臺灣博碩士論文加值系統

乳癌是全球女性發生率位居第一的癌症，死亡率為第二。近20年來發現另一個影響乳癌治療結果的危險因子是人類表皮生長因子受體(HER2)，此受體過度表達會加速癌細胞分裂、轉移、造成抗藥性，導致治療失敗。因此，HER2基因是影響乳癌前兆的一個重要因素，大約有25%-30%左右的乳癌患者，受到體內癌細胞HER2基因過量表現的影響，刺激乳癌細胞以不受控制的方式生長和分裂，這被稱為HER2陽性乳腺癌。HER2之胞外區片段(ECD)於正常人血液中的濃度在2到15 ng ml-1之間，而患有陽性乳腺癌的患者的HER2-ECD濃度超過15 ng ml-1。
本研究利用Au/MXene與HER2-ECD抗體-1 (antibody-1, Ab1)修飾在拋棄式金電極上 (Disposable gold electrode, DGE)，再利用NG/CuCoMn MOF衍生物(Nitrogen doped graphene/CuCoMn MOF derived material, 簡稱NG/CuCoMn MOFd)連接HER2-ECD抗體-2 (antibody-2, Ab2)，並使用HER2-ECD抗原(antigen, Ag)連接Ab1/Au/MXene及NG/CuCoMn MOFd/Ab2形成NG/CuCoMn MOFd/Ab2/Ag/Ab1/Au/MXene/DGE三明治型免疫感測器。研究中利用X射線繞射儀(XRD)、傅立葉轉換紅外線光譜(FTIR)、化學能譜儀(XPS)、掃描式電子顯微鏡(SEM)確認其表徵，並使用電化學循環伏安法(CV)和微分脈伏安法(DPV)作電化學分析。利用DPV顯示感測器的電流響應對HER2-ECD具有線性關係，其線性範圍在1.0 × 10−4 至 50.0 ng mL−1，R2值為0.98247 (n=5, RSD<5%)，偵測極限(LOD)為8.0 × 10−4 ng mL−1。此免疫感測器具有高選擇性、穩定性及再現性，以及利用真實樣品血清測量具有良好的回收率，有望用於乳癌的早期發現與診斷。

Breast cancer is the most frequently diagnosed cancer in women and ranks second among causes for cancer related death in women. Clinically, Human Epidermal growth Receptor 2 (HER2) is one of the most diagnostic biomarkers to facilitate breast cancer cell proliferation and malignant growth. The extracellular domain (ECD) of HER2 can be shed into the bloodstream. It can be quantified to provide an essential contribution to diagnostics and patient follow-up.
In this study, a sensitive sandwich-type electrochemical immunosensor was developed for the quantitative detection of HER2-ECD. Herein, a disposable gold electrode (DGE) modified by gold nanoparticles decorated Ti3C2Tx (Au/MXene) was utilized as a sensing platform to immobilize the primary antibody (Ab1/Au/MXene). Subsequently, nitrogen doped graphene with the copper-cobalt-manganese organic framework being calcinated (NG/CuCoMn MOF derived material) was tagged as NG/CuCoMn MOFd, which was used for labeling the secondary antibody (Ab2) to form a probe. Then, HER2-ECD antigen (Ag) was conjugated with Ab1/Au/MXene and NGO/MOF/Ab2. Lastly, the sandwich-type immunosensor (NG/CuCoMn MOFd/Ab2/Ag/Ab1/Au/MXene/DGE) was manufactured to detect HER2-ECD. The chemical structure, crystalline properties, and morphology of the materials were characterized by XRD, FTIR, Raman, XPS, FESEM, and TEM. Under optimized conditions, the prepared immunosensor displayed an excellent linear range of 1.0 × 10−4 to 50.0 ng mL−1, and the detection limit was 8.0 × 10−4 ng mL−1 . This immunosensor had high selectivity, good reproducibility, stability, and acceptable repeatability. Moreover, the proposed immunosensor showed good applicability for determining HER2-ECD in human and BALB/c Nude mice serum samples, indicating its ability to clinical monitor the tumor marker.

