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研究生:孫雅庭
研究生(外文):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
論文名稱(外文):Supramolecular Polymeric Micelles Constructed by Self-Complementary Multiple Hydrogen Bonding for Controlled Drug Delivery
指導教授:鄭智嘉
指導教授(外文):Chih-Chia Cheng
口試委員:賴君義楊銘乾蔡協致江偉宏李愛薇
口試委員(外文):Juin-Yih LaiMing-Chien YangHsieh-Chih TsaiWei-Hung ChiangAi-Wei Lee
口試日期:2019-07-30
學位類別:碩士
校院名稱:國立臺灣科技大學
系所名稱:應用科技研究所
學門:自然科學學門
學類:其他自然科學學類
論文種類:學術論文
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 systemSupramolecularMicelles
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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
1.1研究背景 1
1.2研究動機與目的 4
第2章 文獻回顧 6
2.1超分子化學(Supramolecular Chemistry) 6
2.2分子自組裝(Self-Assembly) 8
2.4分子識別(Molecular Recognition) 9
2.5氫鍵(Hydrogen Bond) 10
2.5.1三重氫鍵互補 12
2.5.2四重氫鍵互補 14
2.5.3六重氫鍵互補 17
2.6刺激應答(Stimuli-Responsivenesss) 19
2.7藥物載體(Drug Delivery System) 20
2.8高分子奈米載體(Polymeric Nanocarriers) 22
2.9超分子載體(Supramolecular Carrier) 23
2.10 EPR效應(Enhanced Permeation and Retention Effect) 24
2.11聚乙二醇(Polyethylene Glycol,PEG) 25
2.12點擊化學(Click Chemistry) 27
2.13阿黴素(Doxorubicin,Dox) 29
第3章 實驗材料與方法 30
3.1研究設計 30
3.2實驗材料 31
3.2.1實驗藥品 31
3.2.2實驗溶劑 35
3.2.3細胞實驗材料 39
3.2.4相關實驗材料 41
3.3實驗儀器與設備參數 42
3.3.1旋轉塗佈機(Spin Coaters) 42
3.3.2桌上型酸鹼度計(pH Meter) 42
3.3.3酵素免疫分析儀(Enzyme-Linked Immunosorbent Assay,ELISA) 43
3.3.4二氧化碳培養箱(CO2 incubators) 43
3.3.5流式細胞儀(Flow Cytometry) 44
3.3.6振盪混合器(Vortex Mixer) 45
3.3.7光致螢光光譜儀(Photoluminescence,PL) 45
3.3.8熱重分析儀(Thermogravimetric Analysis,TGA) 46
3.3.9紫外線可見光光譜儀(UV/Vis Spectrophotometer) 47
3.3.10凝膠滲透層析儀(Gel Permeation Chromatography,GPC) 48
3.3.11螢光顯微鏡(Fluorescence Microscope) 48
3.3.12原子力顯微鏡(Atomic Force Microscpoic,AFM) 49
3.3.13動態光散射分析儀(Dynamic Light Scattering,DLS) 50
3.3.14差示掃描量熱儀(Differential Scanning Calorimetry,DSC) 50
3.3.15高解析度場發射掃描式電子顯微鏡(Scanning Electron Microscope) 51
3.3.16傅立葉轉換紅外光譜(Fourier Transform Infrared Spectroscopy) 51
3.3.17液態核磁共振光譜(Nuclear Magnetic Resonance Spectrometer) 52
3.3.18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
3.3.19流式細胞分析儀(Fluorescence-Activated Cell Sorter Aria IIIu,FACS) 54
3.4實驗合成步驟 56
3.4.1實驗架構 56
3.4.2合成前驅物11-azidoundecanoic acid(2) 58
3.4.3合成DAP-N3(3) 59
3.4.4合成UPy-N3(5) 60
3.4.5合成BU-DAP-PEG4000 61
3.4.6合成BU-UPY-PEG4000 62
3.5樣品製備 63
3.5.1空奈米微胞製備 63
3.5.2 Dox奈米微胞(Sample/Dox)製備 63
3.5.3臨界奈米微胞濃度(Critical Micelle Concentration,CMC) 63
3.5.4 Dox藥物濃度檢量線(Dox Drug Concentration Calibration Curve) 64
3.5.5Dox包覆率(Drug Loading Efficiency) 64
3.5.6體外藥物釋放模擬 65
3.5.7奈米微胞穩定性測試 65
3.5.8奈米微胞刺激響應測試 65
3.6細胞生物性製備 66
3.6.1磷酸鹽緩衝生理鹽水(Phosphate buffered saline,PBS) 66
3.6.2胰蛋白酶(Trypsin - EDTA) 66
3.6.3細胞培養基(Dulbecco's Modified Eagle Medium,DMEM) 66
3.6.4細胞解凍培養 67
3.6.5細胞培養條件 67
3.6.6染色與數細胞 67
3.6.7細胞生物毒性測試 68
3.6.8螢光顯微鏡製備 68
3.6.9製備Annexin-binding buffer 69
3.6.10製備Propidium iodide(PI) 69
3.6.11流式細胞儀(Flow cytometer) 69
第4章 結果與討論 71
4.1材料鑑定 72
4.1.1 傅立葉轉換紅外光譜FTIR 74
4.1.2 核磁共振氫譜1H NMR 76
4.1.3基質輔助雷射脫附游離飛行時間質譜儀MALDI-TOF 85
4.1.4凝膠滲透層析儀GPC 86
4.1.5 熱重分析儀TGA 90
4.1.6 熱差式分析儀DSC 92
4.2材料性質分析 96
4.2.1臨界微胞濃度CMC 96
4.2.2粒徑分析DLS 100
4.2.3奈米微胞穩定性分析 102
4.2.4奈米微胞刺激響應 104
4.3藥物奈米微胞分析 108
4.3.1藥物包覆率與粒徑分布 108
4.3.2藥物奈米微胞穩定性分析 112
4.3.3藥物奈米微胞刺激響應 114
4.3.4掃描電子顯微鏡SEM、原子力顯微鏡AFM 116
4.3.5體外藥物釋放Drug Release In Vitro 120
4.3.6細胞毒性測試Cytotoxicity Test 123
4.3.7螢光顯微鏡CLSM 127
4.3.8細胞攝取的機制Cell Uptake 131
4.3.9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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