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研究生:邱緯真
研究生(外文):Wei-Jane Chiu
論文名稱:功能性奈米材料應用於偵測纖溶相關蛋白與循環腫瘤細胞及腫瘤細胞的光治療
論文名稱(外文):Applications of Functional Nanomaterials for Detection of Fibrinogen-Related Protein and Circulating Tumor Cells, and Cancer Cell Phototherapy
指導教授:黃志清黃志清引用關係
指導教授(外文):Chih-Ching Huang
口試委員:何彥鵬吳彰哲林翰佳許邦弘黃郁棻
口試委員(外文):Yen-Peng HoChang-Jer WuHan-Jia, LinPang-Hung, HsuYu-Fen Huang
口試日期:2016-01-11
學位類別:博士
校院名稱:國立臺灣海洋大學
系所名稱:生命科學暨生物科技學系
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:157
中文關鍵詞:奈米材料纖溶酶雷射脫附游離質譜循環腫瘤細胞腫瘤光治療
外文關鍵詞:nanomaterialsplasminlaser desorption/ionization mass spectrometrycirculating tumor cellstumor phototherapy
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本研究中我們主要為開發功能性奈米材料應用於偵測纖溶相關蛋白(Fibrinolytic-Related Proteins)、循環腫瘤細胞(Circulating Tumor Cells; CTCs)及光治療(Phototherapy)腫瘤細胞(Tumor Cells)。於偵測纖溶相關蛋白及循環腫瘤細胞部分,結合雷射脫附游離質譜(Laser desorption/ionization Mass Spectrometry; LDI-MS)作為一分析工具進行檢測。纖溶系統為一藉由纖溶酶(plasmin)將纖維蛋白降解而回復正常血管功能的機制,於第一個研究工作中,在仿生理條件下將修飾纖維蛋白原的金奈米粒子(FibrinogenGold Nanoparticles; FibAu NPs)探針和纖溶酶反應後,降解金奈米粒子表面之纖維蛋白原,導致金奈米粒子聚集,再將其吸附上混合纖維素脂膜(Mixed Cellulose Ester Membrane; MCEM)。因纖溶酶降解FibAu NPs後使其與MCEM吸付能力降低,故在脈衝雷射(355 nm, 6 ns)照射MCEM下,碎裂Au NPs所形成金團簇訊號強度會下降,藉由金團簇訊號改變可定量溶液中纖溶酶。MCEM在LDI-MS中可降低背景雜訊干擾,提高偵測靈敏性亦提供良好的再現性(相對標準偏差小於5%)。利用此方法可成功的在人類血清環境中高度靈敏地偵測纖溶酶(偵測極限: ca. 0.1 nM) 並具有高度選擇性。此簡單、快速、靈敏、高通量的檢測法,於臨床醫學檢驗蛋白活性上相當具有發展性。於第二個研究中我們探討金奈米薄膜(Gold Nanofilms; Au NFs)於不同厚度(10100 nm)在脈衝雷射(355 nm, 6 ns)照射下形成Au NPs大小、密度以及金團簇訊號強度的變化,研究發現Au NFs厚度、脈衝雷射能量與金奈米粒子的形成有相當的關係,較薄Au NFs與高雷射能量易形成高密度小粒子的Au NPs。隨後,我們藉由金硫鍵結(Au-S bond)於Au NFs(厚度20 nm)表面修飾具與特定腫瘤細胞專一性結合MUC1的功能性核苷酸適合體(MUC1 Aptamer; AptMUC1),合成出具專一性之AptMUC1−Au NFs偵測平台,結合雷射脫附游離質譜可透過監測金團簇訊號強度變化靈敏地在人類全血環境中高選擇性的檢測乳癌腫瘤細胞(MCF-7),其偵測極限可達至10顆癌細胞。我們所開發出偵測循環腫瘤細胞的方法具有簡單、快速和易操作等優點,將來可應用於腫瘤轉移的研究。於第三部分研究中,我們致力於發展奈米材料應用於結合腫瘤細胞的光熱治療(Photothermal Therapy; PTT)及光動力治療(Photodynamic Therapy; PDT)的雙重療效(PTT/PDT)試劑並成功的在荷瘤老鼠實驗上獲得良好的治療效果。我們利用二價鐵離子在三羥甲基氨基甲烷硼酸鹽溶液反應下會與還原型氧化石墨烯(reduced Graphene Oxide; rGO)自組裝形成氫氧化鐵/氧化鐵石墨烯複合(FeOxH‐rGO)的方式簡易製備雙重光治療之複合型奈米材料。奈米石墨烯及其氧化衍生物具有較大的比表面積和優異的光熱效果等性質,已成為奈米醫學領域中備受關注的研究重點。由於氧化石墨烯特殊表面結構及官能基使其在紅外光區域有很強的吸收及光熱轉換效率,大幅增加了腫瘤細胞光熱治療的應用性。而我們所製備的FeOxH‐rGO表面沉積之不規則氫氧化鐵/氧化鐵在光照射下則會進行類似Fenton反應於水溶液中產生氧化自由基(Reactive Oxygen Speices; ROS)促進腫瘤細胞凋亡達到光動力治療之效果。我們使用808 nm雷射作為FeOxH–rGO進行腫瘤細胞光治療的光源,在體外(in vitro)及體內(in vivo)動物實驗部分均有相當顯著的治療效果。此一結合光熱及光動力治療(PTT/PDT)效果之奈米複合型材料,不僅製備簡易、成本較低,其以近紅外光源做為啟動治療開關達到雙重治療效果,大幅降低了在臨床腫瘤細胞治療上風險及後遺症,在臨床治療上相當具有發展潛力。
In this thesis, we describe a pulsed-laser desorption/ionization mass spectrometry (LDI-MS)-based approach for the detection of plasmin with subnanomolar sensitivity through the analysis of gold (Au) clusters desorbed from fibrinogen-modified gold nanoparticles (Fib−Au NPs) on a mixed cellulose ester membrane (MCEM) and for the detection of tumor cells through the analysis of gold cluster ions [Aun]+ from aptamer-modified gold nanofilms (Au NFs). In the first part, the sensing mechanism of Fib−Au NPs probe is based on the plasmin-mediated cleavage of the Fib−Au NPs and the reduced interaction between Fib−Au NPs and MCEM. The Fib−Au NPs were deposited onto the MCEM to form a highly efficient