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研究生： 溫延展
論文名稱： 三功能性氧化釓摻雜銪結合核酸適體之奈米粒子應用於核磁共振/斷層掃描/螢光 分子影像研究
Studies of Gd2O3：Eu-AP Nanoparticles for Trimodal MRI/CT/Fluorescence Molecular Imaging
指導教授： 陳家俊
學位類別： 碩士
Master
系所名稱： 化學系
Department of Chemistry
論文出版年： 2012
畢業學年度： 100
語文別： 中文
論文頁數： 106
中文關鍵詞： 氧化釓摻雜銪 、核磁共振 、斷層掃描 、螢光 、核酸適體 、分子影像
英文關鍵詞： Europium doped-gadolinium oxide, Magnetic Resonance Imaging, Computed tomography Imaging, Fluorescence Imaging, Aptamer, Molecular Imaging
論文種類： 學術論文
相關次數： 點閱：759  下載：18 
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    • 開發單一奈米材料兼具多功能之應用價值是目前奈米生醫領域研究與探討的課題。本文製備同時具有螢光、核磁共振訊號與X-ray吸收特性的多功能性奈米粒子-氧化釓摻雜銪，接著在奈米粒子外面包覆核酸適體（aptamer），希望透過其專一性的表現而能應用於分子影像顯影。
    首先經由多元醇法合成出氧化釓摻雜銪的奈米粒子，並且以TEM、XRD、UV-PL、SQUID與EDS等儀器來加以分析與鑑定。接著再以FT-IR、TGA和 zetasizer來鑑定氧化釓摻雜銪奈米粒子表面修飾之檸檬酸基。最後則是透過qPCR 和confocal 來說明核酸適體的確有與我們所合成之奈米粒子結合。
    將氧化釓摻雜銪奈米粒子應用於in vitro MRI上，經由實驗可得其 r1為5.0199 s-1mM-1，相比於T1-MRI常用之釓金屬類錯合物顯影劑如Gd-DOTA、Gd-DTPA（r1皆為4.1s-1mM-1）有較高的relaxivity，表示其MRI對比顯影效果較佳；而在in vitro CT的應用上，在重量濃度為350毫克/每毫升時，氧化釓摻雜銪奈米粒子的HU值高於常用之CT含碘顯影劑IOHEXOL，但低於350毫克/每毫升時，其HU值仍是低於含碘顯影劑IOHEXOL。

    Recent nano-biomedicine have devote to research the topics for the development of single nano-materials possessing multifunctional properties. In this thesis, we synthesized the multifunctional europiumdoped gadolinium oxide ( Gd2O3:Eu ) nanoparticles which equipped with
    fluorescence, magnetic resonance signal and X-ray absorption. Then we applied the specific targeting aptamer encapsulated outside the nanoparticles for molecular imaging.
    First, Gd2O3:Eu nanoparticles were synthesized via the polyol method and were characterized based on TEM, XRD, UV-PL, SQUID and EDS. Then we identified the surface capping ligand citric acid of Gd2O3:Eu nanoparticles through FT-IR, TGA, and zetasizer. Ultimately,we employed qPCR and confocal to confirm the binding of Gd2O3:Eu-AP
    nanoparticles.
    Gd2O3:Eu nanoparticles were applied on the in vitro MRI. Compared to the conventional T1 MRI gadolinium chelated complex such as Gd-DOTA、Gd-DTPA（r1 4.1s-1mM-1）, the relaxivity of Gd2O3:Eu nanoparticles（r1 5.0199s-1mM-1）was much higher. In other words, the effect of MRI enhanced contrast image by Gd2O3:Eu nanoparticles was better. On the in vitro CT, there was a much higher HU value of Gd2O3:Eu nanoparticles at the weight concentration of 350 mg/ml than
    the common CT iodine contrast agent IOHEXOL. But less than 350 mg/ml, the HU value of Gd2O3:Eu nanoparticles was still lower than IOHEXOL.

