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系統識別號 U0026-1208201014470100
論文名稱(中文) 以金奈米材料攜帶核酸及訊息胜肽對細胞之影響
論文名稱(英文) The Cellular Effect of Oligonucleotide and Signal Peptide Conjugated Gold Nanoparticles
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 98
學期 2
出版年 99
研究生(中文) 蔡宗霖
研究生(英文) Tsung-Lin Tsai
學號 S5894103
學位類別 博士
語文別 英文
論文頁數 89頁
口試委員 指導教授-謝達斌
共同指導教授-蘇五洲
召集委員-張文粲
口試委員-葉晨聖
口試委員-凌斌
口試委員-陳家俊
口試委員-李紫原
口試委員-張俊彥
中文關鍵字 三股寡核甘酸  DNA切割  奈米金  訊息胜肽  細胞自噬  細胞凋亡 
英文關鍵字 Triplex-Forming Oligonucleotide  DNA cleavage  gold nanoparticles  nuclear localization signal (NLS)  autophagy  apoptosis 
學科別分類
中文摘要 奈米科技在醫學領域上已由實驗室走入真實的臨床應用。奈米醫學已成為本世紀重要發展脈絡。結合奈米材料科技及生醫技術更是現代醫療的新興趨勢。而奈米材料由於可以提供特殊的材料性質而有機會打破傳統醫學診治上的瓶頸,為醫學領域帶來重要的改變以及龐大的生物醫學產業經濟利益。在本研究中,我們將分為兩個主要篇幅,第一部份將探討利用三股寡核甘酸(Triplex Forming Oligonucleotides)及光激發DNA切割試劑(Hydrazone)所組成具有專一DNA辨識能力之奈米剪的製成及其應用,其中經由TFO的導引除了本身對於基因的調控外,亦可增加切割試劑的專一性,且亦可增強TFO對於標的基因的負調控並產生永久性的破壞。此外,13奈米金是目前被廣為研究及應用的奈米材料,基於奈米材料的高表面/體積比、高密度堆積以及高結構組合彈性的特徵,可將已修飾上Hydrazone的TFO與金奈米做連結,在此奈米金除了可以當成攜帶的載體外,又因奈米材料本身的高模組性特徵,可將標的不同基因的TFO攜帶於同一個奈米載體上,進而達到同時負調控不同基因的效果。於本研究中利用EMSA,共同沉澱法(co-precipitation)及DNA切割效能,來評估研究策略在體外(in vitro)是否能專一的鎖定標的序列並做切割的動作;並於建立之綠色螢光(EGFP)細胞模式實驗中,亦可得到相同的基因壓抑效果。第二部份則為探討組裝不同訊息胜肽(adenoviral及SV40 large T NLS)之金奈米粒子於子宮頸癌細胞(HeLa)中所產生的影響。藉由不同訊息胜肽所組裝之金奈米粒子,於細胞中會產生相異的分佈,經由adenoviral NLS所導引之金奈米粒子會通過細胞核膜而進入核內,而SV40 large T NLS則會累積於細胞核膜外而導致細胞死亡,而其死亡機制則是此研究的目的。經由雷射共軛焦及光學顯微鏡證實不同訊息胜肽所組裝之金奈米粒子會產生核內及核膜外的分佈。且隨金奈米粒子的濃度及作用的時間增加,會產生顯著的細胞死亡現象。此外對於細胞內部的影響,由於SV40胜肽修飾之金奈米粒子會於細胞核膜外累積,而使得核內RNA的輸送被阻礙而滯留於核內,核外蛋白質如STAT1及NF-κB則是無法傳遞而停滯在細胞質中。再經由西方墨點法來更詳細解析細胞的死亡機制,發現細胞會以非耗能的機制如細胞自噬(Autophagy)來替代需耗能之機制如細胞凋亡(Apoptosis),而驅使細胞逐漸走向死亡。本研究的發現,對於目前蓬勃發產的奈米醫學上,在細胞面對修飾不同分子材料(DNA及胜肽鏈)的奈米粒子時所產生的一些生理機制及影響,或許可以提供一些有用及詳細的資訊。
英文摘要 Nanotechnology has become part of our lives, especially with regard to medical applications, in the 21st century. Integration of nanotechnology and biomedicine has been a new trend in medical treatment of the time. Nanomaterials provide unique characteristics that can be used to provide tools for breaking through innovations beyond the limitations of current traditional medicine and bring about a powerful revolution in health care and biomedical industrial profits. There are two issues to be addressed in this thesis. The first part is the application of specific gene regulation by an artificial, targeted, light-activated nanoscissor (ATLANS). ATLANS was developed for precision photonic cleavage of DNA at selectable target sequences. The ATLANS is comprised of nanoparticle-core and a monolayer of hydrazone-modified triplex-forming oligonucleotide (TFO) which recognize and capture the targeted DNA duplex. Upon photo-illumination (λ=460nm), the attached hydrazone “scissor” specifically cleaves the targeted DNA at a pre-designed nucleotide pair. Electrophoretic mobility-shift and co-precipitation assays revealed sequence-specific binding with the short-fragment and long-form plasmid DNA of both TFO and TFO-nanoparticle probes. Restriction mapping and direct sequencing showed that light activation introduced a double-stranded break 12 bp downstream from the 3’-end of the TFO sequence. In addition, within established EGFP cell model, both genomic and protein level of target gene was down-regulated by ATLANS treatment. Gold nanoparticles (GNPs) multiplexed the cutting efficiency and potential for simultaneous manipulation of multiple targets, as well as protected DNA from non-specific photo-damage. This photon-mediated DNA manipulation technology will facilitate high spatial and temporal precision in simultaneous silencing at the genome level, and advanced simultaneous manipulation of multiple targeted genes. The second part is evaluated the effect of different signal peptide modified gold NPs inside cervical cancer cell HeLa. We and other investigators found that gold NPs modified with the nuclear localization signal (NLS) from SV40 virus (GNP-PEG/SV40) accumulated around the cytoplasmic side of nuclear membrane in HeLa cells. The accumulation of GNP-PEG/SV40 around nucleus induced a nucleocytoplasmic transport blockage that prevents export of RNA and translocation of signaling proteins (STAT1 and NF-κB) into nucleus. The long-term nucleocytoplasmic transport blockage results in a dramatically cell death. The cellular death was not caused by apoptosis, because there was no activation of caspase 3, 9 and no enhanced expression of Annexin V/PI in the HeLa cells after treatment. According to images of transmission electron microscopy (TEM), we found early autolysosome and degraded autolysosome after 72 hours with GNP-PEG/SV40 treatment. The GNP-PEG/SV40 induced autophagy was further confirmed by the appearance of EGFP-LC3 aggregation and LC3-II. Therefore, GNP-PEG/SV40 induced cell death is primarily via autophagy pathway. The findings may have implications in the development of new therapeutic modality for specific cancer cells or prevention of long-term toxicities from treatment with peptide modified NPs.
