脂肪體學 (Lipidomics)，定義為生物系統中針對脂質分子的特徵及有興趣的
部分進行系統性分析 (systems-level analysis)。在生物分子中，脂質扮演相當重要
的角色，除了構成細胞膜的骨架外，也參與能量儲存、蛋白質表現、基因調控等
生化反應。在2002 年，諾貝爾化學獎頒發給Koichi Tanaka，原因是他將
MALDI-MS 應用在生物分析領域上，也開啟了基因體學、蛋白質體學、脂肪體
學等跨領域研究。隨著奈米科技的引進，應用於MALDI 質譜的奈米分析方法已
經能夠靈敏的偵測/分析真實樣品。
第一部分，利用簡單的有機溶劑萃取癌症及癌症幹細胞的脂肪，以石墨烯輔
助雷射脫附游離質譜法 (GALDI-MS) 分析癌症及癌症幹細胞之脂肪體學。在樣
品點樣方法，以石墨烯為基質使用四種不同方法找到最佳化，也證實最佳的偵測
模式。我們也試著利用石墨烯為基質及石墨烯的共同基質 (co-matrix) ，對於癌
症及癌症幹細胞的脂質進行MALDI-MS 分析。
第二部分，探討不同氧化鋅奈米材料的大小/形狀對於革蘭氏陽性
(gram-positive) 和革蘭氏陰性細菌 (gram negative) 的影響。藉由細菌在各種濃度
的氧化鋅奈米材料培養下，研究細菌生長曲線並和觀察奈米材料對於細菌的毒性
/生物相容特性。為了確認氧化鋅奈米材料與細菌可能的作用模式，萃取出細菌
的總量脂肪 (total lipids) 進行MALDI-MS 分析，找出細菌脂肪樣品在
MALDI-MS 的最佳基質及偵測模式。最後，利用MALDI-MS 質譜圖說明殺死致
病菌的機制和細菌脂肪破壞對於殺死細菌的影響為何。
第三部分，將綠膿桿菌的複合內毒素添加到人類尿液中，在沒有任何純化及
樣品處理技術下，利用殼聚糖所修飾的奈米磁鐵 (nanomagents) 直接進行質譜分
析。結果顯示，兩種殼聚糖奈米磁鐵皆能有效濃縮尿液中的內毒素，並提高在
MALDI-MS 的偵測靈敏度。最後，對於奈米磁鐵與內毒素的分離機制進行探討。
此研究提供一個新穎的MALDI-MS 平台，未來可應用在生醫/臨床上對於細菌感染達快速、直接、有效的偵測。
第四部分， 利用奈米質譜法 (nano-MALDI-MS) 及奈米拉曼光譜法
(nano-Raman) 對於七種不同的細菌 (三種革蘭氏陽性菌、四種革蘭氏陰性菌) 進
行脂肪體學研究。在MALDI-MS 部分，以傳統基質結合奈米材料 (Au, Pt,
Au/Pt)，進行不同種類細菌的脂質分析，除了有明顯的質譜峰外，也能區分革蘭
氏陽性菌和革蘭氏陰性菌；另外，在拉曼光譜部分，以不同脂質樣品配製方法 (固
相、液相) 找到雷射強度及資料收集時間的最佳化。在固相樣品下，利用Au 和
Pt 奈米粒子，以及不同比例的Au/Pt 做為基材 (substrate)，對於特定的細菌脂質
進行拉曼訊號分析。

Lipidomics can be defined as the characterization of lipid molecules and their interactions in biological systems i.e. a system-level analysis for lipidome. Lipids are an integral part of biomolecules. In addition to this, they also are a part of cell membranes, store energy, participate in the expression of proteins and are involved in gene regulation for biochemical actions. The Nobel Prize in Chemistry in 2002, Koichi Tanaka and John Fenn was awarded to the development of MALDI and ESI techniques. Both these techniques have been applied to biomolecule analysis and paved a doorway for interdisciplinary research involving, genomics, proteomics, lipidomics. With the introduction of nanotechnology, the detection sensitivity and the ability to analyze real samples have been made possible through nanomaterial based mass spectrometry. In the first application, lipids from cancer and cancer stem cells where extracted in organic solvent systems and graphene has been used as matrix for the analysis of the cancer lipids using MALDI-MS analysis. For the first time the application of graphene-assisted laser desorption ionization mass spectrometry (GALDI-MS) for lipidomics profiling of cancer and cancer stem cells has been demonstrated. We have also used this matrix for the successful differentiation between normal breast cells and breast cancer cells and cancer stem cells. This approach can be used for the discovery of potential biomarkers in biomedicine based on lipidomic profiling. In the second application, we reported the successful inhouse synthesis of ZnO nanoparticle (NPs), quantum dots (QDs) and nanorods (NRs). All these three ZnO nanomaterials were tested for their toxicity/compatibilty towards Pseudomonas aeruginosa and Staphylococcus aureus. The growth pattern of both these bacterial pathogens in the presence of the ZnO nanomaterials and the subsequent lipidomic changes were assessed using MALDI-MS. In the third application, for the first time, the use of CuFeO2@chitosan and Fe3O4@chitosan nanomagnets for affinity based separation and enrichment of trace levels of endotoxin and direct detection using MALDI-MS has been reported. The results showed that the CuFeO2@chitosan nanomagnets appeared to be more effective than Fe3O4@chitosan nanomagnets. Consequently, this approach proposes a novel MALDI-MS platform that can be further applied for biomedicine/clinical applications for rapid, direct and effective detection of bacterial infections. In the fourth application, rapid differentiation of gram negative and gram positive bacteria based on nanoparticle enabled fatty acid profiling using nano-Raman and nano-MALDI-MS. The results showed that Au/Pt NPs in the ratio of 1:1 combined with 9-AA matrix could lead to distinct lipid profiling for differentiation between gram positive and gram negative bacteria using nano-MALDI-MS. Also, in case of nano-Raman using Au NPs/Pt NCs as solid Raman substrates, specific peaks unique to specific bacteria were identified.