    總目錄........................................................................................................I 圖目錄.....................................................................................................VII 表目錄......................................................................................................XI 中文摘要.................................................................................................XII 英文摘要...............................................................................................XIII 謝誌........................................................................................................XV 第一章 緒論..............................................................................................1 1-1 磁性奈米粒子性質與其應用.............................................................1 1-1-1順磁性與超順磁性...................................................................1 1-1-2 磁性奈米材料的應用.............................................................2 1-2 多功能性奈米材料與其影像顯影方式.............................................4 1-2-1複合性奈米材料.......................................................................4 1-2-2多功能性之奈米材料...............................................................5 1-2-3多功能性之奈米材料顯影方式...............................................8 1-3 稀土元素與其金屬氧化物發光、合成與應用.................................12 1-3-1 稀土元素的簡介...................................................................12 1-3-2鑭系金屬的發光原理.............................................................14 1-3-3鑭系金屬的合成方法與應用.................................................15 1-3-4鑭系金屬於NCT與MRT治療上的潛力............................17 1-4螢光粉體之發光與影響因素............................................................20 1-4-1螢光粉體的發光原理............................................................20 1-4-2影響螢光效率的因素............................................................20 1-5 MRI核磁共振造影原理與顯影劑..................................................23 1-5-1 MRI的簡介............................................................................23 1-5-2 MRI的原理............................................................................24 1-5-3 MRI顯影劑............................................................................26 1-5-4市售的MRI顯影劑................................................................27 1-5-5 結合T1 與T2 -weighted MRI 顯影劑...................................29 1-5-6 釓金屬氧化物粒徑大小對 MRI 的影響............................30 1-6 CT高解析電腦斷層掃描原理與顯影劑..........................................31 1-6-1 CT的簡介...............................................................................31 1-6-2 CT的原理...............................................................................32 1-6-3 CT含碘顯影劑......................................................................33 1-6-4 其它CT顯影劑.....................................................................35 1-7 aptamer核酸適體與antibody抗體.................................................36 1-7-1 aptamer之簡介.......................................................................36 1-7-2 aptamer與 antibody之比較..................................................37 第二章 實驗............................................................................................39 2-1 研究動機與目的...............................................................................39 2-2 實驗儀器...........................................................................................41 2-3 實驗藥品...........................................................................................45 2-4 實驗合成步驟...................................................................................46 2-4-1 製備氧化釓Gd2O3.................................................................46 2-4-2 製備氧化釓摻雜銪Gd2O3：Eu.............................................47 2-4-3 製備氧化釓摻雜銪修飾檸檬酸基Gd2O3：Eu-CA...............48 2-4-4 製備氧化釓摻雜銪修飾檸檬酸基以醯胺鍵和核酸適體結合Gd2O3：Eu -CA -NH2 aptamer（Gd2O3：Eu -AP）...........49 2-5 細胞毒性測試...................................................................................50 2-6 核磁共振顯影檢測...........................................................................52 2-7 高通量即時螢光定量PCR (qPCR)檢測..........................................53 2-8 共軛焦螢光顯微鏡（confocal）細胞處理步驟...............................55 第三章 結果與討論................................................................................56 