臺灣博碩士論文加值系統

青光眼位居全球致盲眼疾之次位。就臨床醫學而言，藥物療法確實頗具契機；但其傳輸效能卻也受到眼部組織屏障所侷限。本論文之主要目標即開發青光眼治療應用的注射型生物降解原位凝膠藥物傳輸系統，期藉由生醫材料工學探索，以改善藥物生物可利用率及強化青光眼疾治療功效。第2與3章分別著重於延長釋藥及功能擴充之水膠材料設計與評估。在第2.1章，以三種不同布魯姆指數之明膠進行接枝聚異丙基丙烯醯胺，並分析其藥物釋放與活性影響。接續在第2.2章，利用四種不同碳鏈長度之鏈轉移劑合成感溫性高分子刷，進而接枝於胺基化明膠，作為青光眼藥物傳輸系統。有鑑於青光眼係一種需長時間控制眼壓之眼疾，故第2.3與2.4章也思及更換原本明膠主體，而改採降解較慢之幾丁聚醣，並藉由調控去乙醯化程度，以獲致長效眼藥傳輸與疾患療效。此部分結果顯示當布魯姆指數愈高與碳鏈長度愈長，載體材料具較佳之抗青光眼藥物傳輸應用潛力。此外，以天然多醣類材料作為可降解主體分子更可大幅延長眼內藥物釋放期程。
另一方面，過高眼壓與氧化壓力儼然已成為診斷罹患青光眼病徵之重要風險因子。因此，本研究也思及將沒食子酸導入水膠載體材料以製備一具有抗氧化功能之眼前房藥物遞送系統，並探索應用於改善因過高眼壓/氧化壓力而產生之角膜曲率、視網膜生理訊號與組織變異。第3.1章，利用氧化還原法製備一多功能高分子，並探討其作為可緩解氧化壓力之藥物載體可行性。第3.2章則接續評估不同氧化還原反應時間對所製備的藥物載體組成特性與傳輸效能影響。有鑑於抗氧化藥物載體最佳化對視網膜組織修復具顯著影響，第3.3章擬分析不同氧化還原反應溫度合成材料在青光眼疾之眼後節組織療效。此部分結果顯示可經由氧化還原法成功製備一具抗氧化功能之生物降解原位凝膠，並調控反應時間/溫度，以最佳化藥物載體。第4章擬以感溫與降解之高分子共聚物混入兒茶素衍生物合成一具有兼具抗發炎/抗氧化效能之載體應用於乾眼症動物模組，將高分子藥水滴入下眼瞼的結膜囊以形成一非侵入式藥物儲艙，藉此達到延長藥物釋放能力。結果顯示此含藥之藥物載體可延緩眼表發炎反應，並降低角膜上皮與杯狀細胞凋亡，有助於緩解乾眼症所導致的嚴重發炎問題。
基於上述研究發現，藉由調控不同材料之因子(布魯姆指數/碳鏈長度/乙醯化程度)以製備一高分子接枝聚異丙基丙烯醯胺，能夠建立一套長效型藥物載體應用於青光眼治療之新策略。另一方面，藉由抗氧化分子功能化修飾於注射型凝膠，不僅可使載體具降眼壓藥物釋放能力，同時亦可緩解眼內氧化壓力及避免視網膜組織 損害。總結本論文之成果，以生物降解原位凝膠藥物傳輸系統應用於眼部藥物傳輸系統治療確實極具潛力。

Glaucoma is the second worldwide leading cause of blindness. Eye drops are frequently used to administer medication for ocular disease treatment. However, the main challenges with this type of dosage form include short precorneal residence time, poor corneal penetration, and low ocular bioavailability. Hence, to improve ocular bioavailability and pharmacological response, we used intracameral administration of drug containing thermo-sensitive biodegradable copolymer for glaucoma therapy. In chapter 2 and 3, these charpters focused on “Extended Drug Delivery System” and “Antioxidation Functionalization Biodegrable Hydrogel”. In chapter 2.1, three different Bloom numbers of gelatins were used to synthesize thermosensitive hydrogels and recognize effects on pharmacological treatment. In chapter 2.2, four kinds of alkyl chain length of monothiol-terminated alkyl carboxylic acids were used to synthesized various carboxylic end-capped PNIPAAm samples. In addition, the glaucoma is considered to be a chronic disease requiring lifetime medical therapy and it often takes years to monitor disease progression. In chapter 2.3 and 2.4, the polysaccharide-based drug delivery systems with various deacetylation degree were developed for extended drug release prolife and improved delivery performance. The result of the first stage, the higher Bloom number and longer alkyl chain length can enhance antiglaucoma efficacy and therapeutic effectiveness. Furthermore, the chitosan-based thermogels can be higher potentially utilized as ophthalmic biomaterial carriers for extended drug release and improved delivery performance.
