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研究生:徐繹翔
研究生(外文):Hsu, I-Hsiang
論文名稱:利用奈米金粒子訊號放大及磁性粒子分離技術進行核酸序列及汞離子之分析研究
論文名稱(外文):Gold nanoparticle (AuNP)–based amplification and magnetic bead separation method for the detection of oligonucleotide sequences and mercuric ion
指導教授:孫毓璋
口試委員:楊末雄張憲彰黃承文吳東昆
口試日期:2011-8-11
學位類別:博士
校院名稱:國立清華大學
系所名稱:生醫工程與環境科學系
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2011
畢業學年度:100
語文別:英文
論文頁數:88
中文關鍵詞:奈米金粒子奈米銀粒子磁性微米粒子核酸序列汞離子
外文關鍵詞:AuNPAgNPMagnetic microparticleDNAmercuric ion
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本研究旨在發展一套奈米粒子訊號放大結合磁性粒子分離技術,並實際應用於核酸序列及汞離子的分析工作上。在核酸序列的研究中,依據目標序列設計兩種DNA探針,並搭配磁性粒子的使用來達成樣品基質分離的目的,最後再利用分析靈敏度極佳的感應耦合電漿質譜儀測定源自金奈米粒子的金離子訊號,並藉此達到訊號放大的效果。過程中為了提升偵測靈敏度及降低因金奈米粒子非特異性吸附所造成之背景訊號問題,針對捕捉探針之使用濃度及待測物雜合時間及清洗次數等操作參數進行最佳化的探討;在最佳化的條件下,待測物序列之偵測極限可達 80 zmol (相當於50 μL 的樣品中含有1.6 fM之待測物序列)。根據所獲致的實驗結果可知,此技術確實可應用於複雜基質樣品中微量核酸序列的分析外,同時也具有極佳之靈敏度與選擇性;另外,相較於常用於測定登革病毒之空斑計數試驗而言,由於本研究所開發的方法具有更佳的分析靈敏度,因此不但可達到快速分析的目的,更可滿足早期診斷的需求。根據上述分析方法的操作原裡,研究中更進一步將此核酸檢測技術,應用於同時測定多種型別之登革病毒,在此實驗中,藉由金和銀兩種奈米粒子所製備成的兩種奈米探針,開發出一套可針對登革病毒1型及2型之寡核苷酸序列,同時定性及定量的分析技術。根據實驗結果顯示,此分析技術除可同時針對兩種型別之序列進行定量分析外,其偵測極限亦可達50 fM (樣品體積50 μL)。由於訊號測定係使用對金屬分析靈敏之感應耦合電漿質譜技術進行源自金奈米粒子與銀奈米粒子的金及銀離子的測定,因此可大幅縮短整個分析流程所需的時間至約二個小時左右。
在汞離子分析方法開發的過程中,研究過程係利用奈米粒子探針搭配磁性粒子分離技術,最終再藉由電熱式原子吸收光譜法測定源自金奈米粒子的金原子訊號,來達到訊號放大的目的。汞離子檢測主要係藉由(i)磁性探針,橋樑序列及金奈米探針所組成之三明治結構中可專一辨識汞離子的結合位置—thymine–thymine (T–T)進行樣品中汞離子的錯合,(ii) 三明治結構快速且均勻的反應及基質分離,(iii)金奈米粒子可在最後測定時釋放出大量的金原子等的特點,來達到高靈敏測定汞離子的目的。根據所獲致的實驗結果可知,此方法之偵測極限可達0.45 nM (0.09 μg L-1),遠低於美國環保署所針對飲用水中所製訂的法規標準(10 nM)。由於測定試劑製備容易且操作簡單,反應時間亦經過最佳化調整,因此整體分析速度極快(半小時內約可處理約24個樣品)。為了進一步提升方法的靈敏度,方法開發過程亦使用了較大粒徑的奈米粒子(55 nm)來製作探針,以利偵測訊號的放大。研究結果顯示,較大的奈米粒子除本身可達到更好的訊號放大效果外,亦可藉由改變三明治結構Tm值,來進一步提升分析系統分析的靈敏度。根據所獲致的實驗結果可知,藉由上述兩個效應,可使得汞離子的偵測極限大幅壓低至28 pM (5.6 ng L-1)。

