通過自身互補充多重氫鍵構建的超分子聚合物微胞應用於藥物控制傳遞

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研究生：	孫雅庭 Ya-Ting SUN
論文名稱：	通過自身互補充多重氫鍵構建的超分子聚合物微胞應用於藥物控制傳遞 Supramolecular Polymeric Micelles Constructed by Self-Complementary Multiple Hydrogen Bonding for Controlled Drug Delivery
指導教授：	鄭智嘉 Chih-Chia Cheng
口試委員:	賴君義 Juin-Yih Lai 楊銘乾 Ming-Chien Yang 蔡協致 Hsieh-Chih Tsai 江偉宏 Wei-Hung Chiang 李愛薇 Ai-Wei Lee
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：	2019
畢業學年度：	107
語文別：	中文
論文頁數：	172
中文關鍵詞：	藥物傳輸系統、超分子、奈米微胞
外文關鍵詞：	Drug delivery system, Supramolecular, Micelles
相關次數：	點閱：182 下載：0
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基於多重氫鍵的結合，超分子聚合物的簡單構造而具有所需的化學和物理性質，以實現高效、安全和可靠的藥物傳載及治療仍具有高度的挑戰性。在本論文中，我們成功開發了含有自身互補性四重/六重氫鍵基團的新型超分子聚合物，它們在水性環境中能自發組裝成奈米球狀的微胞。該系統產生之超分子微胞可以容易地控制而獲得所需的結構穩定性，因此展現出良好的生物相容性、優異的pH響應性和藥物負載能力。所得的藥物微胞顯示出可調節的藥物負載能力，在血清存在下具有優異的長效穩定性，因此促進高效藥物裝載的過程。此外，體外釋放結果表明，裝載藥物的微胞在微酸性條件下能有效地快速觸發藥物釋放。更重要的是，所得的螢光影像和流式細胞儀分析結果清楚地證實，藥物微胞可被癌細胞有效地內吞以誘導細胞凋亡；因此，這些新開發的超分子微胞可作為多功能的藥物載體，用於安全、高效的控制藥物釋放，以實現所期望的化學治療效果。

Facile construction of supramolecular polymers, based on the incorporation of multiple hydrogen bonds, with the desired chemical and physical properties to achieve the effective, safe and reliable delivery of drugs for chemotherapy treatment remains highly challenging. In this thesis, we successfully developed new supramolecular polymers containing self-complementary quadruple/sextuple hydrogen bonding groups, which undergo spontaneous assembling into nanospherical micelles in an aqueous environment. This system generates supramolecular micelles that can be readily controlled to attain the desired structural stability with good biocompatibility, excellent pH-responsive and drug-loading capabilities. The resulting drug-loaded micelles revealed a tunable drug loading capacity with excellent long-term stability in the presence of serum, thus promoting highly efficient drug-loading processes. In addition, in vitro release results indicated that drug-loaded micelles can be used to rapidly trigger drug release under slightly acidic conditions. More importantly, the resulted fluorescence images and flow cytometric analysis clearly demonstrated that drug-loaded micelles can be effectively endocytosed by cancer cells to induce apoptosis; therefore, these newly-developed supramolecular micelles could serve as versatile drug vehicles for safe and effective controlled drug release to achieve a desired chemotherapeutic effect.

