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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林文貞(Wen-Jen Lin) | |
dc.contributor.author | Tze-Dan Chen | en |
dc.contributor.author | 陳姿丹 | zh_TW |
dc.date.accessioned | 2021-06-12T17:58:44Z | - |
dc.date.available | 2010-02-20 | |
dc.date.copyright | 2008-02-20 | |
dc.date.issued | 2008 | |
dc.date.submitted | 2008-01-29 | |
dc.identifier.citation | Ahn, J.S., Choi, H. K., Cho, C. S., A novel mucoadhesive polymer prepared by template polymerization of acrylic acid in the presence of chitosan, Biomaterials, 22(9), 923-928, 2001.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/27236 | - |
dc.description.abstract | 近年來天然材料在生醫方面的研究不勝枚舉,而幾丁聚醣(Chitosan)因其廣泛的存在於自然界,且在工業、食品和製藥上也有所研究與開發,其應用價值及商機備受矚目。幾丁聚醣具有生物可相容性、生物可分解性以及低毒性的優點,其在藥物遞送系統上的研究已有所聞,而在標靶式(target) 基因遞送系統(gene delivery system)上也逐漸顯示其重要性。
本實驗中以幾丁聚醣為遞送載體的骨架來進行化學性修飾,目的是將一親水性基團甲氧基聚乙二醇(methoxy poly (ethylene glycol),MPEG)以醚鏈鍵結(ether linkage)的方式接枝在幾丁聚醣的第六位碳上,並將一具有肝標靶作用的醣基以共 價鍵結(covalent bond)的方式接枝於幾丁聚醣第二位碳上,而本實驗中所用的醣基為乳醣基(Lactobionic acid),其含有可與去唾液酸胎醣蛋白(asialoglycoprotein;ASGP-R)進行辨識的半乳糖(galactose)分子。經由化學修飾後的幾丁聚醣變成具有親水基團的標靶式遞送載體後,接著以具有負電荷的三聚磷酸鈉(TPP)和幾丁聚醣以離子凝膠法形成奈米粒,並對此奈米粒進行物性探討。另一方面,針對去唾液酸胎醣蛋白已解出的H1 次單元結構進一步進行醣基分子與此醣蛋白間辨識作用的位向及構形上的分析,本實驗使用電腦模擬自動嵌合軟體(AutoDock 3.05)針對小分子半乳醣及乳糖基對去唾液酸胎醣蛋白進行結合關係的預測。 所用來進行一系列化學修飾之幾丁聚醣是先經過去乙醯化反應得到去乙醯化幾丁聚醣,再接著以去聚合作用方式控制去乙醯化幾丁聚醣的數目平均分子量在5000~10000之間,以膠體滲透層析系統做分子量評估。接枝甲氧基聚乙二醇前先以鄰苯二甲酸酐進行幾丁聚醣二位碳之胺基基團保護,並用元素分析儀的測定計算鄰苯二甲酸酐取代度,接著以此進行甲氧基聚乙二醇六位碳之氫氧基接枝。經聯胺去保護基後以核磁共振儀、紅外線光譜儀、紫外光光譜儀和示差掃描熱分析儀確認分子結構、定量計算甲氧基聚乙二醇的接枝比例與分子熔點和溶化熱。對此接枝型幾丁聚醣聚合物繼續做乳糖基的修飾,將其接枝在幾丁聚醣之二位碳上,以核磁共振儀確認結構並以積分方式推估乳糖基的接枝比例。將同時具有甲氧基聚乙二醇和乳糖基接枝的聚合物以離子凝膠法(ionotropic gelation method)包覆帶有負電荷之三聚磷酸鈉形成奈米粒並測其粒徑和表面電位。 由MPEG對幾丁聚醣六位碳上接枝的結果發現,MPEG對未經去聚合作用之幾丁聚醣的接枝比例較高介於14.18%~16.28%,但對經去聚合作用之幾丁聚醣的接枝比例則只有2.86%~4.59%,接枝後的幾丁聚醣仍只能溶於1%醋酸水溶液中。乳糖基對於去乙醯度達94.6%且經去聚合作用之幾丁聚醣第二位碳上的接枝比例隨乳糖基的反應莫耳比增加而提高,但對已接有MPEG之幾丁聚醣接枝的比例達28%時即不再增加,經由乳糖基接枝後的高分子化合物皆可水溶。同時接有MPEG 和乳糖基的幾丁聚醣相較只有乳糖基接枝的幾丁聚醣與帶有負電荷TPP所形成的奈米粒為小且接近電中性。以電腦模擬小分子半乳醣及乳糖基和去唾液酸胎醣蛋白的醣基辨識功能部位(carbohydrate recognition domain; CRD)進行結合關係的預測,由於乳糖基在結構上較半乳糖多了葡萄醣酸分子所以在對整個醣基辨識功能部位做嵌合的結果其最低嵌合能量之區域較易落在Ca2+ site 2寬廣的結合袋區域,而半乳糖出現的區域則較隨機。針對Ca2+ site 2的區域做嵌合時,最低能量之乳糖基構形是以葡萄醣酸和Ca2+ 2以及鄰近的胺基酸作用,而最低能量之半乳糖構形則是以第六位碳上氫氧基和Ca2+ 2以及鄰近的胺基酸作用。 | zh_TW |
dc.description.abstract | Studies in Biomedical materials have been widely explored in recent years, especially chitosan. Because of the advantages in biocompatibility、biodegradability and low toxicity, the application of chitosan in drug delivery system were well known and the importance in target delivery has gradually been mentioned.