This thesis focuses on developing a sensitive gold nanoparticle (AuNP)–based amplification and magnetic separation method for the detection of oligonucleotide sequences and mercuric ion. In the study on oligonucleotide sequences analysis, the assay relies on (i) the sandwich-type binding of two designed probe sequences that specifically recognize the target oligonucleotide sequences, (ii) magnetic bead separation, and (iii) AuNP-based ICP-MS amplification detection. To enhance the analytical signal and minimize the background signal resulting from nonspecific binding, we performed a series of experiments to evaluate the effects of various parameters (the concentration of the capture probe; the time required for hybridization; the number of washings required to eliminate nonspecific binding). Under the optimized conditions, the detection limit was 80 zmol (corresponding to 1.6 fM of the target sequence in a sample volume of 50 μL). Compared with the “gold standard” methodology (plaque assay) for the quantification of dengue virus, our method has the capability to allow early detection of dengue virus in complicated and small-volume samples, with high specificity, good analytical sensitivity, and superior time-effectiveness.
Moreover, this simple, high sensitive and selective method was also applied to simultaneously quantify two different types (type 1 and 2) of dengue viruses through the utility of AuNP and AgNP probes. Based on the experimental results, our developed nanoprobing technique for quantifying and typing viruses was proven to be applicable for the simultaneously determination of two types of analyte oligonucleotides in 50 μL of samples with detection limit of 50 femtomolar. Because the involvement of a shorter hybridization and ICP-MS measurement, a relatively simple and rapid (ca. 2 h) procedure for the quantification and typing of two viruses was provided.
In the study on mercuric ion analysis, we have developed a sensitive gold-nanoparticle-based (AuNP-based) graphite furnace atomic absorption spectrometry (GFAAS) amplification and magnetic separation method for the detection of mercuric ions (Hg2+). The assay relies on (i) a sandwich-type structure containing two thymine–thymine (T–T) mismatches for selectively recognizing Hg2+ ions; (ii) magnetic beads for homogeneous separation; and (iii) AuNP-based GFAAS amplification detection. The limit of detection (LOD) of this assay is 0.45 nM (0.09 ?慊 L-1) ?{ one order of magnitude lower than the United States Environmental Protection Agency (US EPA) limit for Hg2+ in drinking water. Furthermore, because a shorter hybridization step and a simpler AuNP-based GFAAS amplification detection were employed, a faster analytical run time allowing us to analyze a batch of 24 samples within 0.5 h. We demonstrated the feasibility of the developed approach for the determination of Hg2+ in urine and aqueous environmental samples.
In addition, to further improve the analytical sensitivity, a large DNA–gold-nanoparticle (AuNP) probe coupling with the analytical principle described above was also established for the detection of Hg2+. Our findings indicated that using large AuNP (55 nm) probe could increase the ΔTm and provide a sharper melting profile of the sandwich structure when compared with that of AuNP (20 nm). That is, using a larger AuNP probe to detect the Hg2+ can improve the analytical sensitivity of the detection system. Under the optimized conditions, the detection limit of Hg2+ was 28 pM (5.6 ng L-1) and the obtained relative standard deviations (RSD) for different Hg2+ concentrations were in the range of 4.1% to 13.2%. The acceptable recoveries obtained for both spiked tap water (88.7%) and urine samples (97.3%) indicated that this approach could be used to accurately determine Hg2+ concentrations in both samples.

