本論文主要是利用合成的奈米材料結合表面輔助雷射脫附游離質譜法(SALDI-MS)來偵測尿液中卡特普、茶葉中茶氨酸與四種兒茶素分子及寡聚去氧核苷酸分子濃度，且應用於蛋白質間相互作用之分析。論文分成五個章節，第一章內容包括質譜儀基本原理、基質輔助雷射脫附游離法、表面輔助雷射脫附游離法的簡介及待測分析物(卡特普，兒茶素，蛋白質與蛋白質-蛋白質之複合體，寡聚去氧核苷酸)的介紹。第二章利用修飾內標準品(4-MBA)之金奈米粒子(14 nm)作為SALDI-MS之內標準品，來分析尿液中卡特普之含量。先利用未經修飾之金奈米粒子抓取分析物後，再混合吸附4-MBA之金奈米粒子來進行分析，其偵測極限為1 uM (訊雜比為3)，線性範圍2.5–25 μM，顯示此法對卡特普偵測具有良好之線性範圍與再現性(相對標準誤差: <10%)，更可準確定量尿液樣品中卡特普濃度。第三章利用二氧化鈦奈米粒子與卡特普分別作為無機基質與內標準品，偵測茶葉樣品中茶氨酸和四種兒茶素分子濃度(如兒茶素、(_)-表沒食子兒茶素、(_)-表兒茶素沒食子兒茶素沒食子酸酯和(_)-表沒食子兒茶素沒食子兒茶素沒食子酸酯)。此法不僅提供良好的定量線性和靈敏度(偵測極限:介於femtomole-to-picomole之間)，亦展現再現性佳及變異性小(<13%)等特點，由實驗結果說明台灣和其他四個國家的茶葉樣品之鑑定有不同的質譜圖譜表現，不同季節和城市採收(台灣)的茶葉亦會有不同的成份組成。第四章利用汞-碲(HgTe)奈米材料為無機基質，在介面活性劑(Brij 76)和鋅離子存在下，分析蛋白質與蛋白質-蛋白質複合體(如a1-抗胰蛋白酶-胰蛋白酶和免疫球蛋白G -蛋白質G複合體)。此方法可以在溫和條件與低濃度(picomole)下，進行蛋白質及其複合體的分析，也可分別觀察到此兩種複合體的多價態訊號。此方法具簡單和再現性（RSD<25％）之特性，對於蛋白質體學上的其他蛋白質及其複合體之分析具有極大潛力。第五章利用汞-碲(HgTe)奈米材料為無機基質，偵測單股與雙股寡聚去氧核苷酸分子。此方法具有高靈敏度（偵測極限於femtomole-to-picomole level）和再現性（變異性：<23％）佳等特點，可用於偵測單股(最大達50-mer)與雙股(最大達30 base pairs)寡聚去氧核苷酸分子，並應用於分析一單核苷酸多態性鐮狀巨幼紅細胞中，b-珠蛋白(b-globin)上纈氨酸殘基之表現，相信未來應用於基因診斷具極大潛力。

