈米粒子表面上的檸檬酸基團彼此之間存在靜電排斥力,當Tween-20金奈米粒子溶液中含Adenosine時,帶正電荷的Adenosine會吸附於表面帶負電的Tween-20金奈米粒子並使表面電荷趨於電中性,此時BODIPY-ATP與Tween-20金奈米粒子之間的靜電排斥力減少,彼此間距離更加靠近,使NSET所產生的消光現象更加顯著,則螢光下降量增加,因此可藉由螢光下降量來對Adenosine進行定量分析,此探針具有高靈敏性、選擇性並且成功應用於尿液樣品中Adenosine的定量分析。
Abstract
(a) A Polyadenosine-Coralyne Complex as a Novel Fluorescent Probe for Sensitive and Selective Detection of Heparin in Plasma
  This study presents the development of a simple, label-free, sensitive, and selective-detection system for heparin based on the use of a complex of 20-repeat adenosine (A20) and coralyne. Coralyne emitted relatively weak fluorescence in an aqueous solution. Upon the addition of A20, coralyne molecules were placed into A20 through the A2-coralyne-A2 coordination. An increase in the fluorescence of coralyne was observed because coralyne stayed away from water in the hydrophobic environment of the folded A20. The presence of heparin forced coralyne to remove from the A20-corlayne complex as a result of the formation of the coralyne-heparin complex. Because heparin promoted coralyne dimerization, the fluorescence of coralyne decreased as a function of the concentration of added heparin. This detection method is effective because the electrostatic attraction between heparin and coralyne is much stronger than the coordination between A20 and coralyne. Under optimal conditions, the heparin selectivity of this probe is approximately 100-fold over hyaluronic acid and chondroitin sulfate. The probe’s detection limit for heparin was determined to be 4 nM. This study validates the practicality of the A20-corlayne complex to determine heparin in plasma.
(b) Fe3O4 Nanoparticles-induced Fluorescence Quenching of Adenosine Triphosphate-BODIPY Conjugates:Application to Alkaline Phosphatase.  
This study report that Fe3O4 Nanoparticles act as an efficient quencher for BODIPY-ATP that is highly fluorescent in bulk solution. BODIPY-ATP molecules attached to the surface of Fe3O4 NPs through the coordination between the triphosphate group of BODIPY-ATP and Fe(3+)/Fe(2+) on the NP surface. The formed complexes induced an apparent reduction in the BODIPY-ATP fluorescence, because of an oxidative-photoinduced electron transfer (PET) from the BODIPY-ATP excited state to an unfilled d shell of Fe(3+)/Fe(2+) on the NP surface. Because alkaline phosphatase can hydrolyzes the triphosphate group of BODIPY-ATP, the hydrolyzed BODIPY-ATP was incaple of binding onto Fe3O4 NPs. As a result, the presence of alkaline phosphatase restore the fluorescence of BODIPY-ATP; the detection limits at a signal-to-noise ratio of 3 alkaline phosphatase were determined to be 0.2 pM. The selectivity of this assay for other enzyme and protein is particularly high.
(c) Tween 20-Stabilized Gold Nanoparticles Combined with Adenosine TriphosphateBODIPY Conjugates for the Fluorescence Detection of Adenosine with More Than 1000-Fold Selectivity
This study describes the development of a simple, enzyme-free, label-free, sensitive, and selective system for detecting adenosine based on the use of Tween 20-stabilized gold nanoparticles as an efficient fluorescence quencher for BODIPY-ATP and as a recognition element for adenosine. BODIPY-ATP can interact with Tween 20-AuNPs through the coordination between the adenine group of BODIPY-ATP and Au atoms on the NP surface, thereby causing the fluorescence quenching of BODIPY-ATP through the nanometal surface energy transfer (NSET) effect. When adenosine attaches to the NP surface, the attached adenosine exhibits additional electrostatic attraction to BODIPY-ATP. Accordingly, in this study, the AuNP-induced fluorescence quenching of BODIPY-ATP progressively increased as the concentration of adenosine increased. The proposed system reflected a detection limit of 60 nM adenosine. The selectivity of the proposed system was greater than 1000-fold more for adenosine than for any adenosine analogs and other nucleotides. Furthermore, the proposed system combined with a phenylboronic acid-containing column was successfully applied to the determination of adenosine in urine.
