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研究生:朱泓霖
研究生(外文):Hung-lin Chu
論文名稱:核磁共振造影劑Dotarem於離子與大分子擁擠劑Ficoll 70下的行為評估
論文名稱(外文):The Performance Evaluation of MRI Contrast Agent Dotarem in the Presence of Ions and Macromolecular Crowder Ficoll 70
指導教授:丁尚武
指導教授(外文):Shangwu Ding
學位類別:碩士
校院名稱:國立中山大學
系所名稱:化學系研究所
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:91
中文關鍵詞:電導率磁共振鬆弛化學位移離子水溶液聚蔗糖磁共振造影劑磁共振影像
外文關鍵詞:AC impedanceChemical shiftNMR relaxationIonic conductivityIons in aqueous solutionFicollMagnetic resonance imaging (MRI)MRI contrast agent
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磁共振影像(Magnetic resonance imaging, MRI)是一項現今非常有用且不使用游離輻射源又能提供三維空間資訊的非侵入式檢測方法;因此,它已成為廣泛使用的醫療診斷方法,並在許多研究領域中,如食品科學、生物化學、材料科學等都取得豐富的成果。實際使用MRI時,為了增加影像品質和幫助診斷與解釋,常透過加入MRI造影劑(其中高順磁性的金屬離子可以有效且有選擇性的加速水分子上1H核的鬆弛速率)來提高影像對比度(如病變部位或發生特定生化反應的區域)並進一步提升影像分析的準確性,現今醫學上約有40%的磁共振影像掃描會使用到造影劑。然而現今的MRI造影劑理論假定造影劑處於一小分子組成的稀釋溶液中以便獲得一個較簡單、容易處理的近似環境,但此與真實環境下並不相符,因為生物細胞內是一個非常擁擠且複雜的環境。細胞中充斥著水、賀爾蒙、維生素等小分子及離子外,還有核酸、核醣體、蛋白質等其他細胞胞器與生物大分子以及膜蛋白等。因此在細胞內MRI造影劑的行為與功能可能會被環境中的離子與生物大分子影響。了解造影劑如何與細胞中其他分子與離子間之作用對MRI影像的更精準判讀以及MRI的進一步發展至關重要。
本工作聚焦於常見小離子對MRI造影劑於擁擠環境下的影響。我們選用的MRI造影劑為醫院常用的釓多酸水溶液(Dotarem);以生物體中常見的鹽(LiCl, NaCl, KCl, MgCl2, CaCl2)作為離子源;使用的擁擠劑為人工合成具網狀結構的聚蔗糖(Ficoll 70)[1]以模擬真實細胞內的擁擠環境。再利用液態400 MHz NMR、固態500 MHz NMR 與交流組抗儀分別量測在擁擠環境下各離子溶液的水分子及離子之化學位移(CS),縱向鬆弛速率(R1)和電導率(1/Ω),探討離子在擁擠環境下對造影劑的影響以及溶液中分子、離子間的交互作用。我們發現隨著環境中離子濃度的增加對水分子上1H的化學位移與鬆弛都有明顯的規律,當然也有例外。也發現溶液電導率隨擁擠劑濃度增加而下降;隨離子濃度上升而上升,卻與Debye–Hückel理論結果有所偏離。本工作對鹽離子與擁擠環境下造影劑對水分子動態的影響,在MRI影像對比度的微觀機制之確認,以及減少MRI影像解讀上的誤判,具有重要參考價值。
Magnetic resonance imaging (MRI) is one of the mostly useful non-invasive techniques in many fields because of the advantage of providing three dimensional details images without using damaging ionization radiation, making it a powerful tool in various fields from medical diagnosis, food science, biochemistry, materials science to experimental psychology and linguistics. To increase image quality and assist diagnosis or interpretation, an image contrast agent (MRICA) may be employed, which accelerates nuclear relaxation of the imaged spins via paramagnetic ions, to enhance image contrast which usually converts to a higher accuracy in image analysis. In clinical diagnosis, for example, over 40% of MRI scans are carried out with the assistance of a contrast agent. The traditional theory of MRI contrast agents, assuming that they are located in a dilute, small molecular solution, gives good approximation in many situations. However, the cellular environment is typically complex, filled with many macromolecules, small molecules, ions and water. Consequently, understanding how a contrast agent interact with the other molecules in human cells is very important.
This work focuses on the effect of MRI contrast agent from the common ions in organism and a much used simulated crowder. We use Dotarem which is the mostly used in medical diagnosis as the MRI contrast agent. The ions rich in body ( LiCl、NaCl、KCl、MgCl2、CaCl2 ) are used as the ion source. Then we select a macromolecule crowder (Ficoll 70, M.W. 70kDa, an artificial inert macromolecule, with cross-linking structure in aqueous solutions) to mimic the cellular crowded environment. To investigate the interaction between MRI Contrast Agent and water in the presence of ions and macromolecular crowded environment, 1H chemical shift and relaxation rate of water is measured on 400 MHz NMR and 500 MHz NMR spectrometers, respectively. The conductivity of the solution is measured with AC impedance analysis. It is found that the chemical shift and longitudinal relaxation coefficient are sensitive to ion concentration. We also found that the conductivity of the solution is affected by crowder, and shows some deviation from Debye-Hückel theoretical results. This work is valuable for understanding ionic influence on water dynamics in presence of macromolecular crowder and MRI contrast agent, for better description of the microscopic mechanism of MRI contrast generation and for reducing misinterpretation of MRI images in clinic and other applications.
