利用寡聚精胺酸促進去氧寡核苷酸輸送

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顏欣柔(SHIN-ROU YAN) 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

利用寡聚精胺酸促進去氧寡核苷酸輸送
(The Use of Oligoarginine for Oligodeoxynucleotide Delivery)

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摘要(中)

本研究中以聚精胺酸R9作為基礎，利用各種不同方法形成不同的載體模式來探討對去氧寡核苷酸(ODN)的輸送效果，這些載體模式包含PEI/ODN、R9/ODN、R9C/ODN(二聚體)、PEI10/R9/ODN(三成分)、PEI10/R9C/ODN(三成分)與PEI-R9C/ODN(接枝)六種。在表面電位與粒子大小方面，不同形式載體與ODN依照的各種氮磷(N/P)比混合，可發現在PEI、R9C和PEI-R9C與ODN可藉靜電力形成複合粒子，且表面電位亦隨劑量增加，相對的R9僅能吸附於ODN，減低ODN斥力並造成ODN聚集。而所有粒子大小皆在巨噬細胞的巨噬範圍裡(0.3~10µm)。關於載體的包覆率，除了R9載體之外，其他載體皆有隨載體劑量而提升，能使複合物更穩定。接下來，在螢光顯微鏡中，除R9/ODN之外，其他皆能使複合物進入細胞內，甚至優於PEI/ODN的控制組。還有，在雷射共軛焦顯微鏡結果顯示在有R9C參與的載體系統中，ODN皆能成功從核內體逃脫進入細胞質。細胞毒性測試證實各載體並無明顯毒性出現。最後為了確認是否能應用至基因沉默上，我們進行TNF-α的蛋白質的抑制實驗，並利用不同實驗條件證實穿膜與胞吞的結果，結果指出R9C不論是單獨使用或配合PEI，均可直接穿膜以抑制TNF-α的表現。相較之下PEI所參與的輸送方式是藉由包吞進入細胞，因此ODN藥效的時間上較為延後。綜觀而言，PEI10/R9C/ODN可兼具兩種輸送的途徑優勢，因此得以延長基因沉默的療效，這將有助於臨床上的應用。

摘要(英)

Oligoarginine, R9, is investigated of its potential on oligodeoxynucleotide (ODN) delivery. Cysteine modified R9 (R9C) and polyethylenimine (PEI) were also co-administrated so that there were 6 different delivery modes in this study, including PEI/ODN, R9/ODN, R9C/ODN, PEI-R9C/ODN (conjugates), PEI10/R9/ODN, and PEI/R9C/ODN. These carriers were complexed with ODN in different N/P ratios. Zeta potentials of formed nanoparticles increased with increasing carrier molecules. In contrast, R9 can only adsorb onto ODN without nanoparticle formation, which resulted in reducing repulse forces and leading ODN aggregation. However, the formed particle-sizes in all groups were ranged between 0.3 to 10µm, which were suitable for macrophage uptake. About the encapsulation, all carriers effectively loaded ODN except R9, and the loading efficiency increased with increasing carriers. The fluorescent microscopy illustrated that that all groups can deliver ODN into cells except the R9/ODN group. The confocal microscopy results suggested that R9C involving carrier systems (R9C/ODN, PEI10/R9C/ODN, and PEI-R9/ODN) can even facilitate endosomal escape. The biocompatibility assay suggested all carriers did not elicit severe cytotoxicity. Finally, we applied these systems to deliver anti-TNF-α ODN to evaluate their gene silence efficiencies. The results indicated that R9C/ODN and PEI10/R9C/ODN can inhibit TNF-α expression through transmembrane pathway. In contrast, PEI/ODN and PEI10/R9C/ODN can be uptake through endocytosis. Because PEI10/R9C/ODN can deliver ODN by both direct penetration and endocytosis pathways, the period of gene silence can be elongated, which should be an optimal delivery mode for clinical application.

關鍵字(中)

★ 精胺酸
★ 聚乙烯亞胺
★ 去氧寡核苷酸

關鍵字(英)

★ arginine
★ polyethylenimine
★ oligodeoxynucleotide

論文目次

摘要 I
Abstract II
誌謝 III
目錄 V
圖目錄 VIII
表目錄 X
第一章緒論 1
1-1 研究背景 1
1-2 研究動機 2
第二章文獻回顧 3
2-1免疫反應 3
2-1-1免疫系統 3
2-1-2免疫失調 3
2-1-2-1腫瘤壞死因子(Tumor necrosis factor α) 4
2-1-2-2免疫失調疾病與治療 4
2-2基因治療 5
2-2-1用於基因沉默之基因抑制藥物 5
2-3基因載體 9
2-3-1病毒型載體 9
2-3-1-1反轉錄病毒 9
2-3-1-2腺病毒 10
2-3-1-3腺聯病毒 11
2-3-2非病毒型載體 11
2-3-2-1針頭注射 12
2-3-2-2基因槍 12
2-3-2-3電穿孔 13
2-3-2-4超聲波穿孔 13
2-3-2-5脂質體 13
2-3-2-6陽離子型高分子 15
2-4胜肽 17
2-4-1穿膜胜肽 17
2-4-2 穿膜胜肽進入細胞機制 19
2-4-3胜肽應用於寡核苷酸輸送 20
2-5聚乙烯亞胺(PEI) 22
2-5-1質子海綿效應 22
2-6胜肽與PEI對基因的輸送方法 24
2-6-1胜肽修飾PEI 24
2-6-2三成分摻混對基因的輸送 24
第三章材料與方法 26
3-1 材料 26
3-1-1 合成 26
3-1-2 細胞培養 27
3-2儀器 30
3-3實驗方法 32
3-3-1溶液配製 32
3-3-2 HPLC與MASS分析測試 35
3-3-3合成 35
3-3-3-1PEI-Peptide conjugation 35
3-3-4NPS製備 37
3-3-5 粒徑大小與表面電位(DLS) 39
3-3-6 接枝率分析 40
3-3-6-1 TBNSA 40
3-3-7包覆率實驗 42
3-3-7-1製膠(1% agarose膠片) 42
3-3-7-2跑膠與照膠 42
3-3-7-3螢光標定法 43
3-3-8細胞轉染實驗 45
3-3-8-1細胞存活率(MTT) 45
3-3-8-2螢光顯微鏡(Fluorescent microscope) 45
3-3-8-3雷射共軛焦顯微鏡(Confocal) 45
3-3-8-4蛋白質抑制實驗 46
3-3-8-4-1轉染 46
3-3-8-4-2 Lipopolysaccharide(LPS)刺激TNFα產生 46
3-3-8-4-3 MTT Normalize 47
3-3-8-4-4ELISA蛋白質分析 47
第四章結果與討論 48
4-1 材料分析 48
4-1-1 HPLC 48
4-1-2質譜儀 49
4-2奈米粒子物性鑑定 52
4-2-1TNBSA分析交聯劑接枝率 52
4-2-2DTNB分析胜肽接枝率 52
4-2-3 表面電位 54
4-2-4 粒子大小 56
4-2-5粒子包覆率 59
4-3奈米粒子對細胞攝取的影響 63
4-3-1螢光顯微鏡分析細胞攝取量 63
4-3-2雷射共軛焦顯微鏡探討細胞攝取 68
4-4奈米粒子對細胞存活率之影響 72
4-5奈米粒子對蛋白質表現的影響 75
第五章結論 84
第六章參考文獻 86

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指導教授

胡威文(Wei-Wen Hu)

審核日期

2016-8-29

推文