摘要 i
ABSTRACT iii
目錄 v
表目錄 xi
圖目錄 xii
第一章 緒論 1
1.1 研究動機 1
1.2 研究目的 2
第二章 文獻回顧 3
2.1 電化學感測器 3
2.1.1 生物感測器 5
2.1.2 免疫感測器 7
2.1.3網印刷電極於感測器上的應用 8
2.2 有機金屬框架 (Metal Organic Frameworks, MOFs) 10
2.2.1 ZIF-67 13
2.2.2 有機金屬框架 (Metal Organic Frameworks, MOFs)於感測器上的應用 15
2.3 氧化石墨烯(Graphene oxide, GO) 17
2.3.1 氮摻雜石墨烯 (Nitrogen-doped Graphene, NG) 18
2.3.2 氮摻雜石墨烯(Nitrogen-doped Graphene, NG) 於感測器上的應用 19
2.4 MXene 20
2.4.1 金奈米顆粒/碳化鈦(Au/MXene) 23
2.4.2 MXene於感測器上的應用 23
2.5 乳癌 24
2.5.1 人類表皮生長因子受體(HER2-ECD) 25
2.5.2 人類表皮生長因子受體(HER2-ECD)於感測器上的檢測 26
第三章 材料與方法 27
3.1 實驗藥品與儀器 27
3.1.1 實驗藥品 27
3.1.2 實驗儀器 29
3.2 實驗架構與儀器檢測 30
3.2.1 掃描式電子顯微鏡 31
3.2.2 穿透式電子顯微鏡 32
3.2.3 X射線繞射儀 33
3.2.3 X光光電子能譜 34
3.2.4 傅立葉轉換紅外線光譜儀 35
3.2.5 拉曼光譜 36
3.2.5 電化學分析儀 37
3.3 實驗步驟 39
3.3.1 銅鈷錳-有機金屬框架(CuCoMn MOF)的製備 39
3.3.2 氮摻雜孔洞石墨烯(NG)的製備 39
3.3.3 氮摻雜石墨烯/銅鈷錳-有機金屬框架(NG/CuCoMn MOF derived material)的製備 39
3.3.4 碳化鈦(MXene)的製備 40
3.3.5 金奈米顆粒/碳化鈦(Au/MXene)的製備 40
3.3.6 電極活化之步驟 40
3.3.7 HER2-ECD感測器之製備與檢測 41
3.3.8 TEM試片之製備 43
3.3.9 FESEM試片之製備 43
3.3.10 XPS試片之製備 43
3.3.11 細胞毒性測試 44
第四章 結果與討論 45
4.1 材料性質分析 45
4.1.1 場發式掃描式電子顯微鏡(FE-SEM) 45
4.1.2 穿透式電子顯微鏡(TEM) 48
4.1.3 X射線繞射分析(XRD) 50
4.1.4 化學能譜儀分析(XPS) 52
4.1.5 傅立葉轉換紅外線光譜(FT-IR) 55
4.1.6 拉曼光譜 56
4.2 電化學分析 57
4.2.1 不同組成修飾電極 57
4.2.2 抗體(Antibody)最佳修飾條件 58
4.2.3 牛血清蛋白(BSA)最佳修飾條件 60
4.2.4 抗原(Antigen)最佳修飾條件 61
4.2.5 pH值與溫度的最佳修飾條件 62
4.2.6 感測器的逐層電化學分析 64
4.2.7 不同掃描速率的分析 66
4.2.8 不同濃度之HER2-ECD測試 68
4.2.9 干擾測試 70
4.2.10 穩定性和再現性測試 71
4.3 真實樣品分析 74
4.3.1 酵素免疫法分析 74
4.3.2 真實樣品測試 76
4.4 體外試驗(In vitro test) 78
4.4.1 細胞毒性分析 78
4.4.2 動物血清測試 79
第五章 結論 81
參考文獻 82

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