Contents Page
中文摘要 I
Abstract III
Contents VI
Table contents VIII
Figure contents VIII

1. Introduction 1
1.1. Detection of dengue virus 2
1.2. Detection of mercuric ions 11

2. Experimental section 16
2.1. Gold Nanoparticle–Based Inductively Coupled Plasma Mass Spectrometry Amplification and Magnetic Separation for the Sensitive Detection of a Virus-Specific RNA Sequence
2.1.1. Instrumentation 16
2.1.2. Chemicals and Materials 17
2.1.3. Synthesis of silver nanoparticle 18
2.1.4. Preparation of AuNP and AgNP probes 18
2.1.5. Preparation of MMP probes 19
2.1.6. Procedure for dengue virus type 2 detection 19
2.1.7. Procedure for multiplex dengue viruses detection 20
2.1.8. DENV2 preparation 21
2.1.9. Plaque assay of DENV2 22

2.2. Gold-nanoparticle-based Graphite Furnace Atomic Absorption Spectrometry Amplification and Magnetic Separation Method for Sensitive Detection of Mercuric Ions
2.2.1. Instrumentation 22
2.2.2. Chemicals and materials 23
2.2.3 55-nm AuNP synthesis 24
2.2.4. Preparation of AuNP probes 24
2.2.5. Preparation of MMP probes 26
2.2.6. Determination of optimum separating temperature 27
2.2.7. Detection procedure 27
2.2.8. Predetermination of Hg2+ in pond water, tap water and urine 28

3. Results and Discussion 29
3.1. Gold Nanoparticle–Based Inductively Coupled Plasma Mass Spectrometry Amplification and Magnetic Separation for the Sensitive Detection of a Virus-Specific RNA Sequence
3.1.1. Sensing rationale 30
3.1.2 Characterization of MMP/Target/AuNP complexation 30
3.1.3. Optimization of Sandwich Hybridization Assay 32
3.1.3.1. Concentration of MMP probes 32
3.1.3.2. Hybridization time 34
3.1.3.3. The effect of the number of washing 36
3.1.4. Analytical performance 38
3.1.5. Comparison of different methods 39
3.1.6. Application for DENV detection 41
3.1.7. Summery 43

3.2. Development of Sensitive Nanoprobing Techniques for Quantifying and Typing Viruses by Coupling with ICP-MS Detection
3.2.1. Sensing rationale 45
3.2.2. Characterization of AgNP 46
3.2.3. Characterization of MMP/Target/NPs complexation 48
3.2.4. Optimization of Sandwich Hybridization Assay 49
3.2.5. Analytical performance 49
3.2.6. Comparison of different methods 51
3.2.7. Summery 53

3.3. Gold-nanoparticle-based Graphite Furnace Atomic Absorption Spectrometry Amplification and Magnetic Separation Method for Sensitive Detection of Mercuric Ions
3.3.1. Sensing rationale 54
3.3.2. Optimization of sandwich hybridization assay 57
3.3.2.1. Heating time 57
3.3.2.2. Number of washings 57
3.3.3. Analytical performance 58
3.3.4. Analysis of Hg2+ in real samples 61
3.3.5. Summery 63

3.4. Ultrasensitive Detection of Mercuric Ions by Large Gold-nanoparticle-based Graphite Furnace Atomic Absorption Spectrometry Amplification
3.4.1. Sensing Rationale 65
3.4.2 Determination of the Tm shift of sandwich structures 67
3.4.3 Analytical performance 69
3.4.4 Analysis of Hg2+ in real samples 74
3.4.5. Summery 75
4. Conclusions and prospects 76

5. References 80

6. Appendix 88

Table contents
Table 1-1 Disease severity and pleural effusion index (PEI) in children infected with dengue virus type DEN-2 compared with those infected with other dengue virus serotypes. 10
Table 2-1 Operating Conditions of Agilent 7500a ICP-MS System. 16
Table 2-2 Operating Parameters for GFAAS 23
Table 3-1 Comparison of analytical characteristics between this and previous related studies. 40
Table 3-2 Comparison of analytical characteristics between this multiplexed detection method and previous related studies. 52
Table 3-3 Analytical Results for Mercury in Environmental Aqueous Samples and Urine SRM 2672a 63
Table 3-4 Analytical results for mercury in environmental aqueous samples and urine sample. 75
Table 4-1 Different functions of AuNPs in biosensor systems. 77

