核磁共振造影（magnetic resonance imaging, MRI）是最靈活的非侵入性影像方法，已經在材料、化學、生物以及醫學、語言學和心理領域獲得廣泛的應用。為了進一步提高解析度和選擇性，最近幾十年又開發出了2000多種造影劑。MRI造影劑中的順磁性離子與水之間的偶極作用力，造成與它接近的水之NMR訊號鬆弛速率改變，進而改變該處的影像對比度。MRI造影劑所處的環境是典型的擁擠環境，雖然研究擁擠效應的文獻甚多，但是到目前為止，沒有有關擁擠效應對MRI造影劑影響的報導。我們採用高分子模擬擁擠環境對這一效應進行研究。我們發現，擁擠高分子對造影劑分子的影響因素中，高分子的親水性對擁擠效應有重要影響，對擁擠效應的體積排除之簡單圖像必須更新。因此，本工作對這一因素做一探討。
本工作主要利用sodium polyacrylate (NaPA), bovine serum albumin (BSA), polyethylene glycol (PEG)等不同親水度的高分子（人工合成或生物大分子）及其混合溶液當作擁擠劑(crowder)，而Dotarem為本實驗的MRI順磁造影劑。改變高分子及順磁離子溶液的濃度，利用1H NMR的T1，T2，化學位移以及T1，T2，擴散加權影像來對擁擠效應進行表徵。我們初步發現，這些分子表現不同的擁擠效應，親水性對NMR鬆弛，化學位移以及影像對比度都有明顯的影響。我們將報告各種不同條件下的親水性對擁擠效應的定量結果，並結合理論計算和模擬對這些現象提出解釋。相信有關結果對進一步理解MRI造影劑的機理以及研發新一代MRI造影劑有啟發。

The power of MRI is tremendously enhanced by the application of various types of MRI contrast agents which increase the relaxivity of water molecules close to them through strong dipolar interactions between water and the paramagnetic ions on the contrast agent. With about 30 years of advancement, MRI contrast agents with various functions, such as signal enhancement, target selection and molecular or event specificity, have been developed. More MRI contrast agents with different purposes are under development today. To better understand the mechanism of MRI contrast agents in various conditions and to develop new generation MRI contrast agents, it is desired that the interactions between the MRI contrast agents and other molecules in their proximity are better understood. We have found that macromolecular crowding effect is an important contributing factor that affects the performance of MRI contrast agents. Therefore, we have decided to carry out a full investigation of this phenomenon with different crowding molecules and MRI contrast agents. This work will report the results with sodium polyacrylate (NaPA) as crowder and Dotarem as MRI contrast agent and focus on the hydrophiliity of macromolecules. A linear relationship is found between the concentration of Dotarem and relaxation rates and chemical shift. A nonlinear relationship is found between the concentration of NaPA and relaxation rates and chemical shift. The hydrophilicity of macromolecular crowders has significant influence on overall crowding effect. The simple picture of volume exclusion must be updated and intermolecular interactions must be taken into account. Morevoer, the details of the crowding effect of NaPA and that of PEG are compared and discussed.

第一章 緒論 - 1 -
1.1 前言 - 1 -
1.2 研究動機 - 3 -
第二章 順磁試劑介紹 - 4 -
2.1核磁共振與造影劑 - 4 -
2.2 商用造影劑 - 4 -
2.2.1 Dotarem (得立顯注射劑) - 5 -
2.2.2 Magnevist (美格維斯注射劑) - 6 -
2.3 順磁分子鬆弛理論15,16 - 6 -
2.3.1 內層質子鬆弛機制 17,18 - 8 -
2.3.2 外層質子鬆弛機制 - 11 -
2.3.3 水分子間的交換機制 - 12 -
第三章 擁擠與侷限效應 - 14 -
3.1擁擠與侷限效應介紹11 - 14 -
3.2熱力學觀點解釋擁擠和侷限 - 14 -
3.3 擁擠∆F_X^crowd與侷限∆F_X^confine估計值 - 18 -
3.4擁擠與侷限締合平衡態 - 19 -
3.5擁擠與侷限位點鍵結平衡態 - 20 -
3.6擁擠與侷限中蛋白質上的兩態折疊平衡 - 21 -
3.7利用變場鬆弛實驗測量孔洞中分子 - 21 -
3.8親水性質 - 22 -
3.8.1疏水交互作用 - 22 -
3.8.2小孔洞與大孔洞的水合化 - 23 -
第四章 實驗部分 - 25 -
4.1 實驗藥品 - 25 -
4.1.1 NaPA ( Polyacrylic acid, sodium salt) - 25 -
4.1.2 PEG (Polyethylene glycol) - 25 -
4.1.3 Dotarem - 26 -
4.2 樣品製備 - 27 -
4.2.1 擁擠試劑製備 - 27 -
4.2.2 Dotarem製備 - 27 -
4.2.3 溶劑製備 - 27 -
4.3儀器實驗配製 - 28 -
4.3.1 鬆弛實驗 - 28 -
4.3.2 擴散實驗 - 28 -
4.3.3 影像實驗 - 29 -
4.3.4 黏度實驗 - 29 -
4.3.5 酸鹼值實驗 - 30 -
4.4儀器設備 - 30 -
4.5儀器條件 - 32 -
第五章 結果與討論 - 34 -
5.1不同濃度高分子水溶液1H 一維光譜和酸鹼值測量 - 34 -
5.2不同濃度高分子水溶液R1測量 - 42 -
5.3不同濃度高分子水溶液R2測量 - 50 -
5.4鬆弛與化學位移 - 56 -
5.5微影像實驗 - 58 -
5.6高分子水溶液擴散係數和黏度測量 - 61 -
第六章 結論 - 64 -
參考資料 - 65 -
附錄 - 69 -

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