In our studies, we used chitosan as the backbone to go through a series of chemical modification. The grafted copolymer composing hydrophilic groups of methoxy poly(ethylene glycol) (MPEG) was synthesized via SN2 reaction at C6-OH of chitosan. The target sugar molecule of lactobionic acid, which can recognize asialoglycoprotein receptor(ASGP-R), was also introduced into the chitosan structure. An ionic gelation method was used to prepare nanoparticles containing tripolyphosphate as a negative charge agent. Computer simulation using AutoDock 3.05 was an approach to predict the interaction between ASGP-R and sugar molecules such as galactose and lactobionic acid. The starting material of chitosan was deacetylated and depolymerized first, then protected with phthalic anhydride before grafting MPEG. The substitution of phthalic anhydride was calculated based on the result of elemental analysis. After deprotection the DADP-CS-g-O6-MPEG was obtained and identified by IR, 1H-NMR, GPC and DSC. The lactobionic acid was further introduce via amide linkage at C2-NH2 of chitosan, and the characteristics were identified by 1H-NMR and GPC. The content of lactobionic acid is calculated from the result of 1H-NMR. Nanoparticles were prepared using tripolyphosphate via an ionic gelation method, and detected the size and zeta potentaial. From the result of MPEG grafted chitosan, the MPEG degree of substitution was higher in DA-CS-g-O6-MPEG (14.18%~16.28%) than in DADP-CS-g-O6-MPEG (2.86%~6.49%). The lactobionic acid was grafted onto the C-2 position of chitosan. The grafting ratio in DADP-CS was increased with LA molar ratio, however, there was no more than 28% grafting ration in DADP-CS-g-O6-MPEG even increase in LA molar ratio. The water solubility was good in LA grafting polymer compare to the non-LA grafting polymer. The nanoparticle was formed by DADP-CS-g-(O6-MPEG)-(N-LA) and TPP, and the size was in the range of 93.8±36.3 ~149.4±95.9 nm with the near neutral zeta potential (-0.2±0.4~13.5±1.2 mV). In predicting the stable binding site in CRD region of ASGP-R, the result of AutoDock simulation shows that the lactobionic acid was apt to bind in the Ca2+ site 2 region comparing to the galactose. The gluconic acid structure of lactobionic acid was prio to interaction with the Ca2+ 2 while the C1-OH of galactose was prio to situate in Ca2+ 3 of CRD region, and the neighbouring amino residues in Ca2+ 2 and Ca2+ 3 were involved in the sugar-protein binding mode. | en |
dc.description.provenance | Made available in DSpace on 2021-06-12T17:58:44Z (GMT). No. of bitstreams: 1 ntu-97-R94423024-1.pdf: 10643497 bytes, checksum: ce962ccbe0b218b7be89a5548f4dd2f5 (MD5) Previous issue date: 2008 | en |
dc.description.tableofcontents | 目錄
中文摘要…………………………………………………………………..iii 英文摘要…………………………………………………………………...v 目錄……………………………………………………………………….vii 圖目錄…………………………………………………………………….xii 表目錄…………………………………………………………………. xviii 第一章 緒論 1 一、幾丁聚醣 1 (一)幾丁聚醣的基本結構和製備方式………………………………………….2 (二)溶解度……………………………………………………………………….3 (三)分子量……………………………………………………………………….4 (四)去乙醯化程度的測定……………………………………………………….4 (五)幾丁聚醣的化學修飾……………………………………………………….5 二、去唾液酸胎醣蛋白接受器 5 三、奈米粒的製備……………………………………………………………………8 四、電腦嵌合 9 (一)分子作用機制……………………………………………………………….9 (二)電腦嵌合………………………………………………………………….....9 (三)演算法…………….……………………………………………………….10 (四)評分函數…………………..