利用Indolicidin衍生胜肽促進去氧寡核苷酸輸送

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邱茹慧(Ju-Hui Chiu) 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

利用Indolicidin衍生胜肽促進去氧寡核苷酸輸送
(The Use of Indolicidin-derived Peptides for Oligodeoxynucleotide Delivery)

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摘要(中)

本研究Indolicidin(IL)衍生胜肽對去氧寡核苷酸(Oligodeoxynucleotide, ODN)的輸送效果，其輸送模式可分為兩種:直接將胜肽與ODN座共價接合或是以接枝於分支型聚乙烯亞胺(branched polyethylenimine, bPEI)的方式形成陽離子載體。在直接結合的部份，所形成的胜肽-ODN接合物均具有良好的生物適合性，但是只有ILC、CIL、及R57F89C的接合物可以被送入細胞。而在胜肽接枝bPEI的載體研究中，藉由調控胜肽改質之bPEI與ODN的氮磷(N/P)比，使ODN能以靜電吸引力與胜肽改質的bPEI自組裝成複合粒子。當低N/P比時，負電的ODN吸附在聚陽離子上，因此粒子表面電位為負。粒子大小皆小於600nm，為胞吞作用可進行範圍。和未改質的bPEI相比，經由接枝IL衍生胜肽改質的載體可以提升生物相容性。螢光顯微鏡和流式細胞儀結果顯示，PEI-ILC和PEI-CIL可以促進細胞攝取ODN。雷射共軛焦顯微鏡結果顯示，PEI-ILC和PEI-CIL可以更進一步的使ODN進入細胞質。最後我們進行TNF-α的抑制實驗，結果顯示陽離子型高分子載體反而會刺激RAW264.7細胞產生TNF-α，而無法成功的使基因沉默，只有使用PEI-ILC以低的N/P比攜帶基因，可以明顯降低TNF-α的表達。綜合以上結果，我們認為PEI-ILC不只可以避免刺激RAW264.7細胞，並且可以使基因沉默，此載體有潛力作為基因治療應用。

摘要(英)

Indolicidin (IL)-derived peptides were studied of their effects on oligodeoxynucleotide (ODN) delivery. These peptides were either directly conjugated to (ODN) or grafted to branched PEI (bPEI) as polycation carriers. The peptide-ODN conjugates demonstrated low cytotoxicities, however, only the conjugates using ILC, CIL, and R57F89C were translocated. For the grafted bPEI method, these vehicles were complexed with (ODN) in different N/P ratios to form self-assembled nanoparticles through electrostatic interaction. Negative zeta potentials of formed nanocomplexes were found when the N/P ratios were low, suggesting anionic ODNs were adsorbed on the surfaces of polycations. The diameters of nanoparticles were smaller than 600 nm which were suitable for endocytosis. Compared to non-modified bPEI, bPEI conjugated to IL-derived peptides demonstrated superior biocompatibility. Fluorescence microscope and flow cytometry results indicated that both PEI-ILC and PEI-CIL promoted ODN internalization. Images captured by confocal microscope revealed that PEI-ILC and PEI-CIL were capable of delivering ODN to cytosol of host cells. Finally, these gene vehicles were applied to inhibit TNF-α expression. Because RAW264.7 cells were sensitive to polycations, the ODN delivered by these vehicles did not result in gene silence. Instead, the levels of expressed TNF-α were highly elicited. Only PEI-ILC in low N/P (N/P 5) significantly reduced TNF-α. These results suggested that PEI-ILC not only avoided to stimulate RAW264.7 cells but also promoted gene silence, which should be a potential vehicle for gene therapy application.

關鍵字(中)

★ 聚乙烯亞胺
★ 胜肽
★ 去氧寡核苷酸

關鍵字(英)

★ polyethylenimine
★ peptide
★ oligodeoxynucleotide

論文目次

摘要 I

Abstract II

誌謝 III

目錄 IV

圖目錄 VII

表目錄 VIII

第一章緒論 1

1-1 研究動機 1

1-2 實驗構想 2

第二章文獻回顧 3

2-1 免疫失調 3

2-1-1 免疫系統 3

2-1-2 免疫失調疾病 4

2-1-3 治療方法 4

2-1-3-1 基因抑制藥物 5

2-2 基因治療 6

2-3 基因載體 7

2-3-1 病毒型載體 7

2-3-1-1 反轉錄病毒載體 7

2-3-1-2 腺病毒載體 8

2-3-1-3 腺聯病毒載體 8

2-3-2 非病毒型載體 9

2-3-2-1 基因槍及電穿孔 9

2-3-2-2 脂質體 10

2-3-2-3 陽離子型高分子 12

2-4 PEI對基因的輸送 14

2-4-1 直鏈型PEI 14

2-4-2 支鏈型PEI 15

2-4-3 胞吞作用 16

2-4-4 質子海綿效應 17

2-5 胜肽對基因的輸送 18

2-5-1 胜肽 18

2-5-1-1 細胞穿膜胜肽 18

2-5-1-2 抗菌胜肽 19

2-5-2 形成孔洞機制 20

2-5-3 胜肽使用策略 22

2-5-4 缺乏核內體逃脫 24

2-6 胜肽接枝PEI對基因的輸送 25

第三章實驗材料、儀器與方法 26

3-1 實驗材料 26

3-1-1 合成材料 26

3-1-2 細胞培養 28

3-1-3 定性定量分析 29

3-2 實驗儀器 31

3-3 實驗方法 32

3-3-1 配製溶液 32

3-3-2 合成 33

3-3-2-1 Peptide-ODN conjugation 33

3-3-2-2 PEI-Peptide conjugation 34

3-3-3 NPs製備 35

3-3-4 粒徑大小與表面電位(DLS) 35

3-3-5 接枝率分析 36

3-3-5-1 TBNSA 36

3-3-5-2 DTNB 37

3-3-6 包覆率分析 38

3-3-7 轉染實驗 39

3-3-8 細胞存活率(MTS) 40

3-3-9 螢光顯微鏡(Fluorescent microscope) 40

3-3-10 流式細胞分析儀(Flow Cytometry) 41

3-3-11 雷射共軛焦顯微鏡(Confocal) 42

3-3-12 蛋白質抑制實驗(ELISA) 43

第四章結果與討論 44

4-1 Peptide-ODN對於細胞存活率之影響 44

4-2 Peptide-ODN對細胞攝取的影響 45

4-3 PEI-peptide物性鑑定 47

4-3-1 表面電位 47

4-3-2 粒徑大小 49

4-3-3 TNBSA分析交聯劑接枝率 51

4-3-4 DTNB分析胜肽接枝率 52

4-3-5 PEI-peptide / ODN包覆率 54

4-4 PEI-peptide對於細胞存活率之影響 55

4-5 PEI-peptide對細胞攝取的影響 58

4-5-1 螢光顯微鏡分析細胞攝取量 58

4-5-2 流式細胞儀分析細胞攝取率 63

4-5-3 雷射共軛焦顯微鏡探討細胞攝取 64

4-6 PEI-peptide對蛋白質表現的影響 67

第五章結論 69

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

2015-8-26

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