Figure contents
Figure 1-1 Map showing the distribution of dengue fever in the world, as of 2006. 7
Figure 1-2 Manifestations of dengue virus infection. 7
Figure 1-3 Mean dengue virus titer by fever day for dengue 2 virus patients experiencing dengue fever, hemorrhagic fever grades 1 and 2, and dengue hemorrhagic fever grade 3. 9
Figure 1-4 Mean plural effusion index and 95% confidence intervals by dengue virus type and antibody response pattern 10
Figure 1-5 Global, historic primary production of Hg, and the total contribution from the two main mining sites in Europe, Almadén in Spain and Idrija in present-day Slovenia. 11
Figure 1-6 Age and sex-adjusted geometric mean blood mercury levels by the prevalence of atopic dermatitis (AD) among Korean adults ≥20years of age. 12
Figure 2-1 SEM image of the AuNP probes (20 nm) after centrifugation. 25
Figure 2-2 SEM image of the AuNP probes (55 nm) after centrifugation. 26
Figure 3-1 AuNP-based “sandwich-type” oligonucleotide detection by ICP-MS. 31
Figure 3-2 TEM image of the sandwich structure; AuNP probes appear fixed on the surface of the MMP through double-helix oligonucleotide. 32
Figure 3-3 Variation of the capture efficiency of the target oligonucleotide with respect to the MMP probe concentration. 33
Figure 3-4 Variation of the analytical signal with respect to the length of the hybridization time between the MMP probe and the mock oligonucleotide 35
Figure 3-5 Variation of the analytical signal with respect to the length of the hybridization time between the MMP–target oligonucleotide complex and the AuNP probes. 36
Figure 3-6 Variation of the signal intensities obtained with and without target oligonucleotide at different number of washings. 37
Figure 3-7 Signal intensity plotted as a function of the concentration of the target sequence. 39
Figure 3-8 Correlation between the concentrations of nucleic acid measured using the ICP-MS–based sandwich assay and the plaque numbers of DENV (Type 2). 42
Figure 3-9 AuNP and AgNP-based “sandwich-type” oligonucleotides detection by ICP-MS. 46
Figure 3-10 The spectrum of the synthesized AgNPs. 47
Figure 3-11 The particle diameter of the synthesized AgNPs. 47
Figure 3-12 TEM image of MMP/target/NPs sandwich structure. 48
Figure 3-13 The EDX result of MMP/target/NPs sandwich structure. 48
Figure 3-14a Signal intensity plotted as a function of the concentration of the target sequence. 50
Figure 3-14b Signal intensity plotted as a function of the concentration of the target sequence. 51
Figure 3-15 AuNP-based GFAAS amplification method for the sensitive detection of Hg2+ ions. 55
Figure 3-16 Melting curve of the sandwich structure (MMP/bridge 1/AuNP) in the presence and absence of Hg2+ ions. 56
Figure 3-17 Variation of Au signal intensities as a function of heating time. 58
Figure 3-18 Variations in signal intensities obtained with and without Hg2+ for different numbers of washings. 59
Figure 3-19 Analytical signal intensities plotted as a function of Hg2+ concentration. 60
Figure 3-20 Relative assay absorbances in the presence of various metal ions. 62
Figure 3-21 (a)AuNP-based GFAAS amplification method for the sensitive detection of Hg2+ ions. (b) Melting curve of the sandwich structure (MMP/bridge 2/AuNP) in the presence and absence of Hg2+ ions. 66
Figure 3-22 Schematic representation of the hypothesis for improvement of the analytical sensitivity of the detection system via the use of a larger AuNP probe. 69
Figure 3-23 Analytical signal intensities plotted as a function of Hg2+ concentration (a) with the MMP-bridge 2-AuNP(55) structure and (b) with the MMP-bridge 3-AuNP(55) structure. 71
Figure 3-24 Schematic representation of the mechanism responsible for the change in the obtained linear range with the use of different bridge sequences. 72
Figure 3-25 Melting curves of the sandwich structure (MMP-bridge 3-AuNP(55)) in the presence and absence of Hg2+ ions (0.5 μM). 73
Figure 3-26 Relative assay absorbances in the presence of various metal ions. 74

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