摘要    I
Abstract    II
致謝    III
目錄    IV
表目錄    IX
圖目錄    X
第1章 緒論    1
1研究背景    1
2研究動機與目的    4
第2章 文獻回顧    6
1超分子化學（Supramolecular Chemistry）    6
2分子自組裝（Self-Assembly）    8
4分子識別（Molecular Recognition）    9
5氫鍵（Hydrogen Bond）    10
5.1三重氫鍵互補    12
5.2四重氫鍵互補    14
5.3六重氫鍵互補    17
6刺激應答（Stimuli-Responsivenesss）    19
7藥物載體（Drug Delivery System）    20
8高分子奈米載體（Polymeric Nanocarriers）    22
9超分子載體（Supramolecular Carrier）    23
10 EPR效應（Enhanced Permeation and Retention Effect）    24
11聚乙二醇（Polyethylene Glycol，PEG）    25
12點擊化學（Click Chemistry）    27
13阿黴素（Doxorubicin，Dox）    29
第3章 實驗材料與方法    30
1研究設計    30
2實驗材料    31
2.1實驗藥品    31
2.2實驗溶劑    35
2.3細胞實驗材料    39
2.4相關實驗材料    41
3實驗儀器與設備參數    42
3.1旋轉塗佈機（Spin Coaters）    42
3.2桌上型酸鹼度計（pH Meter）    42
3.3酵素免疫分析儀（Enzyme-Linked Immunosorbent Assay，ELISA）    43
3.4二氧化碳培養箱（CO2 incubators）    43
3.5流式細胞儀（Flow Cytometry）    44
3.6振盪混合器（Vortex Mixer）    45
3.7光致螢光光譜儀（Photoluminescence，PL）    45
3.8熱重分析儀（Thermogravimetric Analysis，TGA）    46
3.9紫外線可見光光譜儀（UV/Vis Spectrophotometer）    47
3.10凝膠滲透層析儀（Gel Permeation Chromatography，GPC）    48
3.11螢光顯微鏡（Fluorescence Microscope）    48
3.12原子力顯微鏡（Atomic Force Microscpoic，AFM）    49
3.13動態光散射分析儀（Dynamic Light Scattering，DLS）    50
3.14差示掃描量熱儀（Differential Scanning Calorimetry，DSC）    50
3.15高解析度場發射掃描式電子顯微鏡（Scanning Electron Microscope）    51
3.16傅立葉轉換紅外光譜（Fourier Transform Infrared Spectroscopy）    51
3.17液態核磁共振光譜（Nuclear Magnetic Resonance Spectrometer）    52
3.18基質輔助雷射脫附游離飛行時間質譜儀（Matrix Assisted Laser Desorption/Ioniation TIME-OF-FLIGHT Mass Spectrometer）    53
3.19流式細胞分析儀（Fluorescence-Activated Cell Sorter Aria IIIu，FACS）    54
4實驗合成步驟    56
4.1實驗架構    56
4.2合成前驅物11-azidoundecanoic acid（2）    58
4.3合成DAP-N3（3）    59
4.4合成UPy-N3（5）    60
4.5合成BU-DAP-PEG4000    61
4.6合成BU-UPY-PEG4000    62
5樣品製備    63
5.1空奈米微胞製備    63
5.2 Dox奈米微胞（Sample/Dox）製備    63
5.3臨界奈米微胞濃度（Critical Micelle Concentration，CMC）    63
5.4 Dox藥物濃度檢量線（Dox Drug Concentration Calibration Curve）    64
5.5Dox包覆率（Drug Loading Efficiency）    64
5.6體外藥物釋放模擬    65
5.7奈米微胞穩定性測試    65
5.8奈米微胞刺激響應測試    65
6細胞生物性製備    66
6.1磷酸鹽緩衝生理鹽水（Phosphate buffered saline，PBS）    66
6.2胰蛋白酶（Trypsin - EDTA）    66
6.3細胞培養基（Dulbecco's Modified Eagle Medium，DMEM）    66
6.4細胞解凍培養    67
6.5細胞培養條件    67
6.6染色與數細胞    67
6.7細胞生物毒性測試    68
6.8螢光顯微鏡製備    68
6.9製備Annexin-binding buffer    69
6.10製備Propidium iodide（PI）    69
6.11流式細胞儀（Flow cytometer）    69
第4章 結果與討論    71
1材料鑑定    72
1.1 傅立葉轉換紅外光譜FTIR    74
1.2 核磁共振氫譜1H NMR    76
1.3基質輔助雷射脫附游離飛行時間質譜儀MALDI-TOF    85
1.4凝膠滲透層析儀GPC    86
1.5 熱重分析儀TGA    90
1.6 熱差式分析儀DSC    92
2材料性質分析    96
2.1臨界微胞濃度CMC    96
2.2粒徑分析DLS    100
2.3奈米微胞穩定性分析    102
2.4奈米微胞刺激響應    104
3藥物奈米微胞分析    108
3.1藥物包覆率與粒徑分布    108
3.2藥物奈米微胞穩定性分析    112
3.3藥物奈米微胞刺激響應    114
3.4掃描電子顯微鏡SEM、原子力顯微鏡AFM    116
3.5體外藥物釋放Drug Release In Vitro    120
3.6細胞毒性測試Cytotoxicity Test    123
3.7螢光顯微鏡CLSM    127
3.8細胞攝取的機制Cell Uptake    131
3.9流式細胞儀Flow Cytometer    134
第5章 結論    139
第6章 未來展望    141
第7章 參考文獻    142


                                

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