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研究生： 蔡育丞
Tsai, Yu-Cheng
論文名稱： 製備以穀胱甘肽修飾乳鐵蛋白之奈米藥物載體應用於帕金森氏症治療
Synthesis of Glutathione-modified Protein-Based Nanocarriers for Treatment of Parkinson’s Disease
指導教授： 詹正雄
Jan, Jeng-Shiung
學位類別： 碩士
Master
系所名稱： 工學院 - 化學工程學系
Department of Chemical Engineering
論文出版年： 2019
畢業學年度： 107
語文別： 中文
論文頁數： 120
中文關鍵詞： 帕金森氏症 、乳鐵蛋白 、穀胱甘肽 、多巴胺能神經元 、奈米藥物載體 、2-羥丙基-β-環糊精 、苦橄欖素
外文關鍵詞： Parkinson’s disease, lactoferrin, glutathione, dopaminergic neuron, oleuropein, 2-hydroxypropyl-β-cyclodextrin, blood-brain barrier
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    • 本研究致力於合成出穩定、粒徑小、無毒性、且對帕金森氏症具有藥物活性之奈米藥物載體粒子，將血腦屏障穿梭胜肽—穀胱甘肽接枝修飾於同樣能夠通過血腦屏障之乳鐵蛋白胺基酸序列上，並利用肝素高負電密度與能和乳鐵蛋白結合之特性，將藥物吸附後與乳鐵蛋白結合形成同時具有藥物活性和血腦屏障穿梭官能基之藥物奈米粒子，整個系統未用到任何有危害性之溶劑，把毒性降至最低，並探討在不同藥物(特別是幾種新穎之藥物後選例如：苦橄欖素(Oleuropein)、2-羥丙基-β-環糊精(2-hydroxypropyl-β-cyclodextrin)等)、不同組成比例與有無穀胱甘肽修飾等等各種的條件下，評估此藥物載體系統之可行性。
    結果顯示若將條件控制得宜，此系統之粒子大小均可介於80-170nm左右，雖然不同藥物組合有不同的粒徑表現，但對生物體都幾乎沒有任何毒性，也能夠被細胞攝取至細胞質甚至細胞核的位置進行藥物釋放。在有穀胱甘肽修飾的粒子中，結構會較鬆散，但也因此提升了藥物釋放的效率，並且能夠顯著提升粒子被細胞攝取的效率，可做為未來腦部治療相關的藥物載體開發。

    In this study, we developed a protein-based drug carrier, where the nanoparticles(NPs) are non-toxic and possess medicinal activity against Parkinson's disease (PD). Lactoferrin (LF) modified by glutathione (GSH) serve as our NPs skeleton not only provide blood-brain barrier (BBB) shuttle ability, anti-oxidation activity but also enhance the cellular uptake efficiency. After encapsulated with dopamine (Dopa), levodopa (L-Dopa), oleuropein (Oleu), 2-hydroxypropyl-β-cyclodextrin (HPBCD) and rhodamine 6G (Rd), found heparin (Hep) serves a crucial role in crosslinking between LF, LF(GSH) and drugs by electrostatic force and natural binding force, especially Dopa and L-Dopa, making the structure more firmly, possessing higher DLE and sustained drug-release ability. Properties were confirmed by 1H NMR and DLS, data shows that we can acquire the NPs which size between approximately 80 to 170 nm under certain condition. TEM images and UV-Vis spectrums claim that GSH will in certain level affect the structural compactness of NPs, but can increase both release and cellular uptake efficiency, also provide one more target for acceptor (GSH transporter) on BBB to recognize. Investigation of ELISA and confocal microscopy suggested that NPs show low toxicities for both SH-SY5Y cell line and mid-brain organoids. The ability to transport to nuclei and successfully rescue the ratio of dopaminergic neuron in the PD model organoids is another advantage. Furthermore, L-Dopa and HPBCD can form an “inclusion complex” during preparation which significantly improves the DLE and DLC of HPBCD. To sum up, our NPs system has good advantage and potential in the field of brain disease treatment and will conduct animal experiments in the future.