background-free surface assisted LDI substrate. Under pulsed laser irradiation (355 nm, 6 ns), the cleaved Fib−Au NPs decreased the adsorbed on MCEM. As a result, the intensities of the signals of the Au clusters decreased in the mass spectra. This approach provided a highly amplified target labeling indicator for the analysis of plasmin. Under optimized conditions, this probe was highly sensitive (limit of detection: ca. 0.1 nM) and selective (by at least 1000-fold over other enzymes and proteins) toward plasmin; it also improved the reproducibility (<5%) of ion production by presenting a more-homogeneous substrate surface relative to surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS) analysis. Relative to conventional assays, this new probe for plasmin offers the advantages of high sensitivity and selectivity and high throughput, with great potential for practical studies of fibrinolytic-related proteins. In our second study, we observed not only the transformation of Au NFs to gold nanoparticles (Au NPs) but also the formation of gold cluster ions ([Aun]+; n = 1−5) under the irradiation of nanosecond pulsed-laser. The sizes and density of the formed Au NPs and the abundance of [Aun]+ were highly dependent on the thickness of Au NFs (10100 nm). The Au NFs form highly dense Au NPs on substrate and favor to desorption and ionization of gold cluster ions. The signal intensities of the [Aun]+ through the monitoring by mass spectrometry were decreased with increasing the thickness of Au NFs from 10 nm to 100 nm and after modified with thiolated DNA. We further demonstrated that the mucin1-binding aptamer modified Au NFs (AptMUC1−Au NFs) could selectively enrich of MCF-7 cells (human breast adenocarcinoma cell line) in blood samples and coupling with LDI-MS analysis could selectivly detection of MCF-7 cells as low as 10 cells in blood samples by monitoring the [Aun]+. This approach offers the advantages of high sensitivity, selectivity and high throughput for the detection of circulating tumor cells (CTCs), showing great potential as a powerful analysis platform for the application in clinical diagnosis of tumor metastasis. In the third study, we employed iron hydroxide/oxide immobilized-reduced graphene oxide (FeOxH–rGO) nanocomposites as a combination theory of photothermal therapy (PTT) and hotodynamic therapy (PDT) agent for cancer therapy. We investigated the PTT and PDT therapy abilities of FeOxH–rGO nanocomposites in cell line and in living mice. Compared to GO and rGO, which have been well known for great photothermal effect, FeOxH–rGO nanocomposites exhibits much higher photothermal conversion efficiency; ~2.6 and 1.7 fold higher than that of GO and rGO, respectively. FeOxH–rGO also induced >7-fold formation of reactive oxygen species (ROS) under NIR irradiation relative to cell medium only. Furthermore, we demonstrated that FeOxH–rGO nanocomposites have much better phototherapy effects for mice bring tumors relative to rGO. Therefore, FeOxH–rGO nanocomposite has a great potential to develop a high efficacy and safety therapeutic agent of combinatorial PDT/PTT for cancer therapy.
