博碩士論文 100324014 詳細資訊




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姓名 葉喬淳(Chiao-chun Yeh)  查詢紙本館藏   畢業系所 化學工程與材料工程學系
論文名稱 以短鏈胜肽接枝聚乙烯亞胺來進行基因輸送應用之研究
(The use of short peptides conjugated PEI for gene delivery application)
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摘要(中) 本研究將短鏈胜肽接枝於聚乙烯亞胺當作基因載體,並以正負電荷吸引方式,將此載體與質體DNA以不同胺基/磷酸根莫耳比(N/P ratio)組裝成奈米粒子。我們可以藉由動態雷射散射粒徑分析儀測得粒子粒徑大小約分佈在200nm-600nm間;大部份表面電位則為正電,皆為可接受之基因傳送條件。此外,改質過後的PEI,依然能提供質體DNA良好的包覆率。而由MTT分析顯示,改質過後的PEI毒性比未改質前毒性較少,甚至沒有毒性。PEI接枝R9、SAP10兩組載體幾乎沒有轉染效率,IL接枝組不僅有轉染還且優於純PEI組別。我們利用螢光標定以追蹤質體DNA,發現改質過的PEI只有IL接枝組能有效將DNA送入到細胞中。利用Bafilomycin A1 及Chloroquine藥物來探討PEI-IL轉染機制,可發現以PEI-IL所送入的DNA,其內胞逃脫非完全藉由質子海綿效應。最後我們以分子動態模擬來探討這些接枝的胜肽與脂雙層間之交互作用,發現胜肽的疏水端須能進入脂雙層方可穩定其與細胞膜的作用力,進而促進粒子的被吞噬,其中IL的tryptophan 扮演疏水端進入脂雙層的關鍵角色。
摘要(英) In this study, short peptides were conjugated with polyethyleneimine for the application of gene delivery. By electrostatic interaction, self- assembled nanoparticles using PEI-CPPs, and plasmid DNA were prepared in different amine/phosphate (N/P) ratios. The dynamic laser scattering experiment demonstrated that most of particles formed by peptide modified PEI were between the 200 to 600 nm with positive surfaces, suggesting that these nanoparticles were appropriate for gene transfer. In addition, the modified PEI effectively bound DNA. The MTT assays suggested that modification PEI reduced the cytotoxicity. PEI conjugated either by R9 or SAP10 were unable to transfect cells. In contrast, IL conjugated PEI demonstrated better transfection efficiency than that using sole PEI. We used fluorescein labeling to track plasma DNA delivery. Only PEI-IL can carry DNA to cells. To determine the endosomal escape mechanism of PEI-IL, bafilomycin A1 & chloroquine were applied during transfection. Their results suggested that internalized DNA should be released mainly by proton sponge effect; however, the grafted IL may also perturb endosome membrane and eventually causes membrane disruption. Finally, we used molecular dynamic simulation to elucidate the mechanism of grafted CPP interact with lipid bilyaer. The results indicated that only peptides with hydrophobic domain entering lipid bilayer can stabilize their interactions to cell membrane. In addition, tryptophan in indolicidin plays an important role to the insertion of IL to lipid bilayer.
關鍵字(中) ★ 聚乙烯亞胺
★ 胜肽
★ 基因傳送
關鍵字(英) ★ polyethylenimine
★ peptides
★ gene delivery
★ bioconjugation
★ endosomal escape
★ indolicidin
論文目次 摘要 I
Abstract II
致謝 III
目錄 V
圖目錄 IX
表目錄 XII
縮寫表 XIII
第壹章 序論 1
1-1 背景 1
1-2 實驗目的 4
第貳章 文獻回顧 5
2-1 基因傳送療法 5
2-2 基因載體 10
2-3 正電高分子 13
2-3-1聚乙烯亞胺(Polyethyleneimine,PEI) 15
2-4 胜肽 20
2-4-1穿膜胜肽 21
2-4-2鹼性抗生胜肽 25
2-4-2以胜肽進行基因輸送 28
第參章 實驗材料與方法 31
3-1 試藥與原料 31
3-1-1質體DNA 31
3-1-2細胞 32
3-1-3穿膜胜肽(Cell-penetrating peptides) 32
3-1-4藥品 33
3-2 儀器 34
3-3 試藥配製 36
3-4 質體DNA純化 37
3-5 NIH-3T3細胞培養 38
3-6 PEI結合不同種類CPP對轉染效率影響 41
3-6-1細胞轉染 41
3-6-2 ONPG分析 43
3-6-3 X-Gal for β-Galactosidase 45
3-6-4 MTT分析 46
3-7 轉染機制探討 47
3-7-1細胞吸收(uptake)效率(以Fluorescein標記DNA) 47
3-7-2 Bafilomycin A1作用 50
3-7-3 Chloroquine作用 50
3-8 奈米粒子製備及物理化學性質鑑定 51
3-8-1奈米粒子製備 51
3-8-2雷射粒徑分佈儀(dynamic light scattering, DLS)分析 51
3-8-3掃描式電子顯微鏡(scanning electron microscope, SEM) 52
3-8-4包覆率分析 53
3-8-5接枝率分析 55
第肆章 結果與討論 57
4-1 PEI結合胜肽對對轉染效率影響 57
4-2 PEI接枝短鏈胜肽分析 60
4-3 奈米粒子物性鑑定 66
4-3-1表面電位(DLS測定) 66
4-3-2粒徑大小 69
4-3-3包覆率分析 72
4-4 PEI接枝胜肽對對轉染效率影響 76
4-5 X-gal染色 79
4-6 MTT測試對細胞活性分析 80
4-7 轉染機制探討 83
4-7-1細胞吸收效率 83
4-7-2內胞脫離作用(endosomal escape)之抑制劑影響 85
4-8 分子模擬 91
4-8-1分子模擬介紹 91
4-8-2分子模擬結果 94
第伍章 結論 100
第陸章 參考文獻 102
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指導教授 胡威文(Wei-wen Hu) 審核日期 2013-7-26
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