目次 Table of Contents
目錄

誌謝 i
摘要 ii
Abstract iv
目錄 vi
圖次 x
表目錄 xiii
第一章、以Polyadenosine-Coralyne錯合物作為螢光探針設計具有高靈敏度及選擇性的方法偵測人類血漿中的肝素 1
一、前言 1
二、實驗部分 3
2.1實驗藥品 3
2.2化學結構式 4
2.3儀器裝置 5
2.4樣品配置方法 6
2.5實驗過程 7
三、結果與討論 8
3.1感測機制的建立 8
3.2 A20-coralyne錯合物形成之吸收光譜與螢光光譜示意圖 9
3.3以圓二色光譜法與極化螢光光譜偵測A20-coralyne錯合物 12
3.4計算Coralyne與A20-coralyne錯合物的量子產率 12
3.5探討不同聚核苷酸對Coralyne形成錯合物之影響 16
3.6探討不同長度之Poly A對Coralyne形成錯合物之影響 16
3.7探討pH值與NaCl濃度對A20-Coralyne錯合物之影響 19
3.8探討Poly A20濃度對A20-Coralyne錯合物之影響 19
3.9鍵結常數之探討 23
3.10藉由A20-coralyne錯合物偵測Heparin之螢光光譜示意圖 26
3.11探討A20-coralyne錯合物偵測Heparin反應時間 26
3.12探討不同長度之Poly A對偵測Heparin之影響 26
3.13 Heparin的定量分析 30
3.14選擇性探討 30
3.15偵測Protamine 35
3.16人類血漿樣品中Heparin的定量分析 37
四、結論 43
五、參考文獻 45
第二章、以BODIPY-ATP結合Fe3O4奈米粒子作為螢光探針設計具有高靈敏度及選擇性的方法偵測鹼性磷酸酶 48
一、前言 48
二、實驗部分 51
2.1實驗藥品 51
2.2化學結構式 52
2.3儀器裝置 52
2.4樣品配置方法 53
2.5合成氧化鐵奈米粒子 (Bare Fe3O4 Nanoparticle) 53
2.6實驗過程 54
三、結果與討論 55
3.1感測機制的建立 55
3.2以Fe3O4奈米粒子與BODIPY-ATP為基礎偵測ALP之螢光光譜 56
3.3 BODIPY-ATP螢光生命週期之探討 56
3.4探討偵測ALP反應時間 59
3.5 ALP活性的定量分析 59
3.6選擇性探討 63
3.7 BODIPY-ATP毛細管電泳之探討 63
3.8 ALP之動力學探討 66
3.9抑制劑探討 66
四、結論 72
五、參考文獻 74
第三章、以BODIPY-ATP結合Tween-20金奈米粒子作為螢光探針設計具有高靈敏度及選擇性的方法偵測腺苷 77
一、前言 77
二、實驗部分 80
2.1實驗藥品 80
2.2化學結構式 82
2.3儀器裝置 82
2.4樣品配置方法 84
2.5合成Tween 20金奈米粒子 (Tween 20 Gold Nanoparticle) 84
2.5實驗過程 85
三、結果與討論 86
3.1感測機制的建立 86
3.2 Tween20-金奈米粒子與BODIPY-ATP的奈米粒子表面能量轉移(NSET)機制 87
3.3以Tween20-金奈米粒子與BODIPY-ATP為基礎偵測Adenosine之螢光光譜 87
3.4探討偵測Adenosine的反應時間 90
3.5 Tween20-金奈米粒子與Adenosine-attached 金奈米粒子消光機制比較 90
3.6探討Tween20-金奈米粒子濃度對偵測Adenosine之影響 95
3.7探討BODIPY-ATP濃度對偵測Adenosine之影響 95
3.8探討pH對偵測Adenosine之影響 98
3.9 Adenosine的定量分析 98
3.10選擇性探討 102
3.11回收率探討 102
3.12人類尿液樣品中Adenosine的定量分析 106
四、結論 109
五、參考文獻 111
參考文獻 References
第一章
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第二章
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第三章
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