側向流動層析法 (Lateral flow assay, LFA) 是一項能夠進行即時檢測的試紙分析技術。由於此分析裝置具備操作簡易、成本低廉以及訊號易於判讀等特性，目前已被廣泛應用於許多快速臨床診斷，如驗孕試紙、傳染病快篩試紙等。隨著側向流動層析法的應用性拓展，已不再受限於大分子的檢測，亦能透過競爭法的機制來針對不具反應活性之小分子進行偵測。然而，由於競爭法的訊號呈現方式為信號關閉 (signal-off)，與常規認知的判讀方式相反外，於低濃度的分析樣品中也容易造成偽陰性的錯誤判讀，致使其僅有較小的定量範圍。因此，於本研究中，我們以磺胺類藥物作為小分子模板，發展出新型可控親和力側向流動層析法 (Affinity-switchable lateral flow assay, ASLFA)，並於不同生物樣品中進行目標物監測，加以證實ASLFA之可行性。此策略不僅能夠選擇性地針對目標物進行偵測，更是能以信號開啟 (signal-on) 的方式呈現高靈敏度的檢測結果。因此，我們期許這項新型檢測機制可被廣泛地應用於醫學及生物研究領域中，作為體外的即時診斷及快速篩檢。

　　Lateral flow assay (LFA) has been a rapid diagnostic technique in many analytical fields where on-site detection is required. Due to its simple operation, low cost and easy interpretation, this type of assay has been widely applied for some clinical diagnoses, such as pregnancy test and infectious disease screening. Nowadays, with the expansion of the applications, LFA approach is no longer limited to the detection of macromolecules. Currently, competitive LFA is generally used for small molecules detection since they have fewer binding sites. However, competitive assay typically produces signal-off readout, which is different from conventional sandwich assay for macromolecules. In addition, false negative misinterpretation occurs easily in low-concentration analysis samples, resulting in a narrower dynamic range. In this thesis, we develop a new and general affinity-switchable LFA (ASLFA) that can respond selectively and sensitively with signal-on feature for the detection of sulfonamide drugs in various biological samples. Therefore, we expect this novel ASLFA to be a useful approach for the in vitro rapid detection of small molecules in basic biological research and medical diagnosis.

目錄
摘要 i
Abstract ii
謝誌 iii
目錄 v
著作列表 ix
第一章 緒論 1
1-1小分子介紹 1
1-1.1 農業用藥 (Agricultural medicine) 2
1-1.2 畜牧業用藥 (Animal husbandry drugs) 3
1-1.3 人類用藥 (Human medicine) 4
1-1.4 磺胺類藥物 (Sulfonamides) 5
1-2小分子的偵測方法 6
1-2.1 液相層析質譜分析法 (LC-MS) 6
1-2.2 酵素結合免疫吸附分析法 (ELISA) 8
1-2.3 快速篩檢法 (Rapid screening) 10
1-2.3.1 微型電化學傳感器 (Miniaturized electrochemical sensor) 10
1-2.3.2 試紙檢測技術 11
第二章 文獻回顧 12
2-1側向流動層析法 (LFA) 13
2-1.1 三明治法與競爭法 (Sandwich and competitive assay) 14
2-1.2 競爭型側向流動層析法之應用 16
2-1.3 螢光淬滅側向流動層析法 (Fluorescent quenching LFA) 20
2-1.4 非競爭性顯色側向流動層析法 (Noncompetitive chromogenic LFA) 22
2-1.5 基於適體之側向流動層析法 (Aptamer-based LFA) 24
2-1.6 親和力調控之側向流動層析法 (ASLFA) 26
2-1.6.1 籠閉性生物素探針 26
2-2蛋白質開關 (Protein switches) 29
2-2.1 變構蛋白 (Allosteric protein) 29
2-2.2 半合成蛋白 (Semi-synthetic protein) 31
第三章 探針的構思與設計 35
3-1可控親和力側向流動層析法的檢測機制 35
3-2可控親和力生物素探針 (ASB-SFM) 之探針架構 37
3-2.1 生物素端 (Biotin site) 38
3-2.2 反應端 (Reaction site) 41
3-2.3 配體端 (Ligand site) 42
第四章 實驗結果與討論 43
4-1探針AuNPs-ASB-SFM於LFA檢測磺胺類藥物之探討 43
4-1.1 定性測試 (Qualitative test) 45
4-1.2 選擇性測試 (Selectivity test) 47
4-1.3 動力學測試 (Kinetic test) 50
4-1.4 再現性測試 (Reproducibility test) 51
4-1.5 靈敏度測試 (Sensitivity test) 52
4-1.6 穩定性測試 (Stability test) 54
第五章 結論 56
第六章 實驗部分 57
6-1實驗藥品與器材 57
6-2蛋白質表現及純化 58
6-2.1 蛋白質表現 58
6-2.2 蛋白質純化 59
6-2.3 SDS-PAGE膠體電泳 60
6-2.3.1 膠片配方 60
6-2.3.2 SDS-PAGE膠體電泳操作流程 60
6-3側向流動層析實驗藥品配製方法及試紙製備 61
6-3.1 奈米金粒子 (AuNPs) 製備 61
6-3.2 探針ASB-SFM結合奈米金粒子製備 61
6-3.3 抗體結合奈米金粒子製備 62
6-3.4 探針AuNPs-ASB-SFM測試條件 62
6-3.4.1 側向流動層析試紙前處理 62
6-3.4.2 測試磺胺類藥物之實驗條件 63
6-3.4.3 側向流動層析試紙之訊號量化步驟 63
參考文獻 64
附錄 71

 

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