Indolicidin之二聚體形式對輸送去氧寡核?酸的影響

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劉宜旻(Yi-Min Liu) 查詢紙本館藏

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化學工程與材料工程學系

論文名稱

Indolicidin之二聚體形式對輸送去氧寡核?酸的影響
(The Effect of Dimeric Form of Indolicidin-Derived Peptide for Oligodeoxynucleotide Delivery)

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摘要(中)

許多文獻指出腫瘤壞死因子α ( tumor-necrosis factor-α , TNF-α)的過度表達與一些炎症疾病有關，因此在本篇研究中，我們利用基因輸送的方式期望能降低TNF-α的表現以應用在臨床上。Indolicidin(IL)是具有潛力的細胞穿膜胜?，但其高細胞毒性限制了其應用。因此本研究欲開發IL衍生?以輸送去氧寡核?酸(ODN)，並探討二聚體的斷鍵與否對於基因輸送及沉默效果的影響。CIL胜?為IL的N端接上一個半胱胺酸(cysteine)，HPLC和SDS-PAGE結果證實CIL能透過雙硫鍵形成二聚體。另外，我們亦設計一CIL二聚體的類似胜?，但將其半胱胺酸改成結構相似的絲胺酸(serine)，並命名為S28。透過DLS和膠體電泳實驗可以發現CIL和S28不論是分子量或是正電荷個數均高於IL，因此能與ODN有效形成較穩定的複合物，且所形成的粒子大小都在巨噬細胞的吞噬範圍內。由螢光標定結果證實，CIL和S28均可提高細胞攝取率且促進內體逃脫。因此將其應用於TNF-α的基因沉默實驗，其結果顯示CIL和S28均比IL具有更佳的抑制效果。在生物適合性的部份，溶血實驗和MTT結果證實二聚體形式可降低IL所造成的膜擾動及細胞毒性，而又以CIL的細胞毒性最低，推測二聚體於細胞膜的吸附可能會因為其高電荷密度而提高細胞膜內外的電位差，但由於部分CIL可能會與膜上巰基蛋白形成雙硫鍵，並因為濃度梯度而轉移至膜內側，所以降低膜干擾的程度而提高生物相容性。因此CIL以可斷鍵形式所形成的二聚體提供一個理想基因沉默輸送的選擇。

摘要(英)

Overexpression of tumor necrosis factor α (TNF-α) has been indicated as a key cytokine in many inflammatory diseases. In this study, we tended to inhibit TNF-α by gene therapy to promote its clinical application. Indolicidin (IL) is a potential cell-penetrating peptide (CPP); however, its application is restrict due to high cytotoxicity. In this study, we modified IL as dimers and investigated the effect of their cleavability on oligodeoxynucleotide (ODN) delivery efficiency. We added a cysteine residue to the N terminus of IL and denoted it as CIL. The HPLC and SDS-PAGE results demonstrated that this cysteine modification led CIL to self-crosslink as dimers through disulfide bond formation. In addition, we developed a dimeric peptide mimicking CIL and replaced its cysteine with serine, and denoted it as S28. Because both CIL and S28 own more positive charges and larger molecular weights, the results of DLS and gel retardation assay showed that these dimers effectively encapsulated ODN to form stable complexes compared to the IL group, and these particles were all suitable for macrophage uptake. Fluorescent labeling was applied to track ODN delivery, which suggested that both CIL and S28 not only promoted ODN internalization but also facilitated endosomal escape. To evaluate gene silence efficiency, these peptides were applied to RNAi experiments against TNF-α. The results demonstrated that TNF-α expression was highly inhibited by CIL and S28 compared to that of IL. Hemolytic activity and MTT assays were applied biocompatibility evaluation, which indicated that dimeric peptides demonstrated lower membrane perturbation and cytotoxicity that those of IL. Interesting, CIL was the one with the lowest cytotoxicity, We deduced that CIL may form disulfide bonds with exofacial thiols of cell membrance and migrate to the inner side of membrane due to a concentration gradient, so the degree of charge accumulation outside the membrane was not as serious as that of S28, which thus decreased membrane perturbation and increased biocompatibility. Therefore, CIL as a cleavable dimeric peptide provided an ideal choice for ODN delivery.

關鍵字(中)

★ 胜?
★ 二聚體
★ 半胱胺酸
★ 去氧寡核?酸
★ 基因輸送

關鍵字(英)

★ peptide
★ dimer
★ cysteine
★ oligodeoxynucleotide
★ gene delivery

論文目次

摘要 I
Abstract II
目錄 V
圖目錄 IX
表目錄 XI
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 4
2-1免疫反應 4
2-1-1免疫系統 4
2-1-2 免疫失調疾病 4
2-1-2-1腫瘤壞死因子(Tumor necrosis factor α) 5
2-1-2-2現有免疫疾病治療方式 5
2-2基因治療 7
2-2-1基因沉默 8
2-2-1-1核糖核酸干擾 9
2-2-1-2反義寡核?酸 11
2-3基因載體 13
2-3-1病毒型載體 13
2-3-2 非病毒型載體 13
2-3-2-1 脂質體 14
2-3-2-2 陽離子型高分子 14
2-4 胜? 15
2-4-1 細胞穿膜胜? 15
2-4-2 細胞穿膜胜?進入細胞的機制 17
2-4-3 Indolicidin 18
2-4-4 Indolicidin的穿膜機制 19
2-5 以二聚體形式應用於藥物輸送 20
第三章材料與方法 24
3-1實驗材料 24
3-1-1合成材料 24
3-1-2細胞培養用藥 25
3-1-3定性定量分析試劑 25
3-2實驗儀器 27
3-3實驗方法 32
3-3-1溶液配置 32
3-3-2 HPLC分析 36
3-3-3 蛋白質膠體電泳(SDS-PAGE)分析 37
3-3-4 複合物(Peptide/ODN)製備 40
3-3-5 粒徑大小與表面電位(DLS) 41
3-3-6 包覆率 42
3-3-6-1製膠(1% agarose膠片) 42
3-3-6-2跑膠與照膠 42
3-3-6-3螢光標定法 43
3-3-7 胜?溶血活性 44
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) 46
3-3-8-4蛋白質抑制實驗 47
3-3-8-4-1 轉染 47
3-3-8-4-2 Lipopolysaccharide (LPS) Treatment 47
3-3-8-4-3 MTT assay for Normalization 48
3-3-8-4-4 ELISA分析 48
第四章結果與討論 50
4-1二聚體分析 50
4-1-1 HPLC分析 50
4-1-2 SDS-PAGE分析 52
4-2奈米粒子物性鑑定 53
4-2-1 表面電位 53
4-2-2 粒徑大小 55
4-2-3 包覆率 56
4-3生物適合性測試 58
4-3-1溶血活性(人類紅血球細胞) 58
4-3-2 MTT分析 60
4-4複合物對細胞攝取的影響 62
4-4-1螢光顯微鏡分析細胞攝取量 62
4-4-2雷射共軛焦顯微鏡探討細胞攝取 64
4-4-3 複合物對蛋白質表現的影響 66
第五章結論 68
第六章參考文獻 70

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指導教授

胡威文(Wei-Wen Hu)

審核日期

2018-8-23

推文