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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/47385完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張富雄 | |
| dc.contributor.author | Jo-Chieh Tung | en |
| dc.contributor.author | 董若傑 | zh_TW |
| dc.date.accessioned | 2021-06-15T05:57:31Z | - |
| dc.date.available | 2012-09-09 | |
| dc.date.copyright | 2010-09-09 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-08-17 | |
| dc.identifier.citation | Akhtar, S. (1998). Antisense technology: selection and delivery of optimally acting antisense oligonucleotides. J Drug Target 5, 225-234.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/47385 | - |
| dc.description.abstract | 基因治療是指利用適當的方法將基因送入細胞中，繼而穩定的表達其未能正常表現的蛋白質，而當疾病是由於蛋白質表現過量所造成的，就必須抑制其基因的表現。目前用來抑制表現的核酸物質有反意股核苷酸 (antisense deoxynucleotides)以及干擾型核醣核酸 (RNAi)，都可以使轉譯過程被停止而抑制不正常的蛋白質表現，而另外一種基因治療為基因修正，即改變基因上錯誤的鹼基而使基因表現正常。過去用來遞送核酸物質的載體主要可以分為兩種，病毒性載體以及非病毒性載體。由於病毒性載體的不穩定性，目前的遞送方式大多以非病毒性載體為主。
3β-[N-(2-guanidinoethyl)carbamoyl]cholesterol (GEC-Chol)為一以膽固醇為基礎的正價脂質，我們以莫耳數1：1的方式將GEC-Chol與膽固醇(Cholesterol)混合後，再以此GEC-Chol/Chol正價奈米微胞攜帶短鏈核苷酸並觀察其在基因治療上的應用。首先研究的是GEC-Chol/Chol正價奈米微胞攜帶短鏈核苷酸的最適條件，我們分別在不同的氮磷比 (N/P ratio)的情況下測量其大小、表面電荷、包覆率以及遞送效率等等，由實驗結果可以發現當氮磷比為3時可以有極高的遞送效率和包覆率。而在毒性測試中GEC-Chol/Chol正價奈米微胞也展現了低細胞毒性，而低細胞毒性即表示能以其遞送較大量的短鏈核苷酸以達到治療的目的。另外，以細胞存活率以及蛋白表現來觀察GEC-Chol/Chol正價奈米微胞遞送c-myc及bcl-2之反意股核苷酸的應用，也發現其為遞送反意股核苷酸的良好載體。在修正綠色螢光蛋白的實驗中，相較於市售正價微脂體Lipofectamine2000，我們發現使用GEC-Chol/Chol正價奈米微胞有2-3倍的修正機率。總結以上的實驗，GEC-Chol/Chol正價奈米微胞可以在活體外的實驗中有效的遞送短鏈核苷酸，並達到基因治療的目的。 本論文提出GEC-Chol/Chol正價奈米微胞具有高度短鏈核苷酸遞送性以及低細胞毒性，相當適合當作一基因治療的載體，此正價奈米微胞未來也可以同時加入其他藥物或是專一性遞送的導向性分子增加其治療能力。而目前正著手進行初步的活體內實驗，以GEC-Chol/Chol正價奈米微胞攜帶反意股核苷酸直接打入皮下腫瘤中，觀察腫瘤的生長情形，然而此正價奈米微胞若要在活體內應用，其最適化條件可能需要微調才能有效應用在活體治療中，這也是未來可以努力的方向。 | zh_TW |
| dc.description.abstract | Gene therapy is the procedure that a gene is delivered into cells, and subsequently expresses appropriately to compensate for the dysfunctional gene. And a gene needs to be repressed when its abnormal overexpression has resulted in a disease. Presently, the nucleic acids used to inhibit protein expression are antisense oligodeoxynucleotides (ODN) and RNAi, both of which could block translation to suppress abnormal gene-expression. Another type of gene therapy is gene correction which revises the wrong nucleotides to recover the coding sequence of the targeted protein. Viral and non-viral vector have been used to deliver nucleic acid materials. Considering to stability, the non-viral vectors is more prevalent.
