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研究生:陳毅哲
研究生(外文):Yi-CheChen
論文名稱:具可酸解鍵結與螢光共振能量轉移現象之三重刺激響應性阿黴素接枝高分子混合微胞於調控藥物釋放之應用
論文名稱(外文):Triple Stimuli-Responsive and Doxorubicin-Conjugated Polymeric Mixed Micelles with Acid-Labile Linkage and Forster Resonance Energy Transfer for Controlled Drug Release
指導教授:吳文中
指導教授(外文):Wen-Chung Wu
學位類別:碩士
校院名稱:國立成功大學
系所名稱:化學工程學系
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2020
畢業學年度:108
語文別:中文
論文頁數:152
中文關鍵詞:雙親性嵌段共聚高分子藥物接枝高分子溫度響應性酸鹼響應性氧化還原敏感性主動標靶螢光共振能量轉移
外文關鍵詞:amphiphilic block copolymerpolymer-drug conjugatesthermo-responsivepH-responsiveredox-responsivetumor targetingFörster Resonance Energy Transfer
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本研究為了開發出同時具有主動標靶、環境應答與螢光追蹤功能的藥物載體系統,合成出具有聚集誘導螢光(AIE)性質的雙親性嵌段共聚高分子PCL-b-P(TEGMA-co-PPSEMA)及具主動標靶(active targeting)與三重刺激響應性(triple stimuli-responsive)且接上抗癌藥物doxorubicin (DOX)的雙親性嵌段共聚高分子DOX-hyd-PCL-SS-b-P(TEGMA-co-FA),於水中自組裝形成混合微胞,並針對其結構、微胞形態、環境響應性、螢光特性、藥物釋放效果及細胞毒性作一系列的分析與探討。
將poly(ε-caprolactone) (PCL)作為雙親性高分子微胞的疏水內核,並在PCL末端修飾具有酸鹼響應性的鍵結腙鍵(hydrazone bond, hyd)與疏水性藥物DOX連接,triethylene glycol methacrylate (TEGMA)作為具溫度響應性的親水性外殼,而親疏水鏈段之間存在一具有氧化還原響應性的雙硫鍵(disulfide bond, SS),並在親水鏈段上修飾具主動標靶與酸鹼響應性質的folid acid (FA),以形成DOX-hyd-PCL-SS-b-P(TEGMA-co-FA)的藥物接枝高分子(polymer-drug conjugates)。另外,將螢光基團2-(1,2,3,4,5-pentaphenyl-1H-silol
-yloxy) ethyl methacrylate) (PPSEMA)修飾於另一雙親性高分子的親水鏈上,以形成PCL-b-P(TEGMA-co-PPSEMA)。
本研究藉由親水外殼上的FA基團與HeLa細胞上的FA受體結合,達到主動標靶功能以促進細胞對微胞的胞吞作用;再利用酸鹼響應性的腙鍵(hyd)於酸性環境下斷鍵的特性,使藥物能在血液循環運輸時保持穩定,並於腫瘤細胞溶酶體的酸性環境下釋放;另外透過調整溫度響應性TEGMA與酸鹼響應性FA單體於高分子的聚合度,以及PCL-b-P(TEGMA-co-PPSEMA)與DOX-hyd-PCL-SS-b-P(TEGMA-co-FA)高分子在混合微胞中的比例,使最低臨界溶液溫度(lower critical solution temperature, LCST)於中性環境時高於人體體溫37oC,而在酸性環境下則低於37oC,讓混合微胞能在血液循環中穩定運輸藥物,並於腫瘤細胞溶酶體中改變微胞親水外殼特性以促進藥物釋放;在腫瘤細胞的細胞質中,雙硫鍵(SS)會因為高濃度的還原劑榖光甘肽(GSH)作用而斷鍵,造成微胞結構崩解;而螢光物質PPSEMA與藥物DOX之間具有光譜的重疊,當兩者距離夠近時會產生Förster Resonance Energy Transfer (FRET)的現象,可作為監控藥物裝載與釋放的機制;另外,在細胞毒性測試中,證明此藥物接枝的高分子混合微胞系統對於毒殺HeLa細胞具有相當的效果。
The purpose of this study was to develop a drug delivery system with promising functionalities of active targeting, stimuli-responsive, AIE-based fluorescent tracking for potential application in controlled drug release. Towards this goal, we developed a drug-conjugated polymeric mixed micelle system self-assembled from two series of amphiphilic block copolymers, PCL-b-P(TEGMA-co-PPSEMA) with aggregation-induced emission (AIE) characteristic and doxorubicin-conjugated DOX-hyd-PCL-SS-b-P(TEGMA-co-FA) with active targeting and triple stimuli-responsive features. In this research, we investigated the nanostructure, morphology, stimuli-responsive, fluorescent properties, drug release and cytotoxicity to HeLa cells of the multifunctional drug-conjugated mixed micelle
Poly(ɛ-caprolactone) (PCL) is the hydrophobic core of polymeric micelle. The hydrophobic anticancer drug, doxorubicin (DOX), was connected to the chain end of poly(ε-caprolactone) (PCL) backbone via pH-responsive hydrazone linkers. The thermo-responsive monomer, triethylene glycol methacrylate (TEGMA), is the hydrophilic shell of micelle that makes the micelle water-soluble and be able to self-assemble in aqueous solution. Futhermore, the disulfide bond between hydrophobic and hydrophilic blocks is redox responsive. We also introduced pH-responsive and active targeting ligands, folic acid (FA), to hydrophilic block of DOX-hyd-PCL-SS-b-P(TEGMA-co-FA) and the fluorescent moieties, 2-(1,2,3,4,5-pentaphenyl-1H-silol-yloxy) ethyl methacrylate) (PPSEMA) were connected to the other copolymer PCL-b-P(TEGMA-co-PPSEMA).