On the other hand, hypertension and oxidative stress are known to be involved in glaucomatous development and progression. In chapter 3.1, antioxidant gallic acid functionalized thermosensitive biodegradable hydrogel was developed. In chapter 3.2, we have explored the effect of redox reaction time of hydroxyl radicals and the amount of gallic acid grafted onto carrier. Given that ocular hypertension and oxidative stress disrupts axonal transport of retinal ganglion cells and results in cell death. In chatper 3.3, we further discussed the effect of redox reaction temperature of hydroxyl radicals and examined in vivo pharmacological efficacy of drug containing carriers in glaucomatous rabbits. The result of the second stage, a series of polymers were synthesized via adjusting redox reaction time and temperature. In chapter 4, the therapeutic action of epigallocatechin gallate is linked to its strong bioactivities (antioxidant and anti-inflammation capacity), which may be helpful in treating preservative (i.e., benzalkonium chloride)-induced rabbit dry eye. Given that biodegradable in situ gelling delivery systems may have potential applications in the design of ophthalmic pharmaceutical formulations, this study, for the first time, aims to develop carriers for topical antioxidant molecular administration in the treatment of dry eye disease. Our findings suggest that carrier is responsible for enhanced pharmacological efficacy of topically instilled epigallocatechin gallate, thereby demonstrating the benefits of using biodegradable in situ gelling delivery system to overcome the drawbacks of limited dry eye relief associated with eye drop dosage form.
In the present data, we have demonstrated that the ophthalmic biomaterial carriers for extended drug release can be synthesized by adjusting the factors (Bloom number/alkyl chain length/polymer backbone/ deacetylation degree) to optimize the delivery performance. On the other hand, the redox reaction time/temperature-mediated gallic acid grafting amount is a key parameter in the development of antioxidant drug delivery systems for protection against retinal injury, suggesting the benefits of biomaterials to prevent oucalar disease development. Furthermore, the information about the effect of single epigallocatechin gallate drop administration using biodegradable in situ gelling carrier on dry eye relief presents an opportunity for further development of pharmacological interventions. Overall, this obtained data will be of high clinical significance and contribute to the knowledge of materials for management of ocular diseases.

指導教授推薦書
論文口試委員審定書
致謝……………………………………………………………………...iii
中文摘要………………………………………………………………...iv
Abstract…………………………………………….…………………….vi
目錄……………………………………………….……………………..ix
圖目錄…………………………………………………………………xvii
Chapter 1: Motivation and Objectives 1
Chapter 2: Extended Release 4
2.1. On the importance of Bloom number of gelatin to the development of biodegradable in situ gelling copolymers for intracameral drug delivery 4
2.1.1. Introduction 5
2.1.2. Experimental 9
2.1.2.1. Materials 9
2.1.2.2. Imino acid content and triple-helix molecular conformation 10
2.1.2.3. Synthesis of GN 10
2.1.2.4. Phase transition temperature 11
2.1.2.5. Degradability 12
2.1.2.6. Drug encapsulation efficiency 12
2.1.2.7. In vitro drug release profile 13
2.1.2.8. Pharmacological response to pilocarpine 13
2.1.2.9. In vitro biocompatibility 15
2.1.2.10. In vivo biocompatibility 16
2.1.2.11. Antiglaucoma efficacy 18
2.1.3. Result and Discussion…………………………………………….20
2.1.3.1. Imino acid content and triple-helix molecular conformation 20
2.1.3.2. Phase transition temperature 23
2.1.3.3. Degradability 24
2.1.3.4. Drug encapsulation efficiency 25
2.1.3.5. In vitro drug release profile 27
2.1.3.6. In vitro biocompatibility 28
2.1.3.7. Pharmacological response to pilocarpine 29
2.1.3.8. In vivo biocompatibility 30
2.1.3.9. Antiglaucoma efficacy 33
2.1.4. Conclusion 36