3β-[N-(2-guanidinoethyl)carbamoyl]cholesterol (GEC-Chol) is a cationic lipid based on cholesterol (Chol). We mixed GEC-Chol and Chol with molar ratio 1：1 and investigated the applications of the GEC-Chol/Chol cationic nanomicelles carrying ODN in gene therapy. To obtain the most appropriate condition, we measured the size, zeta potential, encapsulation and delivery efficiency of GEC-Chol/Chol cationic nanomicelles with different N/P ratio. We found that the delivery efficiency and encapsulation of oligonucleotides was highest when the N/P ratio was 3. In addition, the cytotoxicity of GEC-Chol/Chol cationic nanomicelles was low which suggested that GEC-Chol/Chol cationic nanomicelles could be used to carry more oligonucleotides in gene therapy. Moreover, we found that GEC-Chol/Chol cationic nanomicelles are fine vectors for antisense ODN delivery by observing the cell viability and protein level in the cancer cells which antisense oligodeoxynucleotides of c-myc and bcl-2 were delivered to. Comparing to the commercial transfection reagent Lipofectamine2000, GEC-Chol/Chol cationic nanomicelles also showed higher efficiency to correct aberrant sequence of enhanced green fluorescent protein (EGFP). In summary, GEC-Chol/Chol cationic nanomicelle is a potential tool for gene therapy owing to its high efficiency of ODN delivery and low toxicity to cells in vitro. Drugs and specific targeting molecules can be capsulated or embedded into this vector to execute their therapeutic functions. However, the in vivo test of intratumor injection of antisense oligodeoxynucleotides carried by the GEC-Chol/Chol cationic nanomicelles is still at the initiation stage. In vivo applications of such nanomicelle needs further study. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T05:57:31Z (GMT). No. of bitstreams: 1 ntu-99-R97442026-1.pdf: 3849871 bytes, checksum: 885d0b05ec6143ef79fcfcdf2c3d1532 (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | 目錄
中文摘要 I 英文摘要 III 第一章 緒論 1 1.1 基因遞送 2 1.1.1病毒性載體 2 1.1.2非病毒性載體 3 1.2 基因遞送的核酸材料 7 1.3 以正價微脂體遞送反意股核苷酸之應用性 9 1.4 目標基因修正 9 1.5 活體內以正價微脂體遞送短鏈核苷酸之應用性 11 1.6 研究動機與目的 12 第二章 材料與方法 13 2.1實驗材料 14 2.1.1 藥品 14 2.1.2 細胞株 14 2.1.3 短鏈核苷酸 15 2.1.4 脂質 15 2.1.5 質體 15 2.1.6 儀器 15 2.1.7 實驗動物 16 2.2實驗方法 16 2.2.1 GEC-Chol之製作 16 2.2.2 正價奈米微胞製備 18 2.2.3 短鏈核苷酸之遞送 18 2.2.4 短鏈核苷酸之遞送效率分析 19 2.2.5 正價奈米微胞粒徑大小、表面電位分析 19 2.2.6 正價奈米微胞包覆短鏈核苷酸之包覆率分析 20 2.2.7 正價奈米微胞遞送短鏈核苷酸之毒性分析 21 2.2.8 正價奈米微胞遞送反意股核苷酸之毒殺效率分析 22 2.2.9 以西方墨點法進行細胞內蛋白質表現量之分析 23 2.2.10 利用定點突變使EGFP質體喪失螢光能力 25 2.2.11 以電子顯微鏡觀察正價奈米微胞與短鏈核苷酸形成之微胞粒徑大小、形狀 26 2.2.12 正價奈米微胞遞送反意股核苷酸在活體內之應用 26 第三章 實驗結果 28 3.1 正價奈米微胞之大小、表面電位分析 29 3.2 正價奈米微胞包覆短鏈核苷酸的效率分析 29 3.3 正價奈米微胞保護其包覆之短鏈核苷酸之情形 30 3.4 正價奈米微胞遞送短鏈核苷酸的效率分析 30 3.5 正價奈米微胞與市售正價微脂體遞送短鏈核苷酸的效率比較 31 3.6 正價奈米微胞遞送短鏈核苷酸之耐受性分析 31 3.7 正價奈米微胞遞送反意股核苷酸的效率分析 32 3.8 以正價奈米微胞遞送反意股核苷酸 32 3.9 正價奈米微胞遞送短鏈核苷酸在目標基因修正中的應用 33 3.10 正價奈米微胞遞送短鏈核苷酸在活體內的應用 34 第四章 討論 35 4.1 正價奈米微胞遞送短鏈核苷酸的特性、包覆率以及遞送 效率討論 36 4.2 正價奈米微胞遞送短鏈核苷酸的毒性分析以及遞送效率比較 37 4.3 以正價奈米微胞遞送反意股核苷酸的應用 38 4.4 正價奈米微胞遞送短鏈核苷酸在目標基因修正中的應用 39 4.5 正價奈米微胞遞送短鏈核苷酸在活體內的應用 39 第五章 圖表 41 參考文獻 59 圖表目錄 圖一：正價奈米微胞特性分析 42 圖二：正價奈米微胞包覆短鏈核苷酸的效率分析 44 圖三：以去氧核糖核酸水解酶保護試驗來分析正價奈米微胞保護其包覆的短鏈核苷酸之情形 45 圖四：正價奈米微胞遞送短鏈核苷酸的效率分析 46 圖五：正價奈米微胞遞送短鏈核苷酸的效率比較 47 圖六：正價奈米微胞遞送短鏈核苷酸之耐受性分析 48 圖七：正價奈米微胞遞送反意股核苷酸至細胞中之作用效率 50 圖八：以正價奈米微胞遞送反意股核苷酸 54 圖九：喪失螢光活性的綠色螢光蛋白之細胞穩定株之製作 55 圖十：以正價奈米微胞遞送EGFP 修正短鏈核苷酸對於目標基因修正的效率分析 56 圖十一：以正價奈米微胞遞送反意股核苷酸在活體內的應用 57 圖十二：正價奈米微胞遞送短鏈核苷酸在活體內的分佈 58 | |
| dc.language.iso | zh-TW | |
| dc.subject | 基因治療 | zh_TW |
| dc.subject | 正價微脂體 | zh_TW |
| dc.subject | GEC-Chol | zh_TW |
| dc.subject | 短鏈核苷 | zh_TW |
| dc.subject | 酸 | zh_TW |
| dc.subject | oligonucleotides | en |
| dc.subject | gene therapy | en |
| dc.subject | Cationic liposmoes | en |
| dc.subject | EC-Chol | en |
| dc.title | 正價脂質奈米微粒與短鏈核苷酸複合體
在基因治療上的應用 | zh_TW |
| dc.title | Application of positively-charged lipid nanoparticles complexed with oligonucleotides in gene therapy | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 許金玉,丁詩同,陳敏慧 | |
| dc.subject.keyword | 正價微脂體,GEC-Chol,短鏈核苷,酸,基因治療, | zh_TW |
| dc.subject.keyword | Cationic liposmoes,EC-Chol,oligonucleotides,gene therapy, | en |
| dc.relation.page | 67 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2010-08-18 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
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