Since HeLa cells are overexpressing folate receptor (FR), folic acid (FA) is often employed to functionalize the hydrophilic shell of micelles for an active tumor targeting and thus to effectively promote cell-specific drug uptake. Due to the pH variation among cellular compartments such as endosomes and lysosomes (pH ≈ 5.0), extracellular tumor tissues (pH ≈ 6.5), and normal tissues (pH 7.4), we introduced a pH-responsive chemical linker, hydrazone bond (hyd), to mixed micelle system which can be cleaved in acidic environment. Also, we adjusted the degree of polymerization of TEGMA and FA and changed the ratio of DOX-hyd-PCL-SS-b-P(TEGMA-co-FA) and PCL-b-P(TEGMA-co-PPSEMA) in mixed micelles to control the lower critical solution temperature (LCST). The LCST should be higher than body temperature (37 °C) in neutral environment but lower than 37 °C when in acidic environment, so the micelles can be steady in blood circulation and release drug in lysosome of tumor cells. Because of the much higher concentration of glutathione (GSH) (approximately 10 mM) in tumor cytosol than the normal cells, the disulfide bonds (SS) could be cleaved under such high reductive environment. Förster Resonance Energy Transfer (FRET) would occur when donor was close enough to acceptor owing to the spectral overlap of PPSEMA and DOX. The FRET phenomenon could serve as a basis for monitoring the drug conjugation or release from the micelles. In addition, in vitro results demonstrated that the drug-conjugated mixed micelles exhibited dose-dependent cytotoxicity to HeLa cells.
摘要 I
Abstract IV
誌謝 XV
目錄 XVI
流程圖目錄 XXI
表目錄 XXII
圖目錄 XXIV
公式目錄 XXXI
第一章、緒論(Introduction) 1
1.1研究背景與文獻回顧(Literature review) 1
1.1.1藥物傳遞系統(Drug delivery system, DDS) 1
1.1.1.1奈米藥物載體(Nano sized drug carrier) 1
1.1.1.2藥物輸送(Drug delivery) 4
1.1.1.3藥物釋放(Drug release) 8
1.1.2多功能性奈米微胞(Multifunctional nanomicellar systems) 10
1.1.2.1雙親性嵌段共聚高分子(Amphiphilic block copolymers) 10
1.1.2.2藥物接枝高分子(Polymer-drug conjugates) 15
1.1.2.3環境響應性(Stimuli-responsive) 17
1.1.2.3螢光材料(Fluorescent materials) 34
1.2研究動機與目的(Motivation) 46
第二章、實驗(Materials and methods) 48
2.1實驗藥品(Chemicals) 48
2.2實驗方法(Experiments) 51
2.2.1單體合成(Synthesis of monomers) 51
2.2.1.1 Hydroxyethl 2-bromoisobutyrate (HEBIB) 51
2.2.1.2 Hydroxyethyl-2’-(bromoisobutyryl) ethyl disulfide (HO-SS-iBuBr) 51
2.2.2高分子聚合(Polymerization) 54
2.2.2.3 Poly(triethylene glycol methacrylate-co-2-(1,2,3,4,5-pentaphenyl-1H-silol-yloxy) ethyl methacrylate) (PCL-b-P(TEGMA-co-PPSEMA)) 56
2.2.2.4 Poly(ɛ-caprolactone)-SS-b-poly(triethylene glycol methacrylate) (PCL-SS-b-P(TEGMA)) 57
2.2.2.5 DOX-conjugated poly(ɛ-caprolactone)-SS-b-poly(triethylene glycol methacrylate) by a carbamate linker (DOX-cbm-PCL-SS-b-P(TEGMA)) 58
2.2.2.6 DOX-conjugated poly(ɛ-caprolactone)-SS-b-poly(triethylene glycol methacrylate) by a hydrazone linker (DOX-hyd-PCL-SS-b-P(TEGMA)) 59