2.2. The role of alkyl chain length of monothiol-terminated alkyl carboxylic acid in the synthesis, characterization, and application of gelatin-g-poly (N-isopropylacrylamide) carriers for antiglaucoma drug delivery 38
2.2.1. Introduction 39
2.2.2. Experimental 42
2.2.2.1. Materials 42
2.2.2.2. Synthesis of carboxylic end-capped PNIPAAm and GN 42
2.2.2.3. Phase transition characterizations 44
2.2.2.4. In vitro degradation tests 45
2.2.2.5. In vitro drug release studies 45
2.2.2.6. Biocompatibility studies 46
2.2.2.7. Animal studies 47
2.2.3. Result and Discussion 48
2.2.3.1. Synthesis of carboxylic end-capped PNIPAAm and GN 48
2.2.3.2. Phase transition characterizations 50
2.2.3.3. In vitro degradation tests 52
2.2.3.4 In vitro drug release studies 53
2.2.3.5. Biocompatibility studies 55
2.2.3.6. Animal studies 56
2.2.4. Conclusion 62
2.3. Chitosan-g-poly(N-isopropylacrylamide) copolymers as delivery carriers for intracameral pilocarpine administration 63
2.3.1. Introduction 64
2.3.2. Experimental 66
2.3.2.1. Materials 66
2.3.2.2. Synthesis and characterization of Chi-PN 66
2.3.2.3. Degradability 67
2.3.2.4. Drug release profile 67
2.3.2.5. Cytocompatibility 67
2.3.2.6. Antiglaucoma efficacy 68
2.3.3. Result and Discussion 69
2.3.3.1. Synthesis and characterization of Chi-PN 69
2.3.3.2 Phase transition temperature 71
2.3.3.3. Degradability 73
2.3.3.4. Drug release profile 74
2.3.3.5. Cytocompatibility 77
2.3.3.6. Antiglaucoma efficacy 78
2.3.4. Conclusion 80
2.4. Effect of deacetylation degree on controlled pilocarpine release from injectable chitosan-g-poly(N-isopropylacrylamide) carriers 81
2.4.1. Introduction 82
2.4.2. Experimental 83
2.4.2.1. Preparation and characterization of CN biodegradable thermogels using chitosan samples with varying DDs 83
2.4.2.2. Drug release profile 84
2.4.2.3. Biocompatibility of CN biodegradable thermogels 84
2.4.2.4. Pharmacological efficacy of drug-loaded CN biodegradable thermogels 84
2.4.3. Result and Discussion 85
2.4.3.1. Characterization of CN biodegradable thermogels using chitosan samples with varying DDs 85
2.4.3.2. Biocompatibility of CN biodegradable thermogels 90
2.4.3.3. In vivo pharmacological efficacy of drug-loaded CN biodegradable thermogels 92
2.4.4. Conclusion 94
Chapter 3：Functional Boost………………………………………..95
3.1. Antioxidant gallic acid-functionalized biodegradable in situ gelling copolymers for cytoprotective antiglaucoma drug delivery systems 95
3.1.1. Introduction 96
3.1.2. Experimental 100
3.1.2.1. Materials 100
3.1.2.2. Synthesis of GA-Functionalized GN (GNGA). 100
3.1.2.4. Characterization of GA-Functionalized GN (GNGA) 100
3.1.2.5. Determination of Scavenging Activity against DPPH Radical 101
3.1.2.6. Phase-Transition, Degradation, and drug release studies 101
3.1.2.7. Measurement of Antioxidant Activity against H2O2 102
3.1.2.7.1. Cell Culture and Treatment 102
3.1.2.7.2. Measurement of Cell Viability 102
3.1.2.7.3. Measurement of Intracellular ROS 103
3.1.2.7.4. Measurement of Intracellular Calcium 103
3.1.2.8. Animal Studies 104
3.1.3. Result and Discussion 105
3.1.3.1. Characterization of GA-Functionalized GN (GNGA) 105
3.1.3.2. Determination of Scavenging Activity against DPPH Radical 106
3.1.3.3. Phase-Transition Characterizations 107
3.1.3.4. In Vitro Degradation Tests 108
3.1.3.5. In Vitro Drug Release Studies 109
3.1.3.6. Measurement of Antioxidant Activity against H2O2 110
3.1.3.7. Measurement of Cell Viability 111
3.1.3.8. Measurement of Intracellular ROS 112
3.1.3.9. Measurement of Intracellular Calcium 113
3.1.3.10. Animal Studies 115
3.1.4. Conclusion 118
3.2. Gallic acid grafting effect on delivery performance and antiglaucoma efficacy of antioxidant-functionalized intracameral pilocarpine carriers 119
3.2.1. Introduction 120
3.2.2. Experimental 123
3.2.2.1. Synthesis of GA-functionalized GN (GNGA) 123
3.2.2.2. Determination of total antioxidant activity and scavenging ability against DPPH radical 123
3.2.2.3. Determination of water content, phase transition temperature, and degradability 124