This thesis focuses on synthesizing nanomaterials through surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS) for the analysis of captopril and catechins in urines and tea samples, respectively, and for the investigation of protein-protein interaction in addition to the detection of single- and double-stranded oligodeoxynucleotides (ss- and ds-ODNs, respectively). The thesis is divided into five parts. Chapter one introduces the framework and background of basic principles of mass spectrometry, the soft ionization method, MALDI, SALDI, generally applied in MS, and analysis of captopril, tea catechins, proteins and protein-protein complexes, and ODNs. In chapter two, an internal standard comprised captopril (CAP) mixed with 14-nm-diameter gold nanoparticles (Au NPs) was introduced. The analytes were first captured using the unmodified 14-nm Au NPs; followed by addition of the internal standard (CAP-Au NPs) and the analysis of the sample using SALDI-MS. This approach provided linearity for CAP over the concentration range 2.5–25 μM, with a limit of detection (signal-to-noise ratio = 3) of 1 μM. This approach provided good quantitative linearity and reproducibility (relative standard deviations: <10%) of CAP for the determination of the levels of CAP in human urine samples. In chapter three, SALDI-MS using titanium dioxide nanoparticles (TiO2 NPs) as the matrix and captopril (CAP) as internal standard were used for the determination of the concentrations of theanine and four catechins—catechin, (_)-epigallocatechin (EGC), (_)-epicatechin gallate (ECG), and (_)-epigallocatechin gallate (EGCG). This SALDI-MS approach provides good quantitative linearity and sensitivity (LOD at the femtomole-to-picomole level) for these five analytes. It also provides good reproducibility, spot-to-spot and batch-to-batch variations of less than 10 and 13%, respectively, for the analysis of tea samples, with identified peaks for theanine and four catechins. Tea samples from Taiwan and four other countries have various SALDI-MS profiles, showing their potential for differentiation of tea samples from different sources. The result also shows that tea samples harvested in different seasons and counties in Taiwan provide significantly different MS profiles. The fourth chapter utilizes the mercury-tellurium (HgTe) nanomaterials chosen as SALDI-MS matrices in the detection of proteins and weak protein–protein complexes, such as a1-antitrypsin–trypsin and IgG–protein G complexes, in the presence of stabilizing Brij 76 surfactant and Zn(II) ions. This soft and sensitive technique allows the detection of weak protein complexes at the picomole level under mild conditions. In addition, we observed multiple charged states for these two complexes, respectively. This simple and reproducible (RSD <25%) approach holds great potential for the detection of other proteins and their complexes for various omics such as proteomics. The fifth chapter describes the use of SALDI-MS with HgTe nanostructures acting as the matrix for the detection of ss- and ds-ODNs. The present approach provides good sensitivity (LOD at the femtomole-to-picomole level) and reproducibility (variation: <23%) for the detection of ss-ODNs (up to 50-mer) and ds-ODNs (up to 30 base pairs). Furthermore, the practicality of this approach was applied for the analysis of a single nucleotide polymorphism (SNP) that determines the fate of the valine residue in the b-globin of sickle cell megaloblasts. This simple and reproducible approach employing HgTe nanostructures as matrices appears to hold great potential for use in genomic diagnosis.

Contents Page
口試委員會審定書 I
誌謝 III
中文摘要 V
英文摘要 VII
Contents IX
Figure Contents XIV
Table Contents XVIII

