Title

表面功能化磁性奈米粒子在親和性質譜技術的應用

Translated Titles

Surface Functionalized Magnetic Nanoparticles for Affinity-Based Mass Spectrometry

Authors

呂穎維

Key Words

磁性奈米粒子 ; 表面功能化 ; 質譜 ; 小分子 ; 醣蛋白 ; 醣蛋白質體 ; 凝集素 ; 硼酸 ; magnetic nanoparticle ; surface functionalization ; mass spectrometry ; small molecule ; glycoprotein ; glycoproteome ; lectin ; boronic acid

PublicationName

清華大學化學系所學位論文

Volume or Term/Year and Month of Publication

2013年

Academic Degree Category

博士

Advisor

林俊成;陳玉如

Content Language

英文

Chinese Abstract

近年來,磁性奈米粒子成為廣泛應用於生物醫學研究的熱門材料之一,鑒於其高度的粒子總表面積對體積比,可在其表面合成高密度的親和性官能基,以提升分子與分子之間的親和作用力。此外,其獨特的磁性特質可輕易地將分析物從複雜的生物環境進行分離。表面功能化的氧化鐵磁性奈米粒子利用其修飾的親和官能基對標的生物分子具有專一性的辨識,可以應用在特定分子的分離及檢測。在此論文中,將合成不同的表面功能化粒子,進行表面功能基鑑定,並進而應用在不同的生物研究主題,其中包括:(1)基質功能化的磁性奈米粒子應用於小分子及金屬離子的偵測;(2)硼酸修飾凝集素的功能化磁性奈米粒子提高醣蛋白的純化效率。藉由穿透式電子顯微鏡分析,磁性粒子的粒徑及型態約為5到30奈米左右的尺寸。使用超導量子干涉磁量儀(SQUID)鑑定粒子的磁性特質;在粒子表面官能基分析可經由傅立葉轉換紅外線光譜儀(FT-IR)加以進行鑑定。 在論文的第一部分,我們發展一套結合Matrix@MNP和介質輔助雷射脫附離子化質譜(MALDI MS)為技術的分析方法成功地應用在小分子的檢測,在質譜上顯示了增強的分析物訊號強度而沒有基質所引發的雜訊干擾。之中,我們發現表層的矽烷層和氧化鐵的比例影響著基質在粒子表面固化的數量。藉由扣除的方法可以定量出粒子表面所固化的基質總數量。另外,此結合技術進而被發展在做為一個簡單且快速的金屬離子檢測工具,經由精確的分子量及金屬離子其具有的特徵同位素質量分析,可以對多種不同的金屬離子達到精準的鑑定。 不正常表現的醣蛋白往往可以做為診斷疾病的標的分子,至今還沒有一個有效的方法可以全面性的鑑定醣蛋白及其醣基所改變的位置。凝集素親和性探針可以對不同種類的醣蛋白提供專一性的辨認,但其限制是與醣基之間的交互作用力是屬於弱的非共價親和力。在論文第二部分的目的,是將凝集素表面修飾上硼酸官能基(BAD-lectin),成為一個新混合型材料的醣蛋白探針,經由surface plasmon resonance (SPR)表面薄膜共振分析所得到與單醣修飾的金晶片具有增強的結合能力說明硼酸與醣基的順式二醇基(cis-diol)所形成的硼酸酯(boronate ester)共價性結合來解決凝集素弱親和力的缺點。進而將此混和型探針功能化於磁性奈米粒子(BAD-lectin@MNPs)上並結合質譜技術成功運用在醣蛋白的純化與分析。結果顯示具硼酸修飾的凝集素可達到2到30倍增強的醣蛋白偵測靈敏度。在HeLa細胞的醣蛋白質體研究中,可以鑑定到295條N端鏈結醣胜肽。其中236條N端鏈結醣胜肽(80%)分別由三種不同的BAD-lectin@MNPs所純化出,顯示這些探針的專一性。此也證明了表面修飾的硼酸並沒有使凝集素對不同種類的醣蛋白失去其選擇性,也在醣蛋白質體學上的表現說明此功能化奈米粒子可以做為有效的且具選擇性的醣蛋白檢測工具。 從這些結果說明了四氧化三鐵的磁性奈米粒子的優點,其中包括其具有高度應用性的表面化學可以做為在生物應用上一個通用的載體;獨特的磁性特質可以避免冗長的樣品除鹽及純化動作而造成生物樣品的損壞;具有高靈敏和高專一的表現可以用來解決低親和作用力分子及樣品中低含量分子的偵測問題。在未來方面,我們預期此表面功能化的磁性奈米粒子可以成為一種有效的分析平台來解決生物醫學上重要且具有挑戰性的問題。例如,在小分子和金屬離子的偵測上,DHB@MNP可發展成為另一個有效且直接的工具在真實的生物樣品中提供快速、靈敏、及準確的微量小分子和金屬離子檢測。而在醣蛋白質體的研究中,我們期許BAD-lectin@MNPs可進一步做為快速及全面的醣蛋白分析以應用於在臨床樣品中生物標靶分子的開發。

