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    题名: 親和性質譜術應用在人類血漿檢測與定量氯屈磷酸;Quantitative Analysis of Dichloromethylene-Bisphosphonic Acid in Human Plasma by Nanoprobe Based Affinity Mass Spectrometry
    作者: 許維;Hsu Wei
    贡献者: 化學研究所
    关键词: 磁性奈米粒子;雙磷酸鹽;基質輔助脫附游離法;氯屈磷酸;Magnetic Nanopatricle;MALDI-TOF MS;Bisphosphonate
    日期: 2009-07-07
    上传时间: 2009-09-22 10:21:26 (UTC+8)
    出版者: 國立中央大學圖書館
    摘要: 氯屈磷酸(Dichloromethylene-bisphosphonic acid, Clodronate),屬於雙磷酸類的一種,這類的化合物常被用於治療許多有關骨頭相關的疾病,例如:惡性病之高鈣血症(hypercalcemia of malignancy)、畸型性骨炎(Paget’s disease)、和溶解性骨轉移(osteolytic bone metastases)、以及骨質疏鬆症(osteoporosis)。目前己經有許多文獻研究氯屈磷酸在人體內的代謝,藉由服藥後的數個時間點內採集尿液與血漿,測量氯屈磷酸的含量並探討其代謝率,作為藥物動力學的依據。但是,在傳統的分析方法中遇到了很大的因難,必須要經過重複性操作固/液相萃取法才能將氯屈磷酸從複雜的生物基質中分離出來,之後還需更進一步將其作衍伸化產物來提高它的偵測極限。 在本篇論文中,我們利用之前發展的磁性奈米結合質譜分析技術(NBAMS)的方法進行快速純化與偵測氯屈磷酸以及定性及定量分析。此技術是利用磁性奈米粒子表面裝載三甘胺酸,然後螯合鈦金屬離子,藉著鈦金屬與氯屈磷酸上面的磷酸根之間的親合性作用力作為純化的工具。在初步的結果,我們己經成功的將氯屈磷酸二鈉從血漿中分離出來,同時結合基質輔助雷射游離脫附質譜法(MALDI-TOF MS)直接偵測氯屈磷酸,不用經過衍伸化產物的處理,偵測極測為0.05 ng。 傳統基質輔助雷射游離脫附質譜法應用上,定量方法的主要限制來自於非均相的結晶所導致訊號的低再現性。為了克服此項限制,我們可藉由外加標準品及提高均勻晶相(seed-layer method)的方式,成功的改進了分子與基質分子在共結晶時的均相性,進而降低了訊號的變異度。經由從人類血漿莘取出來的氯屈磷酸作建立的定量曲線,線性範圍從200-8000 ng/ml,並且具有好的線性 (R2=0.994)。我們展現了磁性奈米結合質譜分析技術的方便性與快速性,並且可以應用在小分子藥物的定量,作為研究藥物動力學的一項有力的工具。 Clodronate, belonging to bisphosphonates, are used in treatment of various bone disease such as hypercalcemia of malignancy, Paget’s disease, osteolytic bone metastases and osteoporosis. In pharmacokinetic studies, many research have been reported for metabolism of clodronate in human biofluid such urine and plasma. However there is still a challenge for direct analysis of clodronate from complex system. Conventional method usually required precipitation and solid/liquid phase extraction for isolation followed by derivatization methods that are tedious and time-consuming. We implemented our previously developed nanoprobe-based affinity mass spectrometry (NBAMS) assay for rapid extraction, detection and quantification of clodronate. Metal-chelating ligand, nitrilotriacetic acid (NTA), was covalently bonded on the MNPs to give NTA-PEG@MNPs and then immobilized with Ti4+ metal ion which provided high affinity for target molecules containing phosphonate group. Ti4+-NTA-PEG@MNP was demonstrated to serve as a high surface-to-volume ratio nanoprobe and applied to effective isolation of clodronate, a bone disease drug structural-containing phosphonate group, from human plasma. In the preliminary result, we have successfully demonstrated feasibility of NBAMS method for effective isolation of clodronate from human plasma. The detection of clodronate was achieved without any derivatization by using of MALDI-TOF MS with the LOD of 0.05 ng. The major limitation in quantification by conventional MALDI MS is non-homogeneous crystallization on sample plate that results in poor signal reproducibility. With the introduction of seed-layer surface and spiked internal standard, we successfully reduced signal fluctuation from the improved homogeneous co-crystallization of analyte and matrix molecule. The calibration curve constructed by clodronate from human plasma has dynamic range from 200-8000 ng/ml with correlation coefficients better than 0.99. We demonstrated that a nanoprobe-based affinity mass spectrometry (NBAMS) is a simple, rapid, reproducible and accurate platform for simultaneous enrichment, detection and quantification of small molecular drugs in pharmaceutical metabolism study.
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