臺灣博碩士論文加值系統

量子點的螢光穩定性常被應用於生物學上做為標示使用，而取代了傳統的螢光染劑。抗體包覆量子點外層去標定抗原的方式與使用分子拓印技術製備類似抗體位子去吸附目標分子的方式相似，因此，利用分子拓印高分子包覆量子點亦可具有模版孔洞與選擇性，本研究以聚乙烯-乙烯醇（poly(ethylene-co-vinyl alcohol), EVAL）混合不同放射波長的量子點加入沉澱槽，利用相轉換的方式進行快速製備分子拓印高分子複合奈米微粒，進行型態、再吸附性質分析，並藉由量子點的螢光穩定性變化檢測尿液中肌酸酐、白蛋白、溶菌酶分子濃度，與醫院生化檢測濃度做準確率之比較。

The high stability of quantum dots (QDots) with photoluminescence has led to their increase use as imaging approaches in biological systems to replace conventional fluorescence labels. The antibodies are generally coated on the surface of QDots to the targeting site, and molecular imprinting polymers are designed to mimic the antibodies. Hence, quantum dots can be incorporated into molecularly imprinted polymers, which provide shape and selectivity, and then respond to template rebinding by emitting quenched photoluminescence. In this study, poly(ethylene-co-ethylene alcohol) creatinine-, albumin- and lysozyme-imprinted polymers nanoparticles are synthesized via phase inversion of poly(ethylene-co-ethylene alcohol) with various ethylene mole ratios when target molecules and hydrophobic quantum dots are mixed within the polymer solution. Finally, those particles were prepared for the detection of creatinine, human serum albumin and lysozyme in real sample (urine) and compared with commercial ARCHITECT ci 8200 system.
Keywords: poly(ethylene-co-ethylene alcohol); creatinine; albumin; lysozyme; molecular imprinting; urine.

目 錄
誌謝........................................................................................................................I
中文摘要.............................................................................................................III
Abstract................................................................................................................IV
目錄.....................................................................................................................VI
表目錄...................................................................................................................X
圖目錄...............................................................................................................XIII
第一章 前 言
1.1 研究背景..................................................................................................1
1.2 研究動機..................................................................................................4
1.3 論文概論..................................................................................................5
第二章 文獻回顧
2.1 分子拓印技術(Molecularly imprinted technology).............................6
2.1.1 分子模版的起源與發展...................................................................6
2.1.2 分子模版之原理...............................................................................7
2.1.3 分子模版對目標物之辨識因素.......................................................8
2.1.4 分子模版之應用.............................................................................10
2.2 聚乙烯-乙烯醇(Poly(ethylene-co-vinyl alcohol), EVAL).....................15
2.2.1 聚乙烯-乙烯醇的結構及原理........................................................15
2.2.2 聚乙烯-乙烯醇球狀結構薄膜的發展............................................15
2.2.3 相轉換理論與機制.........................................................................16
2.2.4 聚乙烯-乙烯醇合成孔洞(pore)或是顆粒(particle)的機制...........18
2.2.5 聚乙烯-乙烯醇之生物相容性及其應用........................................20
2.3 腎臟簡介................................................................................................20
2.3.1 腎臟之構造.................................................................................... 20
2.3.2 腎臟病之特徵.................................................................................22
2.3.3 尿液中疾病指標分子.....................................................................28
2.3.4 蛋白質的結構及特性與臨床意義.................................................30
2.3.5 兩種蛋白之親合性影響.................................................................38
2.4 量子點(semiconductor quantum dots, QDs) .........................................40
2.4.1 史托克位移(Stokes shift) ...............................................................43
2.4.2 量子點的合成方法.........................................................................44
第三章 實驗儀器與步驟
3.1 實驗樣品與儀器....................................................................................45
3.1.1 實驗藥品.........................................................................................45
3.1.2 實驗儀器.........................................................................................47
3.2 實驗方法與步驟....................................................................................48
3.2.1 磷酸緩衝溶液配置.........................................................................48
3.2.2 分子拓印高分子複合奈米微粒之製備.........................................48
3.2.3 分子拓印高分子複合奈米微粒的清洗.........................................50
3.2.4 分子拓印高分子複合奈米微粒吸附.............................................51
3.2.4.1 紫外光可見光光譜原理.................................................................51
3.2.4.2 分子拓印高分子複合奈米微粒之再吸附實驗步驟.....................51
3.2.5 微熱卡計(Isotermal titration Calorimeter, ITC)之原理.................52
3.2.5.1 恆溫滴定微量熱儀量測點.............................................................54
3.2.6 粒徑測量原理.................................................................................55
3.2.7 掃描電子式顯微鏡(SEM, scanning electron microscope) 和X-射
線能量散佈分析儀 (EDS) ............................................................56
3.2.7.1 掃描電子式顯微鏡原理.................................................................56
3.2.7.2 特徵X射線分析法.........................................................................56
3.2.8 界達電位（zeta potential）原理.......................................................60
第四章 結果與討論
4.1 分子拓印高分子複合奈米微粒之表面結構研究. ..............................61
4.1.1 分子拓印高分子複合奈米微粒的粒徑分析.................................61
4.2 分子拓印高分子複合奈米微粒對目標分子再吸附效果....................62
4.2.1 含有不同乙烯比例的分子拓印高分子複合奈米微粒對於目標分
子之吸附性.....................................................................................63
4.2.2 不同吸附時間的吸附量.................................................................69
4.2.3 分子拓印高分子複合奈米微粒之吸附動力分析(Adsorption
dynamic analysis) ...........................................................................71
4.2.4 分子拓印高分子複合奈米微粒之恆溫吸附熱力學.....................75
4.3 分子拓印高分子複合奈米微粒之型態與粒徑....................................78
4.3.1 溫度對型態與粒徑之影響.............................................................78
4.4 分子拓印高分子複合奈米微粒之表面電位變化................................84
4.5 分子拓印高分子複合奈米微粒之螢光特性........................................87
4.5.1 觀察分子拓印高分子複合奈米微粒之螢光放射.........................87
4.5.2 分子拓印高分子複合奈米微粒之螢光衰退.................................89
4.6 干擾因子與吸附性競爭........................................................................93
4.7 吸附尿液分子之檢測............................................................................95
4.8 重複使用性之探討..............................................................................107
第五章結論
一、結論..................................................................................................109
二、未來研究方向................................................................................111
參考文獻
附錄..................................................................................................................119
附錄A 肌酸酐分子在紫外光-可見光光譜儀的檢量線..........................120
附錄B 白蛋白分子在紫外光-可見光光譜儀的檢量線..........................120
附錄C 溶菌酶分子在紫外光-可見光光譜儀的檢量線..........................121
附錄D 肌酸酐分子拓印高分子複合奈米微粒重複使用於檢測尿液之
波長圖...........................................................................................121
附錄E 發表的論文目錄...........................................................................122

