利用溫感型水膠材料以關節內注射的方式輸送抗發炎藥物槲皮素達到治療骨關節炎的目的

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研究生：	丁立慈 Ting, Li-Tzu
論文名稱：	利用溫感型水膠材料以關節內注射的方式輸送抗發炎藥物槲皮素達到治療骨關節炎的目的 The Use of Thermo-Sensitive Hydrogel Methoxy-Poly (ethylene glycol)-Poly (ʟ-alanine)-ʟ-Lysine for Intra-Articular Delivery of Quercetin to Treat Osteoarthritis
指導教授：	朱一民 Chu, I-Ming
口試委員:	姚少凌 Yao, Chao-Ling 劉繼賢 Liu, Chi-Hsien
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：	2018
畢業學年度：	106
語文別：	英文
論文頁數：	70
中文關鍵詞：	胺基酸水膠、藥物控制釋放系統、關節內注射、骨關節炎、槲皮素、溫度敏感、正電荷
外文關鍵詞：	Peptide-based hydrogel, Drug delivery system, Intra-articular injection, Osteoarthritis, Quercetin, Thermo-sensitive, Positively charged
相關次數：	點閱：4 下載：0
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骨關節炎是一種慢性退化的關節疾病，其所伴隨的疼痛感是患者行動不便的主要原因，然而目前的藥物治療方法，例如口服抗發炎藥或注射糖皮質激素、中樞鎮痛劑等，皆需要頻繁的投遞藥物，才能暫緩關節炎症狀，但也伴隨著顯著的副作用如腸胃不適、心血管疾病或使病患產生成癮性。而槲皮素為一種天然的生物性類黃酮，具有良好的抗氧化性、抗發炎作用與極高的生物相容性，因而在近期被廣泛的研究用來作為治療骨關節炎的藥物。在本研究中，我們設計了一種高生物相容性的溫度敏感型正電荷胺基酸水膠材料Methoxy-Poly (ethylene glycol)-Poly (ʟ-alanine)-ʟ-Lysine (簡稱mPAL)來包覆槲皮素，期望透過關節腔注射液態mPAL水膠材料，透過其溫度敏感性而在原位成膠。隨著水膠穩定降解，達到緩釋槲皮素的治療作用，不僅延長藥物滯留時間，也能減少投藥的頻率。研究透過核磁共振氫譜來鑑定所合成的共聚高分子結構，並且利用動態光散射儀、穿透式電子顯微鏡、掃描式電子顯微鏡、全反射傅立葉轉換紅外線光譜儀、流變儀等設備來觀測此水膠的成膠機制與膠體性質，再透過調整水膠藥物載體配方來達到較好的藥物包覆效果，同時也進行水膠載體的藥物釋放與生物毒性測試。初步的研究結果證實我們所合成的mPAL水膠材料搭配槲皮素的藥物載體配方是具有相當大的潛力來作為注射型的緩釋藥物劑型。

Osteoarthritis is a chronic degenerative joint disease and one of the leading causes of disability. However, the recommended treatments, such as oral administrations of analgesics or intra-articular injections of corticosteroids can only provide temporary pain alleviation and are accompanied with undesirable side effects, such as gastrointestinal discomfort or cardiovascular diseases. Quercetin is a natural flavonoid with anti-inflammatory and anti-oxidative functions. Furthermore, owing to its minimal side effects, there are a growing number of studies performed on quercetin as treatments for osteoarthritis. In this study, a positively charged thermo-sensitive hydrogel, Methoxy-Poly (ethylene glycol)-Poly (ʟ-alanine)-ʟ-Lysine, abbreviated as mPAL, is synthesized sequentially by ring opening polymerization of a series of alanine-NCA and lysine-NCA initiated by amine-terminated mPEG. With the encapsulation of quercetin, we design a drug delivery system for intra-articular injection and expect this highly biocompatible and biodegradable peptide-based hydrogel could perform in situ gelation and stable drug release to enhance the efficiency of drug delivery. To examine the properties of mPAL copolymer, it was thoroughly analyzed by 1H NMR, FTIR, DLS, TEM, SEM, and rheometer. Additionally, examinations were also conducted on quercetin loaded mPAL hydrogel, which include the release profile of quercetin and the in vitro cytotoxicity test. Ultimately, the preliminary results indicate that mPAL copolymer could be a potential drug carrier for intra-articular injection in osteoarthritis treatment.

中文摘要                                                            II
Abstract                                                          III
謝誌                                                            IV
Abbreviation                                                      V
Contents                                                        VII
List of Schemes                                                    XI
List of Tables                                                   XII
List of Figures                                                  XIII

Chapter 1: Introduction                                             1
1    Hydrogels                                             1
1.1    Introduction                                             1
1.2    Stimuli-responsive hydrogels                             4
1.3    Thermo-responsive hydrogels                             6
1.4    Peptide-based hydrogels                              10
1.5    Positively charged hydrogels                            12
2    Biodegradable polymers                              14
2.1    Introduction                                            14
2.2    Types of degradation                                14
2.3    Factors that affect the rate of degradation             15
3    Drug controlled release systems                     15
4    Osteoarthritis                                        18
4.1    Introduction                                         18
4.2    Current treatments of osteoarthritis                    19
5    Quercetin                                            20
Chapter 2: Aims and Objectives                                    23
Chapter 3: Materials and Methods                            25
1    Experiment flow chart                                25
2    Materials                                            26
2.1    Amine modification of hydroxyl-terminated mPEG            28
2.2    Preparation of N-carboxyanhydride form of amino acids    29
2.3    Synthesis of mPEG-alanine                               30
2.4    Synthesis of mPEG-alanine-lysine                     31
3    Equipments                                           33
3.1    1H nuclear magnetic resonance (1H NMR) spectroscopy    34
3.2    Dynamic laser scattering (DLS) and zeta potential    34
3.3    Fourier transfer infrared spectrum (FTIR)           34
3.4    Rheological measurement                                    35
3.5    Transmission electron microscopy (TEM)               35
3.6    Scanning electron microscopy (SEM)                    35
3.7    Ultraviolet-visible (UV-Vis) spectroscopy           36
4    In vitro technology                                   36
4.1    Critical micelle concentration (CMC)                 36
4.2    Sol-Gel transition                                    37
4.3    Degradation measurement                             37
4.4    Measurement of quercetin release                    38
4.5    DPPH assay                                          40
4.6    Culturing and harvesting of cell                    41
4.7    Cell viability                                       41
4.8     Live/Dead staining                                    42
Chapter 4: Results and Discussion                           43
1    Characterization of mPAL triblock copolymer          43
2    Properties of mPAL copolymer                         45
2.1    Critical micelle concentration (CMC)                 45
2.2    Particle size and zeta potential of mPAL solution    46
3    Properties of mPAL hydrogel                         48
3.1    Sol-Gel transition of mPAL hydrogel                   48
3.2    The rheological behavior of mPAL hydrogel           50
3.3    Microstructure of mPAL hydrogel                     51
3.4    In vitro degradation of mPAL hydrogel               52
4    Quercetin loaded mPAL hydrogel                        53
4.1    Formulations of quercetin loaded hydrogel             53
4.2    In vitro quercetin release profile                    55
4.3    Antioxidant activity                                  56
5    In vitro cytotoxicity test                          57
5.1    MTT Assay                                           57
5.2    Live/Dead staining                                     58
Chapter 5: Summary and Conclusions                           60
Chapter 6: References                                         62


                                

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