………………………………………………13 (五)經驗式結合自由能函數…………………………………………………..14 第二章 試劑與材料介紹 16 一、幾丁聚醣 16 二、甲氧基聚乙二醇 17 三、鄰苯二甲酸酐 18 四、氧化銀 19 五、乳糖酸 20 六、三聚磷酸鈉 21 第三章 實驗動機與目的 22 第四章 實驗試劑與儀器 23 一、試劑 23 二、儀器 24 三、藥品溶液及緩衝溶液之配製 26 四、電腦模擬部分所用之軟硬體及網站 27 第五章 實驗方法 29 一、接枝型聚合物CS-g-O6-MPEG的合成 30 (一)DA-CS的製備……………………………………………………………..30 (二)DADP-CS的製備.........................................................................................31 (三)PhACS的合成……………………………………………………………..32 (四)MPEG-I的合成……………………………………………………………35 (五)PhACS-g-O6-MPEG的合成……………………………………………….38 (六)CS-g-O6-MPEG…………………………………………………………….41 二、經乳糖基(lactobionic acid)修飾之幾丁聚醣(DADP-g-LA) 44 (一)乙醯化乳糖基……………………………………………………………...44 (二) DADP-PhACS-g-O6-LA之合成………………………………………….46 (三)DADP-CS-g-(N-LA)之合成.........................................................................49 (四) DADP-CS-g-(O6-MPEG)-g-(N-LA)之合成................................................51 三、接枝形幾丁聚醣之奈米粒製備……………………………………………….52 (一)DADP-CS奈米粒………………………………………………………….52 (二)DADP-CS-g-(N-LA)和DADP-CS-g-(O6-MPEG)-g-(N-LA)奈米粒……..53 四、結構及物性測定 54 (一)紅外線分光光譜儀………………………………………………………...54 (二)核磁共振光譜...............................................................................................54 (三)分子量評估-膠體滲透層析……………………………………………….54 (四)溶解度測試………………………………………………………………...56 (五)元素分析(EA)...............................................................................................57 (六)示差掃描熱分析儀.......................................................................................58 (七)奈米粒子的物性測試…………………………………………………….. 58 五、定量分析 58 (一)滴定法測定幾丁聚醣的去乙醯度………………………………………...58 (二)甲氧基聚乙二醇的取代度………………………………………………...63 六、電腦嵌合計算方法 65 (一)小分子結構之建立及處理………………………………………………...66 (二)大分子處理………………………………………………………………...67 (三)建立格網參數檔…………………………………………………………...67 (a)以MBP-A和Man6GlcNAc2Asn asparaginyl-oligosaccharide的共結晶結 構來檢驗嵌合參數的可信度…………………………………………...72 (b)二聚體結構之嵌合……………………………………………………..78 (c)對整個ASGP-R做電腦嵌合…………………………………………..78 (d)對ASGP-R的Ca2+-2結合位置(Ca2+ binding site 2)做電腦嵌合…….79 (四)建立嵌合參數檔…………………………………………………………...79 (五)嵌合計算開始……………………………………………………………...80 第六章 結果與討論 81 一、接枝型甲氧基聚乙二醇-幾丁聚醣高分子的合成(CS-g-O6-MPEG) 81 (一)DA-CS的製備……………………………………………………………..81 (二)DADP-CS的製備.........................................................................................84 (三)PhACS的合成……………………………………………………………..90 (四)MPEG-I的合成…………………………………………………………..108 (五)PhACS-g-O6-MPEG的合成……………………………………………...110 (六)CS-g-O6-MPEG...........................................................................................119 (七)PEG定量…………………………………………………………………133 (八)以示差掃描熱分析儀(DSC)分析CS-g-O6-MPEG……………………...137 二、經乳糖基修飾之幾丁聚醣 143 (一)LA-OAc的合成…………………………………………………………..143 (二)DADP-PhACS-g-O6-LA………………………………………………….146 (三)DADP-CS-g-N-LA之合成.........................................................................157 (四)DADP-CS-g-(O6-MPEG)-g-(N-LA)的合成...............................................164 三、接枝型幾丁聚醣之奈米粒製備 167 (一)DADP-CS奈米粒………………………………………………………...167 (二)DADP-CS-g-(N-LA)奈米粒……………………………………………...171 (三)DADP-CS-g-(O6-MPEG)-g-(N-LA)奈米粒……………………………...173 四、電腦嵌合計算結果與討論 176 (一)以MBP-A(Mannose Binding Protein-A)來檢驗嵌合參數的信任度…...176 (a)相鄰二聚體結構的嵌合……………………………………………... .177 (b)二聚體結構之嵌合…………………………………………………….187 (二)ASGP-R嵌合部分………………………………………………………..190 (a)半乳糖(Galactose)對ASGP-R CRD區域嵌合之結果分析………….190 (b) 乳醣基(Lactobionic acid)對ASGP-R CRD區域嵌合之結果分析…199 (三)ASGP-R Ca2+- site 2之嵌合……………………………………………...209 (a)半乳糖對ASGP-R Ca2+ site 2之嵌合結果分析………………………209 (b)乳糖基對ASGP-R Ca2+ site 2嵌合之結果分析………………………218 第七章 結論 228 第八章 參考文獻 230 | |
dc.language.iso | zh-TW | |
dc.title | 複合式接枝型幾丁聚醣之合成與研究 | zh_TW |
dc.title | Synthesis and Studies of Multi-Grafted Chitosan | en |
dc.type | Thesis | |
dc.date.schoolyear | 96-1 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 林榮信(Jung-Hsin Lin),忻凌偉(Ling-Wei Hsin),王麗芳(Li-Fang Wang) | |
dc.subject.keyword | 幾丁聚醣,合成, | zh_TW |
dc.subject.keyword | Chitosan,synthesis, | en |
dc.relation.page | 238 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2008-01-29 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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