論文審定 書 .................................................................................................................................... i
誌 謝 .................................................................................................................................... ii
中文 摘要 .................................................................................................................................... iii
英文 摘要 .................................................................................................................................... v
目 錄 .................................................................................................................................... vii
圖目錄 ..................................................................................................................................... xi
第一章 緒論.................................................................................................................. 1
1.1 前言……………………………………………………………………………………...1
1.2 基質輔助雷射脫附游離質譜法 .................................................................................... 1
1.2.1 MS 之歷史發展 ....................................................................................................... 2
1.2.2 MS 儀器及工作原理 ............................................................................................... 2
1.2.3 MALDI-MS 基質效應 ............................................................................................. 3
1.2.4 奈米材料在MALDI-MS 之應用 ........................................................................... 4
1.3 脂肪體學 ........................................................................................................................ 5
1.3.1 細菌脂肪體學應用於基質輔助雷射脫附/游離質譜法 ........................................ 5
1.3.2 癌細胞脂肪體學應用於基質輔助雷射脫附游離質譜法 ..................................... 7
1.4 拉曼光譜法 .................................................................................................................... 8
1.4.1 拉曼光譜法概述及原理 ......................................................................................... 8
1.4.2 表面增強拉曼光譜散射 ......................................................................................... 8
1.4.3 表面增強拉曼光譜散射應用在生物領域 .............................................................. 8
1.5 研究目標 ........................................................................................................................ 9
1.6 參考文獻 ...................................................................................................................... 11
第二章 利用石墨烯輔助雷射脫附游離質譜法進行癌症及癌症幹細胞之脂肪體學
研究 .............................................................................................................................. 16
2.1 目的 .............................................................................................................................. 16
2.2 實驗部分 ...................................................................................................................... 17
2.2.1 儀器 ....................................................................................................................... 17
2.2.2 藥品 ....................................................................................................................... 18
2.2.3 膠體石墨烯的製備 ............................................................................................... 18
2.2.4 細胞培養 ............................................................................................................... 19
2.2.5 萃取細胞中的脂肪 ............................................................................................... 19
2.2.6 利用MALDI-MS 對於人類乳房正常細胞、癌細胞、癌症幹細胞之脂質進行分
析 ..................................................................................................................................... 20
2.2.7 MALDI-MS 偵測 ................................................................................................... 21
2.3 結果與討論 .................................................................................................................. 23
2.3.1 石墨烯的特性 ....................................................................................................... 23
2.3.2 基質效應對於癌症和癌症幹細胞之脂肪分析 ................................................... 25
2.3.3 比較石墨烯作為基質及共同基質 ....................................................................... 25
2.3.4 以石墨烯當作基質進行不同的樣品製備 ........................................................... 29
2.3.5 以GALDI-MS 對於癌症細胞和癌症幹細胞脂肪體學進行探討 ...................... 32
2.3.6 石墨烯作為MALDI-MS 基質之機制 ................................................................. 34
2.3.7 推測石墨烯與癌細胞脂質分子間的親和力 ....................................................... 34
2.4 結論 .............................................................................................................................. 36
2.5 參考文獻 ...................................................................................................................... 36
第三章 利用基質輔助雷射脫附游離質譜法探討氧化鋅奈米材料對於致病菌生長
影響和細菌脂肪體學之研究...................................................................................... 40
3.1 目的 .............................................................................................................................. 40
3.2 實驗部分 ...................................................................................................................... 42
3.2.1 儀器 ....................................................................................................................... 42
3.2.2 藥品 ........................................................................................................................ 42
3.2.3 製備氧化鋅奈米材料 ........................................................................................... 43
3.2.4 氧化鋅奈米材料對於細菌生長影響 ................................................................... 44
3.2.5 萃取細菌中的脂肪 ............................................................................................... 44
3.2.6 MALDI-MS 偵測 ................................................................................................... 45