3-1氧化釓Gd2O3奈米粒子之合成、純化處理與鑑定...........................56 3-1-1 氧化釓Gd2O3 奈米粒子的結構分析（XRD）......................58 3-1-2 氧化釓Gd2O3 奈米粒子的外型形貌（TEM）......................59 3-1-3 氧化釓Gd2O3 奈米粒子的表面結構分析（FT-IR）.............60 3-1-4 氧化釓Gd2O3 奈米粒子的元素組成分析（EDS）................61 3-1-5 以多元醇化學合成法來形成奈米粒子之簡單機構探討...62 3-2氧化釓摻雜銪Gd2O3：Eu 奈米粒子之合成與鑑定..........................64 3-2-1 氧化釓摻雜銪Gd2O3：Eu 奈米粒子結構分析（XRD）…....65 3-2-2 氧化釓摻雜銪Gd2O3：Eu 奈米粒子的外型形貌（TEM）....66 3-2-3 氧化釓摻雜銪Gd2O3：Eu奈米粒子元素分析(EDS) ..........67 3-2-4 氧化釓摻雜銪Gd2O3：Eu奈米粒子元素分析(ICP-MS) .....68 3-3氧化釓摻雜銪修飾檸檬酸基Gd2O3：Eu-CA合成與鑑定..................69 3-3-1 氧化釓摻雜銪修飾檸檬酸基Gd2O3：Eu-CA結構分析(XRD) ...................................................................................70 3-3-2 氧化釓摻雜銪修飾檸檬酸基Gd2O3：Eu-CA的外型形貌（TEM）..................................................................................71 3-3-3 氧化釓摻雜銪修飾檸檬酸基Gd2O3：Eu-CA粒徑分析 （DLS）..................................................................................72 3-3-4 氧化釓摻雜銪修飾檸檬酸基Gd2O3：Eu-CA zeta potential 分析........................................................................................73 3-3-5 氧化釓摻雜銪修飾檸檬酸基Gd2O3：Eu-CA 官能基鑑定(IR) .....................................................................................74 3-3-6 氧化釓摻雜銪修飾檸檬酸基Gd2O3：Eu-CA 官能基鑑定(TGA) .....................................................................................75 3-4 氧化釓Gd2O3、氧化釓摻雜銪Gd2O3：Eu與氧化釓摻雜銪修飾檸檬酸基Gd2O3：Eu-CA的光學性質（UV-PL）................................76 3-4-1 氧化釓Gd2O3 奈米粒子的光學性質（UV-PL）...............76 3-4-2 氧化釓摻雜銪Gd2O3：Eu 奈米粒子與氧化釓摻雜銪修飾檸檬酸基的光學性質（UV-PL）............................................77 3-4-3 氧化釓摻雜不同比例銪 Gd2O3：Eu 的螢光表現與淬息80 3-5 氧化釓Gd2O3、氧化釓摻雜銪Gd2O3：Eu與氧化釓摻雜銪修飾檸檬酸基Gd2O3：Eu-CA的磁性質（SQUID）分析.............................81 3-6氧化釓摻雜銪修飾檸檬酸基以醯胺鍵和核酸適體結合Gd2O3：Eu-AP合成與鑑定...........................................................................83 3-6-1 氧化釓摻雜銪修飾檸檬酸基以醯胺鍵和核酸適體結合Gd2O3：Eu-AP......................................................................83 3-6-2 氧化釓摻雜銪修飾檸檬酸基以醯胺鍵和核酸適體結合Gd2O3：Eu-AP qPCR 分析..................................................84 3-7 氧化釓Gd2O3 與氧化釓摻雜銪Gd2O3：Eu磁性奈米粒子之in vitro MRI應用..........................................................................................86 3-8 氧化釓Gd2O3與氧化釓摻雜銪Gd2O3：Eu之in vitro CT 應用...89 3-9氧化釓摻雜銪修飾檸檬酸基Gd2O3：Eu-CA的細胞毒性測試.....91 3-10 氧化釓摻雜銪修飾檸檬酸基以醯胺鍵和核酸適體結合Gd2O3：Eu-AP confocal 分析....................................................................92 3-11 氧化釓摻雜銪修飾檸檬酸基以醯胺鍵和核酸適體結合Gd2O3：Eu-AP之老鼠毒性測試（in vivo）................................................94 第四章 結論............................................................................................98 第五章 未來展望....................................................................................99 參考文獻……........................................................................................100 圖目錄 圖 1-1功能性core-shell的排列組合......................................................5圖1-2 具有三重功能性core-shell的示意圖...........................................7 圖1-3 可捕獲慢中子之元素與其中子捕獲截面值..............................17 圖1-4 以Gd@C82-PEG-b-PAMA 做in vitro neutron irradiation..........19 圖1-5 弛緩時間示意圖 (a)外加磁場 (b) T1弛緩 (c) T2弛緩.............26 圖1-6 T、[C]與R關係圖.....................................................................25 圖1-7 商業化的MRI正增強顯影劑Gd-DOTA與Gd-DTPA...............28 圖1-8 Fe3O4結合Gd-DOTA.................................................................29 圖1-9 NaGdF4 粒徑大小與relaxivity的關係.....................................30 圖1-10 不同組織與元素對於X-ray 的吸收........................................32 圖1-11 改良後的斷層掃描儀................................................................33 圖 2-1 Gd2O3：Eu在螢光、MRI及CT上的應用示意圖.........................40 圖 2-2 製備 Gd2O3 流程圖..................................................................46 圖 2-3 製備 Gd2O3：Eu 合成圖............................................................47 圖 2-4 製備 Gd2O3：Eu-CA 合成圖...................................................48 圖 2-5 奈米粒子和核酸適體鍵結（Gd2O3：Eu -AP）示意圖.................49 圖 2-6 細胞毒性96-well孔盤配置圖.....................................................51 圖 2-7 qPCR總反應所使用之體積圖....................................................53 圖 2-8 qPCR流程圖................................................................................54 圖 2-9 