表目錄
表1-1 近十年台灣男性、女性洗腎統計人數....................................................3
表2-1 分子模版與目標分子非共價鍵結方式..................................................9
表2-2 近年來分子拓印奈米微粒之合成及應用............................................11
表2-3 以肌酸酐為目標分子製備拓印模版....................................................12
表2-4 以血清蛋白為目標分子製備拓印模版................................................13
表2-5 以溶菌酶為目標分子製備拓印模版....................................................14
表2-6 常見的腎臟及尿路症候群....................................................................23
表2-7 慢性腎病之進行階段............................................................................25
表2-8 尿毒症候群之生化特徵........................................................................27
表2-9 尿液中常見的指標分子........................................................................29
表2-10 血清肌酸酐之參考值............................................................................32
表2-11 血清白蛋白之參考值............................................................................34
表2-12 兩種蛋白質分子的胺基酸序列............................................................39
表3-1 四種特徵X射線分析法的比較............................................................58
表4-1 肌酸酐分子拓印高分子複合奈米微粒在不同乙烯莫耳百分比的再
吸附量....................................................................................................65
表4-2 白蛋白分子拓印高分子複合奈米微粒在不同乙烯莫耳百分比的再
吸附量....................................................................................................66
表4-3 溶菌酶分子拓印高分子複合奈米微粒在不同乙烯莫耳百分比的再
吸附量....................................................................................................67
表4-4 分子拓印模版的吸附動力學...........................................................74
表4-5 白蛋白分子拓印高分子複合奈米微粒在不同溫度下吸附白蛋白
分子之熱力學.........................................................................................76
表4-6 分子拓印高分子複合奈米微粒在洗滌目標分子前、後的平均粒徑..83
表4-7 分子拓印高分子複合奈米微粒在清洗目標分子前、後的表面電位
變化.........................................................................................................85
表4-8 肌酸酐分子拓印高分子複合奈米微粒檢測尿液樣品中肌酸酐分子
與義大醫院的結果比較.........................................................................98
表4-9 白蛋白分子拓印高分子複合奈米微粒檢測尿液樣品中白蛋白分子
與義大醫院的結果比較.........................................................................99
表4-10 溶菌酶分子拓印高分子複合奈米微粒檢測尿液樣品中溶菌酶分子
與義大醫院的結果比較.......................................................................100
表4-11混合三種分子拓印高分子複合奈米微粒檢測尿液樣品中肌酸酐分
子與義大醫院的結果比較...................................................................101
表4-12 混合三種分子拓印高分子複合奈米微粒吸附尿液樣品中白蛋白分
子與義大醫院的結果比較...................................................................102
表4-13 混合三種分子拓印高分子複合奈米微粒吸附尿液樣品中溶菌酶分
子與義大醫院的結果比較...................................................................103
表4-14 肌酸酐分子拓印高分子複合奈米微粒存放六個月後檢測尿液樣品
中肌酸酐分子與義大醫院的結果比較...............................................104
表4-15 白蛋白分子拓印高分子複合奈米微粒存放六個月後檢測尿液樣品
中白蛋白分子與義大醫院的結果比較...............................................105
表4-16 溶菌酶分子拓印高分子複合奈米微粒存放六個月後檢測尿液樣品
中溶菌酶分子與義大醫院的結果比較...............................................106
表4-17 重覆清洗肌酸酐分子拓印高分子複合奈米微粒後檢測尿液樣品中
肌酸酐分子與義大醫院的結果比較...................................................108