論文目次 中文摘要 II
Abstract IV
Acknowledgements VI
Contents VIII
Table Contents XI
Figure Contents XII
Abbreviation List XV
Chapter 1 Introduction 1
1-1 What is nanotechnology? 2
1-2 The fundamental characteristics of metallic nanoparticles 3
1-2-1 Surface effect 3
1-2-2 Size effect 3
1-2-3 Quantum effect 4
1-3 Nanobiotechnology 5
1-4 Nanomedicine 6
1-5 Gold nanoparticles 6
1-5-1 Synthesis of gold nanoparticles 7
1-5-2 Bio-applications of gold nanoparticles 8
1-5-2-1 Oligonucleotide conjugated gold nanoparticles 8
1-5-2-2 Peptide conjugated gold nanoparticles 10
1-6 Cellular fate of gold nanoparticles 11
1-7 Cellular death mechanism 12
1-7-1 Apoptosis 12
1-7-2 Necrosis 14
1-7-3 Mitotic catastrophe 14
1-7-4 Autophagy 15
Chapter 2 Experimental Section 18
2-1 Preparing triplex-forming oligonucleotides and conjugating them to gold nanoparticles 19
2-2 Ninhydrin assay for TFO-hydrazone assembly 19
2-3 Characterizing the physical properties of the nanoparticles 20
2-4 Electrophoretic mobility shift assay 20
2-5 Co-precipitation analysis of the designed TFO and the target template DNA 21
2-6 Evaluating the photo-activated N-(β-maleimidobutryloxy) succinimide ester-hydrazone DNA cleaver 21
2-7 Restriction fragment mapping and direct DNA sequencing 21
2-8 Synthesizing oligonucleotides and constructing a plasmid template 22
2-9 Cell culture 23
2-10 Establish of EGFP HeLa cell model 23
2-11 Genomic DNA PCR 23
2-12 Flow cytometry 24
2-13 Sequential assemble of peptide mixed monolayer gold nanoparticles 24
2-14 Cell viability 25
2-15 TEM analysis of cells with internalized peptide modified nanoparticles 25
2-16 Confocal laser scanning microscope 26
2-17 Real-time quantity of total mRNA synthesis 26
2-18 Determination of cell necrosis and apoptosis by PI and Annexin V stain 27
2-19 Western blot analysis 27
Chapter 3 The Downregulate of Target Genes by Photo Activated DNA Nanoscissors 29
3-1 Introduction 30
3-2 Results 31
3-2-1 Self-assembling and characterization of ATLANS DNA cleaver 31
3-2-2 Targeting specificity of TFO and ATLANS 33
3-2-3 ATLANS induced double-strand target DNA cleavage 33
3-2-4 Confirmation of the double strand cleavage site 35
3-2-5 Nuclear targeting compatibility of ATLANS 35
3-2-6 ATLANS mediated specific down-regulation of target gene in cell system 36
3-3 Discussion 37
Chapter 4 The Nucleocytoplasmic Transport Blockage by SV40 Peptide-Modified Gold Nanoparticles Induced Autophagic Cell Death in Cervical Cancer Cells 39
4-1 Introduction 40
4-2 Results 42
4-2-1 Long-term treatment with GNP-PEG/SV40 in HeLa cells results in morphological changes on NPC 42
4-2-2 Long-term treatment with GNP-PEG/SV40 in HeLa cells caused nucleocytoplasmic transport blockage 43
4-2-3 The nucleocytoplasmic transport blockage caused by GNP-PEG/SV40 induced cell death 44
4-2-4 The nucleocytoplasmic transport blockage indueced autophagy rather than apoptosis, necrosis or mitotic catastrophe in HeLa cells 45
4-2-5 The nucleocytoplasmic transport blockage did not induce ER stress pathway 47
4-3 Discussion 47
Chapter 5 Conclusion 50
Reference 85

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