硬脂基化的Indolicidin作為傳送質體去氧核 酸的非病毒載體

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沈筱容(Hsiao-Jung Shen) 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

硬脂基化的Indolicidin作為傳送質體去氧核酸的非病毒載體
(Stearylated Indolicidin as a nonviral vector for plasmid DNA delivery)

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摘要(中)

細胞穿透肽（CPP）已經被廣泛研究作為用於基因傳送的非病毒載體。 Indolicidin（IL）是一種有潛力的細胞穿透肽，其富含陽離子精氨酸、賴氨酸和疏水性的色氨酸。雖然IL已被用作小分子核苷酸的載體，例如siRNA和寡脫氧核苷酸（ODN）的傳送，但它不能單獨遞送大分子質體DNA（pDNA）。雙親性分子其親疏水段鍊可自組裝成膠束或脂質體等微結構，藉此與細胞膜融合達到藥物輸送的效果。因此，本研究將IL的N或C末端進行硬脂基化，並分別將命名為sIL和ILs。
DLS分析硬脂基化胜肽的粒徑及電位，證實sIL和ILs都可進行自組裝，推測結構分別為多層囊泡及反膠束的形式。和DNA複合後分析其裝載率，證實IL的硬脂基化對其與DNA複合的影響不大，而競爭實驗結果顯示自組裝的微結構可以增加複合物的穩定性。由於胜肽載體的輸送取決於其膜擾動的能力，所以我們以鈣黃綠素滲漏實驗進行膜擾動的評估，可以發現N端硬脂化的sIL不利於與膜作用，相較之下，ILs的膜擾動能力與IL相近。當這些胜肽直接用於遞送質粒DNA，從雷射共聚焦顯微鏡和流式細胞儀的結果來看，只有ILs可以促進細胞攝取。轉染結果表明ILs成功轉染HEK-293T細胞，而sIL和IL幾乎沒有轉染。推測sIL的擾膜能力低，且其與DNA的複合物過大，因此不能被宿主細胞攝取。雖然IL可以直接與DNA複合形成合適的大小並且具有優異的包覆率，但穩定性不佳，因此推斷轉染時IL本身易與細胞膜直接吸附而導致DNA在胞外被釋放。相較之下，ILs與DNA複合時，其硬脂基不但可誘使胜肽以其N端與細胞膜接觸達到膜擾動，其自組裝的反膠束結構可增加複合物的穩定性，因此達到促進DNA輸送的目的。

摘要(英)

Cell-penetrating peptides (CPP) have been investigated as a non-viral vector for gene delivery. Indolicidin (IL) is a potential cell-penetrating peptide rich in cationic arginine/lysine and hydrophobic tryptophan. Although IL has been applied as a carrier for small nucleotides such as siRNA and oligodeoxynucleotide, it cannot solely deliver huge plasmid DNA (pDNA). Amphiphilic molecules can self-assemble as micelles or liposomes due to their hydrophilic/hydrophobic domains to promote their fusion with cell membranes for drug delivery. Therefore, we modified IL by stearylating its N and C terminals, and denoted them as sIL and ILs, respectively. The DLS analysis was applied to examine the size and surface charges of these stearylated peptides, suggesting that sIL and ILs were capable of self-assembling as multilamellar vesicles (MLVs) and inverted micelles, respectively. The DNA loading examination demonstrated that stearylation of peptides did not hinder their complexation with DNA. The competition experiments showed that self-assembled structure of stearylated peptides increased the stability of complexes. Because delivery efficiencies of CPPs highly depend on their interaction with cell membranes, calcein leakage was applied to evaluation their membrane perturbation ability. In contrast to sIL which demonstrated poor leakage due to its N terminal-stearylation, membrane perturbation ability of ILs was similr to that of unmodified IL. When these peptides were applied for gene delivery, the results of confocal microscopy and flow cytometry showed that only ILs promoted DNA internalization. The transfection results indicated that ILs successfully transfected HEK-293T cells, whereas sIL and IL demonstrated almost no transfection. Due to poor membrane perturbation ability and huge sizes of sIL/DNA complexes, sIL cannot promote DNA transportation. Although IL can directly complex with DNA with appropriate size and good loading efficiency, these complexes is not stable enough. Therefore, IL may adsorb to cell membrane during transfection to release DNA extracellularly. In contrast, ILs may force its N terminus to interact with cell membrane to promote perturbation. The self-assembly of inverted micelles may also stabilize ILs/DNA complexes. These properties explain the improvement effects of ILs on DNA delivery efficiency.

關鍵字(中)

★ 硬脂基化
★ 細胞穿膜胜肽
★ 基因傳送
★ 質體DNA
★ 非病毒載體

關鍵字(英)

論文目次

摘要 I
Abstract III
致謝 V
目錄 VII
圖目錄 XI
表目錄 XIII
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 基因治療 3
2-2 基因載體 6
2-2-1 脂質體 7
2-2-1-1 脂質體轉染機制 9
2-2-1-2 脂質體用於轉染上的發展 11
2-2-2 胜肽 13
2-2-2-1 細胞穿膜胜肽(Cell Penetrating Peptides, CPPs) 13
2-2-2-2 胜肽轉染機制 15
2-2-2-3 胜肽的改質與應用 16
2-2-2-4 Indolicidin 19
2-2-2-5 Indolicidin的改質與應用 21
第三章實驗藥品、儀器與方法 22
3-1 實驗材料 22
3-1-1 質體DNA 22
3-1-2 胜肽 23
3-1-3 細胞與培養用藥 23
3-1-4 分析藥品 23
3-2 實驗儀器 25
3-3 實驗方法 27
3-3-1 溶液配置 27
3-3-2 質體DNA純化 31
3-3-3 HEK293T細胞培養 32
3-3-4 peptide/DNA奈米粒子複合物製備 35
3-3-5 粒徑大小與表面電位 35
3-3-6 包覆率 36
3-3-6-1 螢光標定法 36
3-3-6-2 電泳膠體 36
3-3-6-3 複合物穩定性Heparin競爭實驗 37
3-3-7 Calcein染劑滲漏實驗 38
3-3-8 細胞存活率 39
3-3-9 轉染效率分析 40
3-3-9-1 雷射共軛焦顯微鏡(Confocal Microscopy) 40
3-3-9-2 流式細胞儀 41
3-3-9-3 轉染與ONPG分析 42
第四章結果與討論 44
4-1 奈米粒子物性鑑定 44
4-1-1 表面電位 44
4-1-2 粒徑大小 46
4-2 胜肽之包覆效果 50
4-2-1 電泳 50
4-2-2 螢光標定法 53
4-2-3 Heparin競爭實驗 54
4-3 生物適合性 56
4-3-1 Calcein染劑滲漏實驗 56
4-3-2 細胞毒性 58
4-4 轉染機制探討 61
4-4-1 雷射共軛焦顯微鏡探討細胞攝取 61
4-4-2 流式細胞儀探討細胞攝取 62
4-4-3 轉染效率 64
第五章結論 66
參考文獻 68

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指導教授

胡威文(Wei-Wen Hu)

審核日期

2019-8-20

推文