圖目錄
圖1.1 十年內洗腎人口統計圖..........................................................................4
圖2-1 分子拓印模版 (MIPs) 之原理示意圖…..............................................8
圖2-2 聚乙烯-乙烯醇結構式..........................................................................15
圖2-3 EVAL固化成膜之三元相圖.................................................................17
圖2-4 腎臟的結構圖........................................................................................21
圖2-5 腎元結構圖............................................................................................22
圖2-6 肌酸酐合成與代謝路徑........................................................................30
圖2-7 肌酸酐分子結構式................................................................................31
圖2-8 白蛋白的結構圖....................................................................................35
圖2-9 溶菌酶的結構圖....................................................................................37
圖2-10 量子點的螢光特色................................................................................41
圖2-11 量子點的組成........................................................................................42
圖2-12 吸收峰與放射峰之間的差距................................................................43
圖3-1 分子拓印高分子複合奈米微粒之製備流程圖....................................49
圖3-2 使用透析膜清洗高分子奈米複合微粒................................................50
圖3-3 恆溫滴定微熱儀....................................................................................53
圖3-4 恆溫滴定微熱儀之結構圖....................................................................54
圖3-5 掃描式電子顯微鏡和X-射線能量散佈分析儀...................................59
圖4-1 包覆量子點的平均粒徑……................................................................62
圖4-2 不同EVAL 乙烯百分率包覆量子點複合微粒進行再吸附...............68
圖4-3 分子拓印高分子複合奈米微粒吸附生理濃度在不同時間下的吸附量............................................................................................................70
圖4-4 分子拓印高分子複合奈米微粒吸附0.1mg/mL濃度時吸附曲線......70
圖4-5 高分子奈米複合微粒之吸附動力分析................................................73
圖4-6 白蛋白分子拓印高分子複合奈米微粒在不同溫度再吸附的微熱量
分析…....................................................................................................77
圖4-7 在不同溫度沉澱槽，聚乙烯-乙烯醇相轉換的微粒SEM....................80
圖4-8 利用SEM圖統計在不同溫度下的粒徑分佈.......................................81
圖4-9 由粒徑量測儀測量不同的分子拓印高分子複合奈米微粒在洗滌目
標分子前後的粒徑分佈........................................................................82
圖4-10 分子拓印高分子複合奈米微粒再吸附目標分子後的表面電位變化
................................................................................................................86
圖4-11 肌酸酐分子拓印高分子複合奈米微粒在不同曝光時間下的螢光顯
微鏡圖....................................................................................................88
圖4-12 肌酸酐分子拓印高分子複合奈米微粒吸附於肌酸酐分子拓印薄膜
................................................................................................................88
圖4-13 由波長355nm的雷射波長激發肌酸酐分子拓印高分子複合奈米微
粒的顏色變化........................................................................................90
圖4-14 雷射光譜儀激發分子拓印高分子複合奈米微粒再吸附目標分子後
螢光強度的變化....................................................................................91
圖4-15 分子拓印高分子複合奈米微粒的life-time ........................................92
圖4-16 分子拓印高分子複合奈米微粒吸附生理濃度的干擾因子圖............94
圖4-17 吸附目標分子的檢量線........................................................................97
圖4-18 重覆清洗肌酸酐分子拓印高分子複合奈米微粒的檢量線..............107

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