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研究生： 楊雅棠
Ya-Tang Yang
論文名稱： 脲基胞嘧啶功能化超分子奈米凝膠應用於選擇性癌症治療
Ureido-Cytosine Functionalized Supramolecular Nanogels for Selective Cancer Treatment
指導教授： 鄭智嘉
Chih-Chia Cheng
口試委員: 謝永堂
劉英麟
陳建光
李愛薇
鄭智嘉
學位類別： 碩士
Master
系所名稱： 應用科技學院 - 應用科技研究所
Graduate Institute of Applied Science and Technology
論文出版年： 2021
畢業學年度： 109
語文別： 中文
論文頁數： 125
中文關鍵詞： 超分子 、奈米凝膠 、藥物載體 、癌症治療 、氫鍵
外文關鍵詞： Supramolecular, Nanogel, drug carrier, cancer therapy, hydrogen bond
相關次數： 點閱：305  下載：0 
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    • 本文成功以聚乙二醇二丙烯酸酯與胞嘧啶、異氰酸正丁酯透過簡單的兩步合成，製備出具高度酸鹼應答能力的兩端遙爪超分子聚合物，透過國家同步輻射中心的小角光散射儀確認後會形成二聚體使結晶厚度增加，並由差示掃描量熱儀、變溫傅立葉轉換紅外光譜儀得知此材料在固體形態下展現出熱可逆性；變溫超導核磁共振儀中更能以溫度轉變超分子結構。
    在臨界微胞濃度實驗中超分子展現於水溶液中，可藉由四重氫鍵基團自發組裝形成奈米球，並具有良好的藥物承載量及可調控的包藥載體尺寸。由藥物釋放實驗得知，在中性環境下呈現出良好的藥物包封性；在酸性環境下則有快速且高效的藥物釋放能力，經過長時間的粒徑觀測了解到包藥載體及超分子本身與水溶液中的穩定性，呈現出藥物和載體之間的交互作用力也能夠增強包封性。
    透過細胞毒殺測試的結果證實超分子具有良好的生物相容性，結合藥物釋放曲線、螢光顯微鏡、流式細胞儀證實，包藥載體憑藉著高度酸鹼應答能力辨識出癌細胞與正常細胞，擁有能夠精確釋放藥物以治療癌細胞的能力。

    This paper successfully synthesized a telechelic supramolecular polymer which made from polyethylene glycol diacrylate, cytosine, N-Butyl Isobutyrate by a simple two steps. It’s containing ultrasensitive pH-resonsive ability.
    National Radiation Center's small angle photometer proved the thickness of crystallization increase due to dimer was formed. The material shows thermoreversible under solid state by measure DSC and Variety temperature-FTIR. The structure of material can be change through temperature by measure Variety temperature-NMR.
    It’s can self-assemble to a nanogel in aqueous solution due to quadruple hydrogen bond groups by measure critical micelle concentration. The nanogel possess excellent drug-loading capability and adjustable size.
    These supramolecular shows structural stability under pH =7.4. And possess fast and excellent drug release capability under pH =6.0. To know the stability between supramolecular and drug carrier by kinetic stability experiment. It's shows the interaction between drug and carrier increase the encapsulation.
    The supramolecular have good biocompatibility was proved by MTT assay. Tumor cell and normal cell can be identied duo to ultrasensitive pH-resonsive ability, then make a decition that kill cell by release the loading drug.