3.3 結果與討論 .................................................................................................................. 45
3.3.1 氧化鋅奈米材料特性 ........................................................................................... 45
3.3.2 氧化鋅奈米材料在綠膿桿菌及金黃色葡萄球菌之毒性及生物相容性探討 ... 47
3.3.3 利用MALDI-MS 進行綠膿桿菌及金黃色葡萄球菌之脂肪分析 ..................... 51
3.4 結論 .............................................................................................................................. 58
3.5 參考文獻 ...................................................................................................................... 59
第四章 殼聚醣奈米磁鐵萃取和質譜檢測尿液中致病菌的內毒素 ....................... 62
4.1 目的 .............................................................................................................................. 62
4.2 實驗部分 ...................................................................................................................... 62
4.2.1 儀器 ....................................................................................................................... 62
4.2.2 藥品 ....................................................................................................................... 63
4.2.3 製備CuFeO2@chitosan 奈米粒子 ....................................................................... 63
4.2.4 製備Fe3O4@chitosan 奈米粒子 ........................................................................... 64
4.2.5 脂多糖萃取方法 ................................................................................................... 67
4.2.6 樣品製備 ............................................................................................................... 67
4.3 結果與討論 .................................................................................................................. 70
4.3.1 CuFeO2@chitosan 奈米粒子特性 ......................................................................... 70
4.3.2 Fe3O4@chitosan 奈米粒子特性 ............................................................................. 70
4.3.3 MALDI-MS 偵測內毒素 ...................................................................................... 73
4.3.4 尿液中偵測內毒素 ............................................................................................... 76
4.3.5 殼聚糖奈米磁鐵對內毒素回收和MALDI-MS 偵測 ......................................... 79
4.3.6 奈米磁鐵對內毒素分離機制 ............................................................................... 83
4.4 結論 .............................................................................................................................. 86
4.5 參考文獻 ...................................................................................................................... 86
第五章 奈米拉曼光譜法和奈米基質輔助雷射脫附游離質譜法應用在脂肪酸研究
達快速區分革蘭氏陰性及革蘭氏陽性細菌 ............................................................. 90
5.1 實驗部分 ....................................................................................................................... 90
5.1.1 儀器 ........................................................................................................................ 90
5.1.2 藥品 ....................................................................................................................... 91
5.1.3 製備金奈米粒子 ................................................................................................... 93
5.1.4 製備Au@MUA 奈米粒子 ................................................................................... 93
5.1.5 製備鉑奈米粒子及鉑奈米方塊 ........................................................................... 93
5.1.6 細菌培養液 ........................................................................................................... 94
5.1.7 萃取細菌中的脂肪 ................................................................................................ 94
5.1.8 MALDI-MS 偵測 ................................................................................................... 95
5.1.9 拉曼分析 ............................................................................................................... 95
5.2 結果與討論 ................................................................................................................... 96
5.2.1 金和鉑奈米材料的特性 ....................................................................................... 96
5.2.2 MALDI-MS 基質最佳化 ....................................................................................... 98
5.2.3 利用nano-MALDI-MS 進行細菌脂質分析 ...................................................... 100
5.2.4 利用nano-MALDI-MS 區分不同種類的細菌脂質 .......................................... 103
5.2.5 拉曼光譜儀對於細菌脂質進行最佳化探討 ..................................................... 105
5.2.6 利用拉曼光譜儀對於細菌脂肪體學進行分析 ................................................. 105
5.2.7 利用nano- Raman spectroscopy 區分不同種類的細菌脂質 ............................. 108
5.3 結論 ............................................................................................................................ 111
5.4 參考文獻 .................................................................................................................... 111
第六章 總結.............................................................................................................. 113

第一章
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(5) Lee, C. H. ; Gopal, J. ; Wu, H. F.“Ionic solution and nanoparticle assisted MALDI-MS as bacterial biosensors for rapid analysis of yogurt”Biosensors and Bioelectronics 2012, 31, 77-83.
(6) Gopal, J. ; Narayana, J. ; Wu, H. F.“TiO2 nanoparticle assisted mass
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第二章
(1) Sarkar, B. ; Dosch, J. ; Simeone, D. M.“Cancer Stem Cells: A New Theory Regarding a Timeless Disease”Chem. Rev. 2009, 109, 3200–3208.
(2) Cao, Lu. ; Zhou, Y. ; Zhai, B. ; Liao, J. ; Xu, W. ; Zhang, R. ; Li, J. ; Zhang, Y. ; Chen, L. ; Qian, H. ; Wu, M. ; Yin, Z.“Sphere-forming cell subpopulations with cancer stem cell properties in human hepatoma cell lines”BMC Gastroenterol. 2011, 11: 71.
(3) Rahman, M. ; Deleyrolle, L. ; Vedam-Mai, V. ; Azari, H. ; Abd-El-Barr ,
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第四章
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第五章
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