中文摘要……………………………………………………………………………….…...……i
Abstract……………………………………………………………………………….……..….ii
目錄…………………………………………………...………………………………..…….....vii
圖目錄…………………………………………………………………………………..………xii
第一章 緒論……………………………………………………………………………..............1
1. 1雷射脫附游離質譜法(Laser desorption/ionization Mass Spectrometry; LDI-MS) 1
1.1.1 LDI-MS 的發展歷史 1
1.1.2 LDI-MS 奈米材料輔助樣品脫附游離機制 2
1.1.2.1 LDI-MS以金奈米粒子為基質之應用 2
1.2 LDI-MS奈米材料與脈衝雷射輔助質譜之應用 4
1.2.1 LDI-MS於重金屬離子之檢測應用 5
1.2.2 LDI-MS於蛋白質之檢測應用 5
1.2.3 LDI-MS於小分子之檢測應用 6
1.2.4 LDI-MS於DNA之檢測應用 7
1.3纖溶系統(fibrinolytic system) 7
1.3.1 纖維蛋白原與其聚合機制簡介 7
1.3.2 纖溶酶與其機制簡介 ….8
1.4 循環腫瘤細胞(Circulating Tumor Cells; CTCs) 9
1.4.1 CTCs與腫瘤臨床分期和診斷 10
1.4.2 CTCs與預後評估 10
1.4.3 CTCs與療效監測 11
1.4.4 CTCs與個體化治療方案 12
1.4.5 CTCs的檢測方式 13
1.4.5.1 CTCs的分離和富集系統 13
1.4.5.1.1免疫磁性分離法 13
1.4.5.1.2基於形態學的富集法 14
1.4.5.2 CTCs的檢測和鑑定系統 15
1.4.5.2.1 免疫細胞化學技術 15
1.4.5.2.2 RT-PCR檢測技術 16
1.4.6 基於奈米材料應用於CTCs的富集系統 16
1.4.6.1 基於磁性奈米材料的CTCs富集系統 17
1.4.6.2 基於非磁性奈米材料的CTCs富集系統 17
1.4.6.3 結合奈米材料與微流體技術應用於CTCs富集系統 19
1.4.7 基於奈米材料應用於CTCs檢測 21
1.4.7.1 基於奈米材料之光學性質應用於CTCs檢測 21
1.4.7.2 基於奈米材料之光聲性質應用於CTCs檢測 22
1.4.7.3 基於奈米材料之電化學性質應用於CTCs檢測 23
1.5 腫瘤細胞的光治療 23
1.5.1 腫瘤細胞的光動力治療 24
1.5.2 奈米材料應用於光動力治療 26
1.5.2.1 奈米材料作為光敏劑之載體 26
1.5.2.1.1 有機奈米載體 27
1.5.2.1.2 無機奈米載體 28
1.5.2.1.3 金屬奈米載體 28
1.5.2.1.4 非金屬奈米載體 29
1.5.2.1.5 以碳材為主的奈米載體 29
1.5.2.1.6 上轉換奈米載體 30
1.5.2.2 奈米材料作為光敏劑 30
1.5.3 腫瘤細胞的光熱治療 31
1.5.4 傳統應用於光熱治療之感光劑 33
1.5.5 奈米材料應用於光熱治療 34
1.5.5.1 金屬奈米粒子應用於光熱治療 34
1.5.5.2 奈米氧化石墨烯應用於光熱治療 37
1.5.5.3 奈米氧化石墨烯複合材料應用於光熱治療 38
1.5.5.3.1 AuGO複合材料 38
1.5.5.3.2 Fe3O4GO磁性複合材料(IONPGO) 39
1.5.5.3.3 TiO2GO複合材料 40
1.5.5.3.4 硫化物-GO複合材料 40
1.5.6 基於複合奈米材料實現腫瘤細胞的光熱/光動力治療 41