English Abstract

The rapid growth of nanotechnology, especially the development of magnetic nanoparticles (MNPs) has promised a new platform in biological applications due to their high surface area-to-volume ratio and unique magnetic properties. In this thesis, the surface functionalized MNPs, including matrix-conjugated MNPs (Matrix@MNPs) and boronic acid-decorated lectin functionalized MNPs (BAD-lectin@MNPs), have been fabricated and optimized for two applications, small molecule detection and glycoprotein enrichment, respectively. The size and morphology of the functionalized nanoprobes were characterized to be about 5–30 nm by transmission electron mircroscopy (TEM). In addition, Fourier transform infrared spectroscopy (FT-IR) and superconducting quantum interference device (SQUID) are used to validate the characteristic functionality on the surface of MNPs and the superparamagnetic property. To develop the effective method for small molecule identification by matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS), the hybrid of immobilized silica and 2,5-dihydrobenzoic acid (DHB) on MNP (DHB@MNP) was fabricated as a general matrix for background-free MALDI detection of low molecular weight compounds and various metal ions. The combination of Matrix@MNPs and MALDI MS was developed as a general method for direct and rapid screening for low molecular-weight compounds. Herein, we also demonstrated that Matrix@MNP can provide as a soft ionization element for analyte detection with MALDI MS analysis. Besides, the ratio between silane and MNP during the synthesis of Matrix@MNP was examined and was found to affect the surface immobilization of matrix on the nanoparticle, critically influence the ionization efficiency of analyte and the interference background in low molecular weight range of mass spectrum. Compared with commercial DHB, the Matrix@MNP-assisted MALDI MS provided superior soft ionization on the detection of new types of synthetic materials used for solar cells, light emitting devices, and glycolipids, including the analytes with either thermally labile structures or poor protonation tendencies. Moreover, the enhancements of the molecular ion signal also provided high quality product-ion spectra allowing structural characterization and unambiguous small molecule identification. Furthermore, this Matrix@MNP-assisted approach was established as a novel technique for simple and rapid analysis of metal ions. Matrix@MNPs significantly enhance the detection sensitivity of metal ions through characteristic isotope patterns and accurate mass. With the advantages stable ability and simple sample preparation, the use of DHB-functionalized nanoparticles combined with high-resolution MALDI MS provides a generic platform for rapid and unambiguous structure determination of small molecules and metal ion. Detection of aberrant glycoproteins in diseases can provide an opportunity to develop glycoprotein biomarkers for diagnosis and prognosis. However, comprehensive identification of carrier proteins and site of glycan-specific alternation still remain intangible. Lectin-based affinity probe can provide glycan-specific recognition, but is restricted by their weak noncovalent affinity with glycoprotein. The weak and variable binding affinities exhibited by lectin–carbohydrate interactions have often compromised the practical utility of lectin in capturing glycoproteins for glycoproteomic applications. We report here the development and applications of a new type of hybrid biomaterial, namely a boronic acid-decorated lectin (BAD-lectin), for efficient bifunctional glycoprotein labeling and enrichment. Our binding studies showed an enhanced affinity by BAD-lectin, likely to be mediated via the formation of boronate ester linkages between the lectin and glycan subsequent to the initial recognition process and thus preserving its glycan-specificity. Moreover, when attached to magnetic nanoparticles (BAD-lectin@MNPs), 2 to 30-fold improvement on detection sensitivity and enrichment efficiency for specific glycoproteins was observed over the use of either lectin or BA. Tested at the level of whole cell lysates for glycoproteomic applications, three different types of BAD-lectin@MNPs exhibited excellent specificities with only 6% overlapping among the 295 N-linked glycopeptides identified. As many as 236 N-linked glycopeptides (80%) were uniquely identified by one of the BAD-lectin@MNPs. These results indicated that the enhanced glycan-selective recognition and binding affinity of BAD-lectin@MNPs will facilitate a complementary identification of the under-explored glycoproteome. Thus, taken together, we demonstrated several advantages, including that iron oxide (Fe3O4) nanoparticles can serve as the general building unit with flexible surface chemistry in biological applications; the unique magnetic separation avoids tedious de-salting and purification process and reduces the handling time to prevent target biomolecules from degradation; the high sensitivity and specificity performance of functionalized MNPs deal with the low affinity interaction and low abundant biomolecule detection. In future perspective, we anticipate that MNPs can serve as a promising platform to tackle the interesting but challenging issues in various biological applications. For small molecule and metal ion detection, DHB@MNP potentially can be developed as an efficient and directive alternative tool for the fast, sensitive, and accurate determination of trace small molecule and metal ions in real samples. In glycoproteomic study, we expect that BAD-lectin@MNPs provide facile and comprehensive glycoprotein analysis for biomarker discovery in clinical specimens.

Topic Category 基礎與應用科學 > 化學
理學院 > 化學系所
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