3.2.2.4. In vitro biocompatibility studies 124
3.2.2.5. Measurement of antioxidant activity against H2O2 124
3.2.2.6. Animal studies 125
3.2.3. Result and Discussion 126
3.2.3.1.Total antioxidant activity and scavenging ability 126
3.2.3.2. Determination of water content, phase transition temperature, and degradability 128
3.2.3.3. In vitro drug release studies 128
3.2.3.4. In vitro biocompatibility studies 132
3.2.3.5. Measurement of antioxidant activity against H2O2 134
3.2.3.6. Animal studies 136
3.2.3.6.1. IOP and pupil diameter 136
3.2.3.6.2. Total antioxidant level and nitrite level 137
3.2.4. Conclusion 140
3.3. In vivo pharmacological evaluations of pilocarpine-loaded antioxidant-functionalized biodegradable thermogels in glaucomatous rabbits 142
3.3.1. Introduction 143
3.3.2. Experimental 146
3.3.2.1. Synthesis of GA-functionalized GN 146
3.3.2.2. Characterization studies 146
3.3.2.3. In vitro antioxidant activity studies 146
3.3.2.4. Animals 146
3.3.2.4.1. In vivo biocompatibility studies 146
3.3.2.4.2. In vivo drug release studies 147
3.3.2.4.3. Glaucoma therapy studies 147
3.3.3. Result and Discussion 150
3.3.3.1. Characterization studies 150
3.3.3.2 In vitro antioxidant activity studies 151
3.3.3.3 In vivo biocompatibility studies 152
3.3.3.4 In vivo drug release studies 154
3.3.3.5 Corneal topography measurements 155
3.3.3.6. Electroretinogram measurements 156
3.3.3.7. Retinal histological examinations 157
3.3.3.8. Biochemical assays 158
3.3.4. Conclusion 161
Chapter 4: Other Application: Dry Eye Disease…...……….………162
4.1 Epigallocatechin Gallate-Loaded GN as a New Ophthalmic Pharmaceutical Formulation for Topical Use in the Treatment of Dry Eye Syndrome……………………………………………………………….162
4.1.1. Introduction 163
4.1.2. Experimental 165
4.1.2.1. Materials 165
4.1.2.2. Characterization of EGCG-loaded GN 165
4.1.2.3. Anti-inflammatory and antioxidant activity studies 165
4.1.2.4. Animal studies 166
4.1.3. Result and Discussion 169
4.1.3.1. Characterization of EGCG loading Gelatin-g-PNIPAAm 169
4.1.3.2. Anti-inflammatory and antioxidant activity studies 171
4.1.3.3. Clinical observations 173
4.1.3.4. Histological examinations 175
4.1.4. Conclusion 178
Reference 179
Bibliography…………………………………………………..……….203













List of Figures
Figure 2.1.1. Schematic representation of development of GN copolymers by using three different Bloom numbers of gelatins………………………4
Figure 2.1.2. (a) Imino acid content of gelatin samples. (b) Deconvolution of amide I band of various samples……..………………………………..21
Figure 2.1.3. (a) Differential scanning calorimetry thermogram (b) lower critical solution temperature (c) Time-course study of the weight remaining (d) Time-course study of the concentration of pilocarpine released……26
Figure 2.1.4. (a) Phase-contrast micrographs (b) Intracellular calcium level………………………………………………………………...……30
Figure 2.1.5. (a) Representative specular microscopic images (b) Specular microscopy measurements………………………………………………32
Figure 2.1.6. (a) intraocular pressure (b) pupil diameter…………………35
Figure 2.2.1. Schematic representation of development of GN copolymers by using four different alkyl chain length of chain transfer agent of carboxyl-terminated PNIPAAm…………………………………………38
Figure 2.2.2. (a) GPC chromatograms (b) FTIR spectra…………………49
Figure 2.2.3. (a) Water contact angle images (b) Graph of contact angle in degrees (c) DSC thermograms (d) GFT thermograms…………….…….51
Figure 2.2.4. (a) Time-course of weight loss (b) Determinations of hydroxyproline released (c) Time-course of the concentration of pilocarpine released (d) Cumulative released……………………..……..54
Figure 2.2.5. (a) Cell proliferation assay (b) live/dead assay (c) IL-6 (d) ATP1A1…………………………………………………………………56
Figure 2.2.6. (a) Time-course of the concentration of pilocarpine released (b) IOP measurement (c) Representative specular microscopic images (d) histological images of retina. ……………………………………………61
