本論文主要是為特定藥物的分析、疾病的檢驗及蛋白質的研究開發新的質譜方法。在開發藥物分析方法方面，我們針對一個化學組成極度複雜的統計型共聚胜肽藥物，建立一個可以比對原廠藥 (Innovator drug) 與生物相似性藥品 (Biosimilar) 之化學組成的質譜方法，並結合主成份分析法 (Principle Component Analysis, PCA) 及階層式集群分析 (Hierarchical Cluster Analysis, HCA) 等多變量統計法則的數據處理，進行其相似性的確認。並採用分類的策略，建立類別模型作為藥物品制控制的標準，利用分類的結果確認每一批次的產品。而針對此複雜藥品的分子量分佈方面，有別於該藥之原廠採用凝膠管柱層析的方法來訂定，本研究開發以基質輔助雷射脫附游離質譜法 (MALDI/MS) 來對此藥物進行分子量分佈一致性的量測，確認其對此類藥品的分子量具有鑑別度，並開發訊號處理方法來評估無法解析的質譜訊號，完成對原廠藥與生物相似性藥品的分子量相似性的評估。
在疾病診斷方面，本論文旨在延續之前所發展的檢驗 albuminuria 之質譜方法，並結合統計法則開發一個半定量 albuminuria 的策略。以尿液樣品不進行前處理為原則，即樣品內不加入任何內標物質，僅混以 MALDI 基質進行樣品結晶，即進行 MALDI-TOF/MS 的正離子線性模式分析。本研究的原理是利用不同濃度下白蛋白不同價數的離子 (一價、二價、三價、四價或五價) 在 MALDI-TOF/MS 偵測所得的離子訊號貢獻度不同的現象，採用主成份分析法及商用軟體中的 2D peaks distribution 程式運算質譜數據，先以添加不同濃度 albumin 的正常人尿液建立模型，再將白蛋白尿患者的尿液樣品以本系統分析，進行對尿液中的白蛋白半定量的工作。
在蛋白質的研究方法上，我們利用液態電噴灑雷射脫附游離質譜法 (Liquid Electrospray Laser Desorption Ionization Mass Spectrometry, Liquid-ELDI/MS) 在沒有任何前處理的情況下直接在各式溶液中確認 蛋白質分子，溶液種類包含酸、鹼、緩衝液、有機溶劑、或洗滌劑等溶液，既然在分析前不需要經過改變酸鹼性或溶劑組成等處理步驟，這項技術對於用來快速篩檢溶液中蛋白質分子結構的完整性是一個非常實用的方法。另一方面，若調整 liquid-ELDI 中電噴灑水溶液的組成，降低酸與有機溶劑的比例，則可以在偵測過程中保留蛋白質的三度空間結構，進而提供溶液中蛋白質的構形 (conformation) 訊息。
另外一個藥物分析的需求是開發一個可以直接偵測固相胜合成樣品的質譜法，確認每一反應步驟完全之後再進行下一步驟，以確保合成的產率與純度。本研究發展的即時監測固相胜肽合成過程的質譜系統 (Real-time monitor solid phase peptide synthesis by mass spectrometry)，利用脈衝雷射及電噴灑的裝置，於大氣壓力下直接偵測連接於一般市售的固相支撐體及linker 上的胜肽產物，整個偵測流程只需要將待測的樹脂置於有機溶劑中，不用水解或分離等前處理流程，即可直接置於質譜儀入口處進行分析，在極短的時間內獲得該段胜肽產物的分子離子訊號，不會有酸性水解所造成碎片訊號。因此利用此快速又準確的特點，固相胜肽合成反應中每一個階段都可以即時用本系統確認產物，如此一來整個固相合成的品質會顯著的提升，對節省成本及提高產率也會有極大的幫助。