    摘要 II Abstract III 致謝 IV 目錄 VI 圖目錄 XI 表目錄 XV 第一章 緒論 1 1.1 研究背景 1 1.1.1 藥物載體的由來 1 1.1.2 超分子化學 2 1.2 研究動機 4 第二章 文獻回顧 6 2.1 腫瘤 6 2.1.1 腫瘤特性 6 2.1.2 EPR效應 7 2.2 靶向治療 8 2.2.1 主動靶向 8 2.2.2 被動靶向 8 2.3 吞噬作用 9 2.4 聚乙二醇化 10 2.5 邁可加成反應 11 2.5.1 α,β-不飽和羰基化合物 11 2.5.2 親核試劑 11 2.5.3 邁可加成反應的機制 11 2.6 超分子自組裝 13 2.6.1 凡得瓦爾力 14 2.6.2 氫鍵 15 2.6.3 π-π堆疊作用力 16 2.7 質子化 17 2.8 阿黴素 19 2.8.1 阿黴素的作用機制 19 2.8.2 代謝阿黴素 20 2.9 文獻回顧總結 20 第三章 實驗材料與流程 21 3.1 實驗設計架構圖 21 3.2 實驗材料 22 3.2.1 實驗藥品 22 3.2.2 實驗溶劑 24 3.2.3 細胞實驗材料 27 3.2.4 相關實驗材料 31 3.3 實驗儀器及參數 32 3.3.1 斜式旋轉濃縮機 32 3.3.2 液態超導核磁共振儀 32 3.3.3 傅立葉轉換紅外光譜儀 33 3.3.4 凝膠滲透層析儀 33 3.3.5 基質輔助雷射脫附游離飛行時間式質譜儀 34 3.3.6 高效能凍乾機 34 3.3.7 紫外線光譜儀 35 3.3.8 高解析度場發射掃描式電子顯微鏡 35 3.3.9 動態光散射粒徑分析儀 36 3.3.10 光致發光光譜儀 36 3.3.11 旋轉塗佈機 37 3.3.12 原子力顯微鏡 37 3.3.13 熱重分析儀 38 3.3.14 差示掃描量熱儀 38 3.3.15 高解析度小角度光散射儀 39 3.3.16 桌上型酸鹼度計 39 3.3.17 試管震盪器 39 3.3.18 CO2培養箱 40 3.3.19 離心機 40 3.3.20 螢光顯微鏡 40 3.3.21 酵素免疫分析儀 41 3.3.22 流式細胞儀 41 3.4 實驗合成步驟 42 3.4.1 合成CyPEG 42 3.4.1 合成UrcyPEG 43 3.5 樣品製備 44 3.5.1 奈米球製備 44 3.5.2 NMR試管製備 44 3.5.3 臨界微胞濃度CMC 44 3.5.4 DOX藥物濃度檢量線 45 3.5.5 奈米球包載DOX製備 45 3.5.6 DOX包覆率 45 3.5.7 SEM矽晶片製備 46 3.5.8 藥物釋放製備 46 3.5.9 奈米球穩定性測試 46 3.6 細胞實驗製備 47 3.6.1 配置磷酸鹽緩衝生理鹽水 47 3.6.2 配置細胞培養基 47 3.6.3 細胞解凍 47 3.6.4 細胞繼代 47 3.6.5 細胞計數 48 3.6.6 細胞生物毒性 48 3.6.7 螢光顯微鏡製備 49 3.6.8 流式細胞儀-細胞攝取製備 50 3.6.9 流式細胞儀-細胞凋亡製備 50 第四章 結果與討論 52 4.1 材料鑑定 52 4.1.1 傅立葉轉換紅外光譜 52 4.1.2 液態超導核磁共振氫譜 55 4.1.3 凝膠滲透層析儀 57 4.1.4 基質輔助雷射脫附游離飛行時間式質譜儀 58 4.2 材料性質分析 59 4.2.1 高解析度小角度光散射儀 59 4.2.2 熱重分析儀 61 4.2.3 差示掃描熱分析儀 63 4.2.4 變溫傅立葉轉換紅外光譜 66 4.2.5 變溫液態超導核磁共振氫譜 69 4.2.6 臨界微胞濃度 71 4.3 材料形貌分析 73 4.3.1 藥物載體的粒徑分析 73 4.3.2 藥物載體的 74 4.4 藥物能力分析 76 4.4.1 藥物載體包覆DOX的DLE、DLC 76 4.4.2 包藥載體的形貌分析 78 4.4.3 藥物釋放曲線 80 4.4.4 微胞的穩定性分析 82 4.4.5 包藥載體在酸性環境下的形貌分析 84 4.5 細胞實驗 86 4.5.1 藥物載體的MTT assay 86 4.5.2 螢光顯微鏡 90 4.5.3 流式細胞儀-細胞攝取 94 4.5.4 流式細胞儀-細胞凋亡 99 第五章 結論 105 第六章 未來展望 106 第七章 參考文獻 107

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