    摘要 I EXTENDED ABSTRACT II 誌謝 XV 目錄 XVII 表目錄 XXIII 圖目錄 XXIV 第一章 緒論 1 1.1前言 1 1.2研究動機 3 1.3研究構想 4 第二章 文獻回顧 5 2.1 帕金森氏症 5 2.1.1 帕金森氏症之簡介 5 2.1.2 血腦屏障 7 2.1.3 藥物載體開發 9 2.2 載體材料 10 2.2.1 胺基酸與蛋白質 10 2.2.2 穀胱甘肽 12 2.2.3 乳鐵蛋白 13 2.2.4 肝素 15 2.3 治療藥物之簡介 17 2.3.1 多巴胺 17 2.3.2 左旋多巴 18 2.3.3 苦橄欖素 20 2.3.4 2-羥丙基-β-環糊精 21 2.3 生物活性測試模型 23 2.3.1 人類神經瘤母細胞SH-SY5Y細胞系 23 2.3.2 中腦-類器官 24 第三章 實驗方法與步驟 26 3.1 實驗藥品 26 3.2 溶劑配製 29 3.2.1 1×, pH7.4, PBS緩衝溶液 29 3.2.2 50mM PB9緩衝溶液 29 3.2.3 細胞培養基 29 3.2.4 Serum-Free細胞培養基 29 3.3 合成GSH修飾之LF, LF(GSH) 30 3.4 NPS之製備 31 3.4.1 LF之空NPs製備方法 31 3.4.2 攜帶Dopa之NPs製備方法 31 3.4.3 攜帶L-Dopa之NPs製備方法 31 3.4.4 攜帶Oleu之NPs製備方法 32 3.4.5 攜帶HPBCD之NPs製備方法 32 3.4.6 攜帶L-Dopa/HPBCD複合物之NPs製備方法 32 3.4.7 攜帶螢光標的物Rd之NPs製備方法 33 3.4.8 接枝螢光標的物Rd之HLL製備方法 33 3.5 核磁共振光譜儀測定 (NMR) 34 3.5.1 LF(GSH)修飾結果測定 34 3.5.2 HPBCD檢量線製作 34 3.6 動態光散射儀測定 (DLS) 36 3.6.1 粒徑測量 36 3.6.2 界面電位(Zeta Potential)測量 36 3.7 UV-VIS吸收光譜測定 36 3.7.1 藥品檢量線製作 36 3.7.2 包覆量(Drug-load content, DLC)與包覆效率(Drug-load efficiency, DLE)測定 36 3.7.3 藥物釋放 37 3.8 穿透式電子顯微鏡拍攝 (TEM) 37 3.9 細胞培養 37 3.9.1 解凍細胞 37 3.9.2 細胞分盤 37 3.9.3 冷凍細胞 38 3.10 細胞毒性測試 (CELL VIABILITY) 39 3.10.1 鋪細胞 39 3.10.2 配藥/加藥 39 3.10.3 呈色 39 3.11 溶血活性測試 (HEMOLYSIS) 40 3.12 DOPA細胞攝取測試 41 3.12.1 加藥 41 3.12.2 Coating 41 3.12.3 Blocking 41 3.12.4 呈色 42 3.13 DOPA細胞攝取玻片染色測試 43 3.14 中腦-類器官(MID-BRAIN ORGANOIDS)之免疫螢光測試 44 3.14.1 加藥 44 3.14.2 切片 44 3.14.3 染色 44 3.15 BBB細胞模型穿透測試 46 3.15.1 腦內表皮細胞毒性測試 46 3.15.2 奈米粒子在BBB細胞模型之通透性測試 46 3.15.3 腦內表皮細胞中之HDL-Rd與HDLG-Rd之可視化測試 47 3.16 實驗儀器與原理 48 3.16.1 核磁共振光譜儀(nuclear magnetic resonance spectrophotometer, NMR) 48 3.16.2 穿透式電子顯微鏡(Transmission Electron Microscope, TEM) 50 3.16.3 動態光散射儀(Dynamic Light Scattering, DLS) 52 3.16.4 紫外光-可見光光譜儀(Ultraviolet/Visible Spectrophotometer, UV-Vis) 53 第四章 結果與討論 54 4.1 LF接枝GSH之探討 54 4.1.1 LF之1H NMR圖譜探討 54 4.1.2 LF之DLS數據探討 55 4.1.3 LF之TEM圖像探討 56 4.2 NPS之性質探討 57 4.2.1 空NPs之性質探討 57 4.2.2 包覆L-Dopa之NPs性質探討 60 4.2.3 包覆Dopa之NPs性質探討 62 4.2.4 包覆Oleu之NPs性質探討 63 4.2.5 包覆HPBCD之NPs性質探討 65 4.2.6 含有Rd之NPs性質探討 67 4.2.7 NPs之性質總表 70 4.2.8 Hep重要性之探討 71 4.2.9 製備條件之探討 73 4.3 NPS之藥物釋放探討 75 4.3.1 Dopa系統與L-Dopa系統之藥物釋放探討 75 4.3.2 Oleu系統與HPBCD系統之藥物釋放探討 76 4.4 NPS之溶血性探討 77 4.5 NPS之細胞毒性探討 79 4.6 NPS之神經細胞攝取探討 81 4.6.1 Dopa系列NPs之神經細胞攝取探討 81 4.6.2 Dopa系列NPs之細胞攝取顯微鏡圖像探討 82 4.7 NPS在ORGANOIDS之生物活性探討 85 4.7.1 HLL-fluo之Organoids治療效果探討 85 4.7.2 各系統NPs之Organoids型態外觀探討 87 4.7.3 各系統NPs之Organoids載體攝取探討 90 4.7.4 各系統NPs之Organoids治療效果探討 95 4.8 NPS在BBB細胞共培養模型之穿透效果探討 97 4.8.1 HDL-Rd與HDLG-Rd在腦內表皮細胞之毒性表現 97 4.8.2 HDL-Rd與HDLG-Rd在腦內表皮細胞之毒性表現 98 4.8.3 HDL-Rd與HDLG-Rd在腦內表皮細胞之毒性表現 99 4.9 L-CD系統之NPS探討 100 4.9.1 L-CD系統NPs之基本性質探討 100 4.9.2 L-CD系統NPs之生物活性探討 107 第五章 結論 108 第六章 參考文獻 110

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