Figure 2.3.1. Schematic representation of development of chitosan-g-PNIPAAm (Chi-PN) biodegradable in situ gelling delivery system……..63
Figure 2.3.2. (a) FTIR spectra (b) EDS spectrogram (c) Efficiency of grafting and grafting ratio. (d) Gross morphological observation………..72
Figure 2.3.3. (a) Time-course of weight loss (b) Mechanical spectra (c) FTIR spectra (d) Time-course of the concentration of pilocarpine released……………………………………………………………….....76
Figure 2.3.4. (a) Cell viability (b) Corneal histology (c) Level of IL-6 protein..………………………………………………………………….77
Figure 2.3.5. (a) IOP and (b) specular microscopic images…………….79
Figure 2.4.1. Schematic representation of effect of deacetylation degree on controlled pilocarpine release from injectable chitosan-g-poly(N-isopropylacrylamide) carriers……………………………………………81
Figure 2.4.2. (a) 1H NMR spectra (b) FTIR spectra (c) grafting ratio……88
Figure 2.4.3. (a) weight loss (b) D-glucosamine concentration in degradation media (c) Drug encapsulation efficiency (d) Cumulative release..…………………………………………………………….……89
Figure 2.4.4. (a) Fluorescence photomicrographs (b) comet tail lengths (c) caspase-3 activities (c) Results are expressed as percentage of Controls..91
Figure 2.4.5. (a) Corneal topographic maps (b) curvature values (c) histological fluorescence images (d) anterior chamber angle values1..…93
Figure 3.1.1. Schematic representation of development of GA-modified GN as a novel multifunctional polymer carrier………………………….95
Figure 3.1.2. (a) UV–vis spectra (b) FTIR spectra (c) Photographs of the reaction of DPPH reagent (d) DSC thermograms……………………....108
Figure 3.1.3. Effect of polymer carrier materials on H2O2-induced cell viability. (a) Representative phase-contrast micrographs (b) fluorescent images (DCFH-DA) (c) fluorescent images (Fura-2AM)……….…….114
Figure 3.1.4. (a) Representative slit-lamp biomicroscopic images (b) specular microscopic images of corneal endothelium (c) Levels of total antioxidant (d) nitrite in the aqueous humor……………………………117
Figure 3.2.1. Schematic representation of functionalization of GN with GA molecules…………………………………………………………..…..119
Figure 3.2.2. (a/b) Total antioxidant activities (c/d) DPPH scavenging activities………………………………………………………………..126
Figure 3.2.3. 1H NMR spectra………………………………………….127
Figure 3.2.4. (a) DSC thermograms (b) Cumulative release (c) Live/Dead (d) Gene expression of IL-6.……………………………………………133
Figure 3.2.5. Effect of polymer carrier materials on H2O2-induced (a/b) cell viability and (c/d) intracellular ROS.………………………………..….136
Figure 3.2.6. Measurements of (a) IOP and (b) specular microscopic images (c) the levels of total antioxidant and (d) nitrite level…………..139
Figure 3.3.1. Schematic representation of functionalization of GN with GA molecules..………………………….……………………….………....142
Figure 3.3.2. (a,b) ROS and (c,d) calcium……………………….…….152
Figure 3.3.3. (a) specular microscopic images (b) corneal histology….153
Figure 3.3.4. (a) IOP (b) Representative corneal topographic maps (c) ERG recordings (d) histological images of retina..…………………….……158
Figure 3.3.5. (a) SOD activity (b) CAT activity (c) GPx activity (d) GSH level...………………………….……………………….………………160
Figure 4.1.1. Scheme of experimental design of the study. A BAC-induced rabbit dry eye model was used to examine therapeutic efficacy of short-term topical EGCG-loaded GN for the treatment of dry eye syndrome…162
Figure 4.1.2. (a) 1H NMR spectra (b) DSC thermograms (c) Time-course of weight loss (d) The concentration of EGCG and cumulative release..170
Figure 4.1.3. Level of (a) IL-6 and (b) MCP-1 (c) Fluorescent images (d) Intracellular levels of ROS……………………………………………..172
Figure 4.1.4. Corneal fluorescein staining (a) images and (b) scores and rose bengal staining (c) images and (d) scores…………………….……174
Figure 4.1.5. (a) Histological images, (b) thickness values (c) conjunctival impression cytological images (d) immunofluorescence images………………………………………………………………….177

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