New methods for drugs analysis, disease diagnosis, and protein analysis by using modern mass spectrometry are developed in this thesis. In drugs analysis, we develop a rapid assessment of molecular similarity between an extremely complex innovator product and a candidate biosimilar by mass spectrometry. Protease digestion combined with Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry were successfully used to peptides mapping and de novo peptides sequencing. Overall ion signals obtained by MALDI-TOF/MS were processed by two multivariate statistics including principle component analysis (PCA) and hierarchical clustering analysis. Based on the variances of the peptide profile, innovator product and normally synthesized biosimilar were grouped on the PCA score plot, while impure biosimilar or abnormally synthesized biosimilar were distinctly separated. The results of hierarchical cluster analysis also revealed high conformity between innovator product and normally synthesized biosimilar. Abnormally synthesized products, as a set of quality controller, could be discriminated from innovator product favorably. Another quality control strategy developed in this study is building classification model, batches of product is successfully evaluated. Furthermore, the similarity of molecular weight distribution between these complex drugs is determined.
Another target of drug analysis is to develop a vital analytical method to directly detect the peptides synthesized on the resin. Except an organic solvent is transformed to disperse the resin-peptides samples, no other sample pretreatments are required before the MS detection. When using conventional destructive analytical methods to characterize masses of compounds on the solid supports, acid hydrolysis or acid cleavage of the peptide molecules depart from insoluble resin is required. In consequence, side-reactions such as de-blocked or de-protected cause additional fragments in the system, and determination of the intermediates or products are confusing and difficult. Unlike these acid release methods, the molecular weight information of the intact peptide molecules can be obtained in our direct analyses system, and sample consumption is also great reduced. Moreover, our strategy performed the analysis in the ambient environment is more straightforward for real-time monitor reaction and quality control than those techniques in high vacuum system. This direct non-destructive on-line monitoring method would allow following step by step peptide solid-phase synthesis be well quality controlled.
In the disease diagnose part, MALDI-TOF mass spectrometry combined with statistics were used to perform semi-quantitative albuminuria diagnoses. Based on the fact that the contributions of singly, doubly, triply, and quadruply charged albumin ions from the samples were inflected according to the concentration change. The severity of albuminuria of patients can be estimated by 2D peaks distribution (peaks ranking by p-value) or supervised principal component analysis (PCA).
In protein analysis study, we use liquid electrospray laser desorption ionization mass spectrometry (liquid-ELDI/MS) to directly characterized the proteins stored in different solutions containing acids, bases, buffers, organic solvents, or detergents without extra sample pretreatment. A drop of the sample solution was applied on a stainless steel plate., and then the surface of the sample drop was irradiated with a pulsed laser. The laser energy absorbed by the metal plate and surrounding solvent led to the desorption of protein molecules or the formation of fine droplets containing protein molecules. The desorbed protein species were then post-ionized within an electrospray plume to generate the ESI-like protein ions. Since no pH or composition adjustment of the sample solution is needed, this technique is useful for rapid and high throughput screening of the proteins in a solution to check their integrality after storage or prior to further biochemical treatment. In addition,, native and denatured conformation of the proteins can be distinctly examined by using acid-free and organic solvent-reduced ESI solutions in liquid-ELDI.

論文審定書…………………………………………………………… ii
誌謝…………………………………………………………………… iii
中文摘要………………………………………………………….….. iv
英文摘要………………………………………..…………………… vi
第 一 章 緒論 ………………………………………………………… 1
1.1現代質譜法 ……………………………………………….……2
1.2蛋白質體學 …………………………………………………….12
1.3多變量統計分析於質譜數據的應用…………………………. 16
1.4生物相似性藥物……………………………………………….28
1.5固相胜肽合成反應…………………………………………… 30
1.6參考文獻…………………………………………………………33
第 二 章 開發一個鑑定及品管生物相似性藥品的質譜方法…42
2.1摘要…………………………………………………………… 42
2.2前言…………………………………………………………… 43
2.3實驗部分………………………………………………………46
2.4結果與討論………………………………………………………50
2.5結論……………………………………………………………115
2.6參考文獻………………………………………………………117
第 三 章 開發以基質輔助雷射脫附游離質譜法來測定複雜之生物相似性藥品的分子量………………………………………118
3.1摘要……………………………………………………………. 118
3.2前言……………………………………………………………119
3.3實驗部分………………………………………………………124
3.4結果與討論……………………………………………………127
3.5結論……………………………………………………………142
3.6參考文獻………………………………………………………143
第 四 章 開發一個可以診斷並半定量尿液中白蛋白的質譜方法…145
4.1摘要………………………………………………………… 145
4.2前言…………………………………………………………… 146
4.3實驗部分………………………………………………………153
4.4結果與討論……………………………………………………156
4.5結論……………………………………………………………176
4.6參考文獻………………………………………………………177
第 五 章 利用液態電噴灑雷射脫附游離質譜法直接偵測各式溶液中的蛋白質分子……………………………………………180
5.1摘要…………………………………………………………180
5.2前言…………………………………………………………… 181
5.3實驗部分………………………………………………………184
5.4結果與討論……………………………………………………188
5.5結論……………………………………………………………202
5.6參考文獻………………………………………………………203
第 六 章 即時監測固相胜肽合成反應的質譜系統…………………206
6.1摘要…………………………………………………………… 206
6.2前言…………………………………………………………… 207
6.3實驗部分……………………………………………………210
6.4結果與討論……………………………………………………213
6.5結論……………………………………………………………239
6.6參考文獻………………………………………………………240

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14. 吳思佑, 民國 99 年國立中山大學化學研究所碩士論文「開發大氣壓力質譜法
之樣品承載裝置」