Chapter 1 1
Introduction 1
1.1 Mass Spectrometry (MS) 2
1.1.1 History 2
1.1.2 Basic Principle of MS 2
1.2 Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry (MALDI-MS) 4
1.2.1 Introduction 4
1.2.2 Choice of Matrix 5
1.3 Surface-Assisted Laser Desorption/Ionization Mass Spectrometry (SALDI-MS) 6
1.3.1 Introduction 6
1.3.2 Applications of NPs in SALDI-MS 7
1.4 Bioanalysis of MS 10
1.4.1 Captopril (CAP) 10
1.4.2 Tea Catechins 12
1.4.3 Proteins and Protein-Protein complexes 14
1.4.4 Oligodeoxynucleotides (ODNs) 14
1.5 Motive of Research 17
1.6 References 20
Chapter 2 44
Quantification of Captopril in Urine Through Surface-Assisted Laser Desorption/Ionization Mass Spectrometry Using 4-Mercaptobenzoic Acid-Capped Gold Nanoparticles as an Internal Standard 44
2.1 Abstract 45
2.2 Introduction 45
2.3 Experimental Section 47
2.3.1 Chemicals 47
2.3.2 Synthesis of 14-nm Au NPs 48
2.3.3 Surface Density of Thiols on Au NPs 48
2.3.4 Analysis of CAP in Urine 49
2.3.5 SALDI-TOF MS Measurements 50
2.4 Results and Discussions 50
2.4.1 Internal Standards 50
2.4.2 Parameter Optimization for SALDI-MS Analysis 51
2.4.3 Quantitative Analyses of CAP 53
2.4.4 Determination of CAP in Urine 54
2.5 Conclusion 54
2.6 References 56
Chapter 3 66
Tea Identification through Surface-Assisted Laser Desorption/Ionization Mass Spectrometry 66
3.1 Abstract 67
3.2 Introduction 67
3.3 Experimental Section 69
3.3.1 Chemicals 69
3.3.2 Preparation of TiO2 NPs 69
3.3.3 Characterization of TiO2 NPs 70
3.3.4 Analysis of tea samples 70
3.3.5 SALDI-TOF MS 71
3.3.6 Electrospray ionization mass spectrometry (ESI-MS) 72
3.4 Results and Discussions 72
3.4.1 TiO2 NPs as assisted matrices and captopril (CAP) as internal standard in SALDI-MS 72
3.4.2 Sensitivity and Linearity 74
3.4.3 Identification of Taiwanese and foreign tea samples 74
3.5 Conclusion 77
3.6 References 78
Chapter 4 91
Using Surface-Assisted Laser Desorption/Ionization Mass Spectrometry to Detect Proteins and Protein−Protein Complexes 91
4.1 Abstract 92
4.2 Introduction 92
4.3 Experimental Section 95
4.3.1 Chemicals and Proteins 95
4.3.2 Synthesis of HgTe Nanostructures 96
4.3.3 Analysis of Protein−Protein Complexes 97
4.3.4 SALDI-TOF MS 98
4.4 Results and Discussions 98
4.4.1 Effect of Surfactant 98
4.4.2 Effects of pH and Salt Concentration 101
4.4.3 Effect of Nature and Concentration of Metal Ions. 102
4.4.4 Stoichiometry of Protein−Protein Interactions 103
4.5 Conclusion 105
4.6 References 106
Chapter 5 118
Using Surface-Assisted Laser Desorption/Ionization Mass Spectrometry to Detect ss- and ds-Oligodeoxynucleotides 118
5.1 Abstract 119
5.2 Introduction 119
5.3 Experimental Section 122
5.3.1 Chemicals and ODNs 122
5.3.2 HgTe Nanostructures 122
5.3.3 Au NPs 123
5.3.4 ODN–Au NP Capture 124
5.3.5 Analysis of ss- and ds-ODNs 124
5.3.6 SNP Analysis 126
5.3.7 SALDI-TOF MS 127
5.4 Results and Discussions 127
5.4.1 Effects of pH and Salt 129
5.4.2 Effects of Metal Ions and Amine 131
5.4.3 Sensitivity and Linearity 133
5.4.4 Detection of ds-ODNs 134
5.5 Conclusion 136
5.6 References 138
Chapter 6 151
Summary and Perspectives 151
6.1 Summary 152
6.2 Perspectives 153
Chapter 7 Publications 155

Figure Contents
Figure 1.1 The five basic architecture in mass spectrometer. 37
Figure 1.2 MALDI-TOF MS. 38
Figure 1.3 MALDI (Matrix-assisted laser desorption/ionization) ionization. 39
Figure 1.4 Nanomaterials absorb energy from the laser irradiation and transfer it efficiently to the analytes, thereby inducing their desorption and ionization, in SALDI-MS. 40
Figure 1.5 Structures of five major catechins and other important components of tea leaves. 41
Figure 1.6 Single-nucleotide polymorphism (SNP). 42
Figure 1.7 Sickle cell anemia (SCA). (A)-(B) Sickle-cell disease, (C) Inherited pattern, (D) Hemoglobin. 43

Figure 2.1 Structures of CAP and five possible internal standards. 59
Figure 2.2 SALDI Mass spectra of the control and thiol-containing compounds when using Au NPs as matrices. 60
Figure 2.3 Schematic representation of the relative quantitation of CAP through SALDI-MS analysis using MBA-Au NPs as the internal standard. 61
Figure 2.4 SALDI-MS signals of CAP in solutions (a) at various concentrations of ammonium citrate and pH values, and (b) at various concentrations of Au NPs.. 62
Figure 2.5 Fluorescence intensities [IF; plotted in arbitrary units (a. u.)] of solutions containing R6G-adsorbed Au NPs (1 nM) in the absence and presence of 1.5–67.5

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