論文審定書 ............................................................................................................... i
謝誌 .......................................................................................................................... ii
摘要 ......................................................................................................................... iii
Abstract ..................................................................................................................... v
目錄 .......................................................................................................................... 1
圖目錄 ...................................................................................................................... 3
表目錄 ...................................................................................................................... 5
第一章 緒論 ............................................................................................................ 6
1.1 前言 ............................................................................................................ 6
1.2 研究動機 ..................................................................................................... 8
第二章 核磁共振原理與磁共振造影劑介紹......................................................... 9
2.1 核磁共振簡介 ............................................................................................. 9
2.2 核磁共振鬆弛 .......................................................................................... 12
2.2.1 T1 縱向鬆弛速率(Longitudinal relaxation) ...................................... 12
2.2.2 T2 橫向鬆弛速率(Transverse relaxation) ......................................... 14
2.3 MRI 基礎原理 ........................................................................................... 15
2.4 造影劑 ....................................................................................................... 18
2.4.1 順磁分子鬆弛理論 ......................................................................... 21
2.4.2 內層水質子鬆弛機制 ..................................................................... 22
2.4.3 外層水質子鬆弛機制 .................................................................... 24
2.4.4 內外層水分子間的交換機制......................................................... 25
第三章 擁擠和局限效應 ......................................................................................27
3.1 擁擠和侷限效應 ....................................................................................... 27
3.2 熱力學觀點解釋擁擠和侷限 .................................................................... 29
第四章 溶液離子效應 ............................................................................................33
4.1 生物體鹽離子水溶液 ................................................................................ 33
4.2 離子水溶液 .............................................................................................. 34
4.3 水合離子半徑、水合交換速率 ................................................................ 36
4.4 構築離子與解構離子 ............................................................................... 39
4.5 霍夫梅斯特序列 Hofmeister Series .......................................................... 41
4.6 水溶液電導度 .......................................................................................... 43
第五章 實驗部分 ..................................................................................................46
5.1 實驗藥品 ................................................................................................... 46
5.1.1 Ficoll 70 .......................................................................................... 46
2
5.1.2 Dotarem (Gd-DOTA) ...................................................................... 47
5.1.3 鹽離子 ........................................................................................... 48
5.1.4 DSS ................................................................................................. 48
5.2 樣品製備 .................................................................................................. 49
5.2.1 擁擠劑水溶液製備 ........................................................................ 49
5.2.2 Dotarem 水溶液製備 ...................................................................... 49
5.2.3 鹽離子水溶液製備 ........................................................................ 49
5.2.4 溶劑製備 ....................................................................................... 49
5.3 儀器實驗配製 ........................................................................................... 50
5.3.1 化學位移與鬆弛實驗 ..................................................................... 50
5.3.2 電導度實驗 ................................................................................... 51
5.4 儀器設備 .................................................................................................. 51
5.5 儀器條件 ................................................................................................... 51
第六章 結果與討論 ................................................................................................53
6.1 不同鹽離子、Ficoll 70 濃度的水溶液1H 一維光譜 ............................... 53
6.1.2 以” structure-breaking/making”模型解釋化學位移變化 ............... 57
6.1.3 以黏度改變解釋化學位移變化 ..................................................... 57
6.1.3 以溶液內水分子周圍環境改變解釋化學位移變化 ...................... 58
6.1.4 鹽離子對溶液中水分子氫鍵所造成的影響 ................................. 58
6.1.5 Mg2+與其他離子之比較 ................................................................. 59
6.1.6 擁擠劑Ficoll 70 對化學位移所造成的影響 ................................ 60
6.2 不同鹽離子、擁擠劑、Dotaram 造影劑濃度溶液中水的鬆弛速率....... 61
6.2.1 電解質離子對溶液中水分子縱向鬆弛所造成的影響 .................. 63
6.2.2 造影劑對溶液中水分子縱向鬆弛所造成的影響 .......................... 64
6.2.3 擁擠劑Ficoll 70 對溶液中水分子縱向鬆弛所造成的影響 ......... 64
6.3 不同鹽離子、擁擠劑、Dotaram 造影劑濃度溶液中水的導電度 .......... 67
6.3.1 電解質離子對溶液電導度所造成的影響 ..................................... 72
6.3.2 擁擠劑Ficoll 70 與造影劑對溶液電導度所造成的影響 ............. 72
6.3.3 水溶液縱向鬆弛與電導度間之相關關係 ..................................... 74
第七章 結論 ...........................................................................................................77
參考文獻 .................................................................................................................79
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