Magnetic resonance imaging (MRI)是當今最有用且不具侵入性的檢測技術之一，不論是在醫療診斷、食品科學和材料研究上，都有豐富的成果。現在常規的MRI造影劑理論中，假定MRI造影劑分子是處於稀薄、小分子組成的溶液體系之中，但在許多真實狀況下此理論可能不完全適用，如典型的生物體內環境是一個高度擁擠且充滿著各類大小分子和離子的體系，MRI造影劑的性能可能顯著地被分子和離子所影響。
在先前的工作中，我們研究了各類型常見高分子擁擠劑對於造影劑之鬆弛效能影響。在本工作中，藉由量測在擁擠環境下各離子濃度溶液的水分子及離子之縱向鬆弛速率（R1），橫向鬆弛速率（R2）和化學移位（CS）探討了離子效應在擁擠環境下對於造影劑的效果影響。我們使用了商用造影劑Dotarem(目前醫學診斷中最常用的MRI造影劑)、PEG作為擁擠劑和KCl, NaCl, LiCl, MgCl2, CaCl2, KI 作為離子來源(這些離子於生物體內佔較多數)，透過LSNMR200MHz、LSNMR500MHz、變場式核磁共振儀 ( NMRD)、SSNMR 500MHz來探討溶液體系下各分子、離子間的交互作用力。
在實驗結果上，這些離子產生之離子效應不僅影響了水分子動態也造成了結構變化，在鬆弛速率的測量結果中，這些離子皆影響了水分子的動態，尤其是，Mg2+, Ca2+影響水分子動態的程度高於其他陽離子。透過化學位移的測量，可發現在各鹽離子溶液中添入擁擠劑，會使其化學位移變化趨勢加大。值得注意的是 MgCl2和其他離子趨勢相反，是隨濃度上升而化學位移上升，顯示著至少有兩種以上之因素影響著溶液結構變化。23Na NMR和NMRD結果也讓我們獲得一些不同的動態和結構資訊。藉由探討擁擠環境下離子效應對於造影劑分子的鬆弛機制，建立此系統之微觀圖像，增加MRI影像對比度判定之精準度。

Magnetic resonance imaging (MRI) is one of the mostly useful non-invasive techniques in medical diagnosis, food science and materials research. The conventional theory of MRI contrast agents, assuming that they are located in a dilute, small molecular solution, gives good approximation in many situations but may fail in real biological systems because it is well-known that a typical organism is a highly crowded environment full of large and small molecules and ions. The performance of MRI contrast agent may be significantly altered by crowders and ions.
In previous work, we have studied the influence of macromolecular crowders on relaxivity of MRI contrast agents. The present study offers the first study on the influence of ions on macromolecular crowding effect on MRI contrast agents by measuring the longitudinal relaxation rate (R1), transverse relaxation rate (R2) and chemical shift (CS) of water and ion as a function of the concentration of ions in the solution system comprising commercial MRI contrast agent Dotarem (the mostly used MRI contrast agent in medical diagnosis), polyethylene glycol (PEG) as crowder and KCl, NaCl, LiCl, MgCl2 CaCl2, KI as ion source (these ions are most common in organisms). Through LSNMR 200 MHz, 500 MHz, NMRD, SSNMR 500 MHz to explore different kinds of interactions between molecules and ions in the solution systems.
From the results, it is found that the ion effect not only affects the dynamics of water molecules, but also the structures of the water-water, water-ion and water-PEG clusters. From the relaxation rates, we find that these ions affect the dynamics of the water molecule, especially Mg2+, Ca2+. The influence of both these two ions is higher than the rest. Through the measurement of chemical shift, we find that when the crowding agent is added in the ion solution, it increases the tendency of change of chemical shift. It is worth to note that the tendency of MgCl2 is opposite to other salt ions. Increasing nonlinearly with the concentration of MgCl2, water proton chemical shift and relaxation rates show that at least two or more factors affecting the changes in the systems. The results of 23Na NMR and NMRD provide us supplementary information on the dynamics and structure of clusters involving water molecules. These results demonstrate the significant effect of the ions under crowding environment on the relaxivity of MRI contrast agent and indicate that a molecular level understanding of the relaxation mechanism of MRI contrast agent in such system helps build the microscopic picture of MRI contrast generation and increases the accuracy of the MRI contrast determination of the image.

目錄
摘要 iii
Abstract iv
圖目錄 viii
表目錄 xi
第一章 緒論 1
1.1 前言 1
1.2 研究動機 3
第二章 擁擠和侷限效應 4
2.1擁擠和侷限效應 4
2.2熱力學觀點解釋擁擠和侷限 6
2.3擁擠效應文獻回顧 12
第三章 溶液離子效應 17
3.1 水溶液鹽離子效應與蛋白質 17
3.2 霍夫梅斯特鹽離子序列 Hofmeister Series 20
3.3 水合離子半徑、水合交換速率 21
3.4 構築離子和解構離子 25
3.5 高分子與離子間交互作用力 27
第四章 磁共振造影劑與核磁共振原理介紹 32
4.1核磁共振簡介 32
4.2 核磁共振鬆弛 35
4.2.1 縱向鬆弛(Longitudinal relaxation) 35
4.2.2 橫向鬆弛(Transverse relaxation) 37
4.2.3 NMRD鬆弛速率隨磁場變化 39
4.2.4 MRI基礎原理 41
4.3商用造影劑 45
4.4.2 外層水質子鬆弛 49
4.4.3 內外層水分子間的交換機制 50
第五章 實驗部分 52
5.1 實驗藥品 52
5.1.1 PEG (Polyethylene glycol) 52
5.1.2 Dotarem (Gd-DOTA) 53
5.1.3 鹽離子之選擇 54
5.1.4 DSS 55
5.2 樣品製備 55
5.2.1 擁擠試劑製備 55
5.2.2 Dotarem製備 56
5.2.3 鹽離子 製備 56
5.2.4 溶劑製備 61
5.3儀器實驗配製 61
5.3.1 鬆弛和化學位移實驗 61
5.3.2 影像實驗 62
5.3.3 NMRD實驗 63
5.4儀器設備 63
5.5儀器條件 63
5.6 分子動力學模擬 65
第六章 結果與討論 66
6.1不同鹽離子、PEG 6k濃度的水溶液1H 一維光譜 66
6.2不同鹽離子、擁擠劑、造影劑濃度的水溶液R1、R2測量 72
6.3在擁擠環境下不同鹽離子、造影劑和R1測量與關係比較 85
6.4 NaCl水溶液中，23Na化學位移、 R1、R2測量 91
6.5分子動力學模擬 95
6.6 1H micro-MRI實驗 112
6.7 1H NMRD實驗 117
第七章 結論 123
參考文獻 125

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