2.2.2.7 DOX-conjugated poly(ɛ-caprolactone)-SS-b-poly(triethylene glycol methacrylate-co-folic acid) by a hydrazone linker (DOX-hyd-PCL-SS-b-P(TEGMA-co-FA)) 62
2.2.3微胞製備(Preparation of micelles) 67
2.2.4臨界微胞濃度(Critical micelle concentration, CMC) 67
2.2.5低臨界溶解溫度(Lower critical solution temperature, LCST) 67
2.2.6藥物接枝與釋放(Drug conjugated and in vitro drug release) 68
2.2.7細胞毒性測試(Cell culture and cytotoxicity assays) 70
2.2.8細胞內螢光影像(Confocal fluorscence imaging) 73
2.3儀器鑑定(Characterization) 73
2.3.1 Gel Permeation Chromatography (GPC) 73
2.3.2 Nuclear Magnetic Resonance (NMR) 74
2.3.3 Dynamic Light Scattering (DLS) 74
2.3.4 Transmission Electron Microscopy (TEM) 75
2.3.5 Ultraviolet-Visilbe Spectroscopy (UV-vis.) 75
2.3.6 Photoluminescence Spectroscopy (PL) 76
2.3.7 Enzyme-Linked Immunosorbent Assay (ELISA) Reader 76
2.3.8 Confocal Laser Scanning Microscope (CLSM) 76
第三章、結果討論(Results and discussion) 78
3.1合成與鑑定(Synthesis and characterization) 78
3.1.1 HEBIB單體合成(Synthesis of Hydroxyethl 2-bromoisobutyrate, HEBIB) 81
3.1.2 HO-SS-iBuBr單體合成 (Synthesis of Hydroxyethyl-2’-(bromoisobutyryl) ethyl disulfide, HO-SS-iBuBr) 82
3.1.3 NSMA單體合成(Synthesis of N-hydroxysuccinimide methacrylate, NSMA) 83
3.1.4 PPSEMA單體合成(Synthesis of 2-(1,2,3,4,5-Pentaphenyl-1H-silol-yloxy) ethyl Methacrylate, PPSEMA) 83
3.1.5 PCL高分子聚合(Synthesis of poly(ε-caprolactone), PCL) 85
3.1.6 SSPCL高分子聚合(Synthesis of SS-poly(ε-caprolactone), SSPCL) 86
3.1.7 [PCL-b-P(TEGMA-co-(PPSEMA))] (PCTAIE) 雙親性嵌段共聚高分子合成(Synthesis of poly[triethylene glycol methacrylate-co- 2-(1,2,3,4,5-penta-phenyl-1H-silol-yloxy) ethyl methacrylate), PCTAIE) 88
3.1.8 [DOX-cbm-PCL-SS-b-PTEGMA] (DOX-cbm-SSPCT) 雙親性嵌段共聚高分子合成 (Synthesis of DOX-conjugated poly(ɛ-caprolactone)-SS-b-poly(triethylene glycol methacrylate) by a carbamate linker, DOX-cbm-SSPCT) 91
3.1.9 [DOX-hyd-PCL-SS-b-PTEGMA] (DOX-hyd-SSPCT) 雙親性嵌段共聚高分子合成(Synthesis of DOX-conjugated poly(ɛ-caprolactone)-SS-b-poly(triethylene glycol methacrylate) by a hydrazone linker, DOX-hyd-SSPCT) 95
3.1.10 [DOX-hyd-PCL-SS-b-P(TEGMA-co-FA)] (DOX-hyd-SSPCTFA) 雙親性嵌段共聚高分子合成 (Synthesis of DOX-conjugated poly(ɛ-caprolactone)-SS-b-poly(triethylene glycol methacrylate-co-folic acid) by a hydrazone linker, DOX-hyd-SSPCTFA) 97
3.2微胞的製備與性質鑑定(Preparation and characterization of mixed micelles) 106
3.2.1藥物接枝量(Drug conjugated content) 107
3.2.2溫度響應性(Thermo-responsive behaviors) 109
3.2.3微胞的微觀形態與粒徑大小(Morphology and size of mixed micelles) 115
3.2.4氧化還原響應性(Redox-responsive behaviors) 118
3.2.4臨界微胞濃度(Critical micelle concentration, CMC) 119
3.2.5混合微胞之螢光性質(Fluorescent properties of mixed micelles) 122
3.3藥物釋放測試(In vitro drug release) 128
3.3.1可酸解鍵結之酸鹼響應性測試 (pH-responsive behaviors based on acid liable bond cleavage) 129
3.3.2混合微胞穩定性 (Stability of mixed micelles) 130
3.3.3混合微胞藥物釋放(In vitro drug release of mixed micelles) 133
3.4細胞毒性測試(Cytotoxicity assays) 137
3.5細胞內螢光影像(Confocal fluorescence image) 142
第五章、參考文獻(References) 147
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