解離曲線流程圖.........................................................................54 圖 3-1 以丙酮離心之Gd2O3 XRD圖....................................................57 圖 3-2 以丙酮離心之Gd2O3 TEM圖....................................................57 圖 3-3 Gd2O3 XRD圖...........................................................................58 圖 3-4 放大倍率200K之Gd2O3 TEM圖..............................................59 圖 3-5 放大倍率300K之 Gd2O3 TEM圖..............................................59 圖 3-6 Gd2O3 FT-IR圖............................................................................60 圖 3-7 Gd2O3 的EDS圖..........................................................................61 圖 3-8 金屬鹽類水合物與二甘醇反應形成金屬氧化物示意圖.........63 圖 3-9 金屬氧化物外包覆二甘醇圖.....................................................63 圖 3-10 Gd2O3：Eu XRD圖....................................................................65 圖 3-11 放大倍率200K之Gd2O3：Eu TEM圖......................................66 圖 3-12 放大倍率300K之Gd2O3：Eu TEM圖......................................66 圖 3-13 Gd2O3：Eu 的EDS圖...............................................................67 圖 3-14 Gd2O3：Eu-CA XRD圖..............................................................70 圖 3-15 Gd2O3、Gd2O3：Eu、Gd2O3：Eu-CA XRD疊圖...................70 圖 3-16 放大倍率各為 200K 和 300K 之 Gd2O3：Eu-CA TEM圖..71 圖 3-17 Gd2O3：Eu 的DLS圖.................................................................72 圖 3-18 Gd2O3：Eu-CA 的DLS圖...........................................................72 圖 3-19 Gd2O3、Gd2O3：Eu和Gd2O3：Eu-CA zeta potential圖...............73 圖 3-20 Gd2O3：Eu、CA和Gd2O3：Eu-CA FT-IR圖.........................74 圖 3-21 Gd2O3：Eu-CA 的TGA圖..........................................................75 圖 3-22 Gd2O3 UV-PL圖.......................................................................76 圖 3-23 Gd2O3：Eu 與Gd2O3：Eu -CA 的UV圖...............................77 圖 3-24 二甘醇（DEG） 的UV吸收圖..................................................78 圖 3-25 Gd2O3：Eu 與Gd2O3：Eu -CA 的PL圖...................................79 圖 3-26 Gd2O3：Eu的PLE圖..................................................................79 圖 3-27 不同摻雜比例Gd2O3：Eu的螢光強度圖.................................80 圖 3-28 Gd2O3、Gd2O3：Eu和Gd2O3：Eu-CA 300K下SQUID圖.............82 圖 3-29 Gd2O3、Gd2O3：Eu和Gd2O3：Eu-CA 5K下SQUID圖.................82 圖 3-30 理論與實際測得的aptamer濃度圖.........................................85 圖 3-31 Gd2O3 MRI image圖..................................................................86 圖 3-32 Gd2O3 MRI relaxivity圖........................................................87 圖 3-33 Gd2O3：Eu MRI image圖...........................................................88 圖 3-34 Gd2O3：Eu MRI relaxivity圖..................................................88 圖 3-35 Gd2O3、Gd2O3：Eu 和IOHEXOL CT image圖.........................90 圖 3-36 Gd2O3、Gd2O3：Eu 和IOHEXOL CT HU值濃度圖.................90 圖 3-37 Gd2O3：Eu-CA MTT圖..............................................................91 圖 3-38 Gd2O3：Eu-CA confocal圖.........................................................93 圖 3-39 Gd2O3：Eu-AP confocal圖.........................................................93 圖 3-40 解剖老鼠與UV燈照射管裝之Gd2O3：Eu-AP圖....................95 圖 3-41 UV燈照射管裝之Gd2O3：Eu-AP與解剖老鼠之器官圖.........95 圖 3-42 注入Gd2O3：Eu-AP CT圖.........................................................96 圖 3-43注入Gd2O3：Eu-AP 前後以CT對膀胱做積分圖.....................96 圖 3-44 不同pH Gd2O3：Eu-AP 圖.......................................................96 圖 3-45 加入葡甲胺至Gd2O3：Eu-AP 前、後與靜置一天圖...............97 表目錄 表1-1 不同顯影方式之特性....................................................................8 表1-2 鑭系元素的電子組態..................................................................13 表1-3 鑭系金屬氧化物的合成方式比較.............................................15 表1-4 aptamer與antibody之比較.......................................................38 表 2-1 不同元素在X-ray強度為50keV時之吸收係數.........................40 表 3-1 由EDS分析測得Gd2O3的元素含量比.......................................61 表 3-2 由EDS分析測得Gd2O3：Eu的元素含量比..............................67 表 3-3 由 ICP-MS 分析測得Gd2O3：Eu的元素含量比.......................68 表3-4 不同體積之EDC/NHS 與aptamer.............................................83 表3-5不同體積、數量與理論/實際測得濃度之aptamer...................85 表3-6 Gd2O3、Gd2O3：Eu、Gd-DOTA與Gd-DTPA relaxivity ratio…….88

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