凝集素與醣體間的交互作用力廣泛存在於多種重要生理反應以及生物機制中。但因為單一的凝集素與醣體之間的交互作用往往非常微弱，為凝集素的研究帶來困難。而解決作用力的不足除了藉由多價性效應之外，開發具有更高親和力的醣體也是解決方法之一。
在本研究的第一部分中，我們針對綠膿桿菌生物膜開發出抑制劑。在抗生素廣泛使用的現代，綠膿桿菌對於多數的抗生素產生抗藥性，而生物膜的形成更加局限治療方法。綠膿桿菌感染以及形成生物膜主要藉由其凝集素LecA針對細胞表面半乳糖殘基結合。近年發現帶有芳香環的半乳糖可以提高LecA的結合能力。我們開發出多種不同的芳香性半乳醣苷來做為配基以探討作用力強弱與結構之關係。同時我們開發出脯胺酸多肽作為多價性骨架，藉由其PPII構形來維持有效距離來針對LecA之相鄰之結合位置結合，並以此骨架合成多價醣肽材料做為抑制劑，此多價性材料設計在微陣列掃描中有不錯的效果。
此外，由於肝細胞表面存在大量特有的凝集素去唾液酸糖蛋白受體(ASGPR)，藉由此受體與半乳糖殘基結合所產生的胞吞作用可以將藥物載體送入細胞內以達到基因藥物作用之目的。所以我們嘗試將開發出的芳香性半乳醣苷修飾於奈米粒子表面上並乘載螢光siRNA，藉由Hep3B肝癌細胞攝取實驗，我們在共聚焦顯微鏡下發現芳香性半乳醣苷比一般未修飾之奈米載體高出十倍，此結果有助於未來發展相關結構之配基來修飾於肝疾病藥物載體。

Carbohydrate-lectin interaction involved in many biological process and mechanism. However, the weak binding affinity of monovalent carbohydrate ligand and lectin is the difficulty to exploit carbohydrate for lectin research. In addition to exploiting multivalent interaction, developing high affinity monovalent carbohydrate derivatives is also a solution to overcome the difficulty.
In past decades, antibiotics were commonly used and cause P. aeruginosa rapidly develop resistance during the course of treating an infection. In addition to the resistance of P. aeruginosa, biofilm formation is a more severe issue for human health. The ability of infection and biofilm formation of P. aeruginosa were mainly caused by LecA lectin to specifically bind to galactose residue of cell surface. Recent years, it was reported that the aromatic galactoside have higher affinity to LecA than galactose. In this part of thesis, we synthesized kinds of aromatic galactoside as ligand to understand the relationship between the aromatic structure and the affinity. Apart from this, we also develop multivalent scaffold by using polyproline for its PPII structure to maintain the effective distance. We designed and synthesized aromatic galactoside conjugated polyproline material as multivalent ligand binding to neighboring binding site of LecA. After microarray scanning, we found that the multivalent materials were effective for LecA binding test.
Furthermore, asiaglycoprotein receptor (ASGPR) is an endocytotic cell surface lectin expressed by hepatocyte, which recognized galactoside residue of asiaglycoprotein. So we tried to use the aromatic galctoside as ligand and modified on nanoparticle carrier to test the uptake ability. After modification of the surface of nanoparticle carrier, the fluorescent siRNA were used as cargo to test the uptake ability of the human hepatoma Hep3B cell line. In Hep3B cell uptake assay, we found that modified nanoparticle was elevated the ability of uptaken by Hep3B about 10 times higher than unmodified under confocal microscopy. These result may be helpful for designing more valid ligand structure to modified drug carrier.

中文摘要 I
Abstract II
目錄 IV
圖目錄 VI
表目錄 VIII
式目錄 IX
流程目錄 X
縮寫表 XI
第一章、緒論 1
1.1.前言 1
1.2.醣類與凝集素之交互作用 2
1.3.多價性效應 3
1.3.1.多價性效應原理 3
1.3.2.多價性效應對於凝集素的研究 7
1.4.脯胺酸多肽的特性及應用 8
1.4.1.脯胺酸多肽結構與特性 8
1.4.2.脯胺酸多肽在生物研究上的應用 9
1.5.綠膿桿菌凝集素抑制劑 10
1.5.1.綠膿桿菌對於人類健康的危害 10
1.5.2.綠膿桿菌生物膜的形成及抗藥性機制 11
1.5.3.綠膿桿菌可溶性凝集素I(PA-IL)的結構與特性 12
1.5.4.綠膿桿菌凝集素LecA抑制劑作為抗綠膿桿菌材料之研究 14
1.5.5. 多價性綠膿桿菌生物膜抑制劑 16
1.6.醣脂質對藥物載體奈米粒子的選擇性控制研究 20
1.6.1. RNAi藥物以及肝相關疾病研究 20
1.6.2. RNAi藥物輸送奈米粒子載體種類與性質 21
1.6.3.藥物輸送奈米粒子材料對於肝病的研究 24
1.6.4. ASGPR結構以及胞吞機制 26
1.6.5.醣分子配體對於ASGPR親和力研究 28
1.7. 研究動機 29
第二章、結果與討論 32
2.1.單價LecA抑制劑合成 32
2.1.1. β-芳基半乳醣苷之合成 32
2.1.2. Gb3醣體之合成 41
2.1.3. 以微陣列(Microarray)篩檢LecA與抑制劑之結合能力 46
2.1.4.微陣列試驗結果與討論 48
2.2.特定間距之二價醣肽LecA抑制劑合成 50
2.2.1.醣肽材料合成之策略 50
2.2.2.多肽固相合成脯胺酸多肽骨架 51
2.2.3.具疊氮基之芳香性半乳醣苷合成 54
2.2.4.疊氮-炔類的[3+2]環化加成 56
2.2.5.圓二色光譜結構分析 58
2.2.6. 微陣列試驗之結果與討論 61
2.3.半乳糖衍生物修飾奈米藥物載體表面對於肝細胞之研究 65
2.3.1.醣修飾脂質材料合成之策略 65
2.3.2.具丙炔基之半乳糖衍生物之合成 66
2.3.3.半乳糖衍生物接合脂質化合物之合成 69
2.3.4. 肝細胞對於奈米粒子攝入實驗 70
2.3.5. NPs攝入結果與討論 72
第三章、實驗方法與材料 75
3.1. Material and methods 75
3.2. Synthetic procedures and characterization 76
第四章、參考文獻 129

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