1.6 研究動機 43
第二章 利用血纖維蛋白修飾之金奈米粒子吸附於纖維膜上透過質譜分析偵測纖溶相關蛋白 ……………………………………………………………………………………………..44
2.1 前言 45
2.2 實驗材料與方法 47
2.2.1 實驗藥品 47
2.2.2 儀器設備 47
2.2.3 金奈米粒子的合成 48
2.2.4 仿生理環境緩衝溶液(Physiological buffer solution; PBS)配製 49
2.2.5 Tris-HCl緩衝溶液配製 50
2.2.6 製備纖維蛋白原之功能性金奈米粒子(FibAu NPs) 50
2.2.7 纖溶酶(plasmin)酵素活性試驗 50
2.2.8 血清樣品中纖溶酶酵素活性與纖溶酶原(plasminogen)濃度試驗 51
2.3 實驗結果與討論 52
2.3.1 以比色法檢測纖溶酶 53
2.3.2 以傳統點盤法LDI-MS檢測纖溶酶 54
2.3.3 Fib−Au NPs/MCEM應用於LDI-MS檢測纖溶酶 56
2.3.4 Fib−Au NPs介導偵測纖溶酶之靈敏性與選擇性。 57
2.3.5 血清樣品中對纖溶酶原濃度之偵定 57
2.4 結論 58
第三章 金奈米薄膜於脈衝雷射照射下形成奈米粒子與離子團簇:應用於循環腫瘤細胞檢測 ……………………………………………………………………………………………..60
3.1 前言 60
3.2 實驗材料與方法 63
3.2.1 實驗藥品 63
3.2.2儀器設備 64
3.2.3製備Au Nanofilm chip (Au NF)和LDI-MS條件 64
3.2.4 LDI-MS分析DNA修飾之Au NF 65
3.2.5細胞培養 65
3.2.6 AptMUC1Au NFs結合LDI-MS檢測MCF-7細胞 66
3.2.7 於真實血液樣品中偵測MCF-7細胞 66
3.3 結果與討論 67
3.3.1 Au NFs形態鑑定 67
3.3.2 雷射誘導的Au NFs相轉變 67
3.3.3 金離子團簇的生成 69
3.3.4 表面覆蓋DNA之Au NFs於雷射照射下之影響 70
3.3.5 以AptMUC1−Au NFs偵測腫瘤細胞 71
3.4 結論 73
第四章一步合成FeOxH–rGO複合奈米材料應用於腫瘤之光熱/光動力雙重治療 75
4.1 前言 75
4.2 實驗材料與方法 78
4.2.1 實驗藥品 78
4.2.2 儀器設備 79
4.2.3 製備氧化鐵還原氧化石墨烯 (FeOxHrGO) 80
4.2.4 細胞培養 81
4.2.5 監測奈米材料於雷射誘導下之升溫曲線 81
4.2.6 監測細胞活性實驗 81
4.2.7 監測細胞ROS產量實驗 82
4.2.8 於動物實驗中進行PTT/PDT實驗 82
4.2.9 組織切片 83
4.3 實驗結果與討論 84
4.3.1 FeOxH–rGO的合成與鑑定 84
4.3.2 FeOxH–rGO複合材料之光熱特性 86
4.3.3 FeOxH–rGO複合材料於腫瘤細胞(in vitro)進行PTT/PDT 88
4.3.4 FeOxH–rGO複合材料於荷瘤小鼠(in vivo)進行PTT/PDT 92
4.4 結論 94
5 總結..........................................................................................................................................96
6 本章圖表 97
7 參考文獻 127

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