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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 沈麗娟(Li-Jiuan Shen) | |
dc.contributor.author | Wen-Heng Chen | en |
dc.contributor.author | 陳文衡 | zh_TW |
dc.date.accessioned | 2021-06-07T23:54:11Z | - |
dc.date.copyright | 2014-02-25 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-10-01 | |
dc.identifier.citation | 1. Stolnik S, Shakesheff K. Formulations for delivery of therapeutic proteins. Biotechnol Lett 2009;31:1-11.
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Gene expression profiling and differentiation assessment in primary human hepatocyte cultures, established hepatoma cell lines, and human liver tissues. Toxicol Appl Pharmacol 2007;222:42-56. 133. Sandberg R, Ernberg I. The molecular portrait of in vitro growth by meta-analysis of gene-expression profiles. Genome Biol 2005;6:R65. 134. Joshi D, Tsui J, Yu R, Shiwen X, Selvakumar S, Abraham DJ, Baker DM. Potential of Novel EPO Derivatives in Limb Ischemia. Cardiol Res Pract 2012;2012:213785. 135. Nairz M, Sonnweber T, Schroll A, Theurl I, Weiss G. The pleiotropic effects of erythropoietin in infection and inflammation. Microbes Infect 2012;14:238-46. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17036 | - |
dc.description.abstract | 近期在藥物開發的發展上,生物藥劑類的大分子藥物被開發比例佔了為數不少,日顯其角色之重要性。紅血球生成素 (erythropoietin, EPO)為目前被普遍運用於臨床上的生物製劑。臨床上用在治療因慢性腎病、化療、放射性治療和懷孕所引起的貧血。近期,EPO更被發現具有組織保護的性質,它能在一些受到外力壓迫的組織的周圍被合成出來並且引發多重的機轉來抑制活細胞的凋亡進而保護組織,包含腦組織。但值得注意的是,由於血腦障壁的障礙使得EPO作為一個神經保護劑必須持續使用遠高於一般治療貧血的劑量,而引發造成血栓副作用的結果。
因此,為了突破EPO作為神經保護劑臨床運用的限制,發展一個藉由修飾或模擬紅血球生成素EPO具備組織保護性,但不具血球生成性的生物製劑為必要趨勢。本研究,欲建立製備EPO次單元helix B的helix B surface peptide (HBSP)胜肽,以具專一反應端之連結子修飾鍵結的製備系統。 固相胜肽合成法,為一個成熟發展的製備方法。於本研究第一部分,本實驗建構方法合成出目標胜肽HBSP,為避免序列胺基酸glutamine自行環化,使HBSP產物為單一結構,我們於N-terminal多增加一個glycine修飾,因此實際合成產物為GHBSP。並且,利用分析級與半製備級Jupiter proteo C12管柱,以0.1 % TFA (trifluoroacetic acid) in water 與 0.1% TFA in acetonitrile作移動相跑濃度梯度,UV吸收215 nm、流速各別為1與4 mL/min作為高效液相層析法 (high-performance liquid chromatography ,HPLC)之系統來分離與純化製備GHBSP,並搭配ESI-MASS (electrospray ionization mass spectrometry)作定性分析。之後,使用水溶性Sulfo-SMPB (sulfosuccinimidyl 4-[p-maleimidophenyl]butyrate)與非水溶性 GMBS (N-[γ-maleimidobutyryloxy]succinimide ester)之兩種連結子鍵結修飾GHBSP。最後部分,我們利用Neuro-2A (老鼠腦神經癌細胞)細胞株作為給藥物目標和staurosporine作為引發細胞毒性的試劑,並以MTT (3-[4,5-dimethylthylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay與PI (propidium iodide)-stain 評估細胞存活率與細胞凋亡而建立神經細胞損傷的模式。 製備系統的條件開發結果發現,以本實驗室建立之固相胜肽合成法以0至20 min:移動相0.1% TFA in acetonitrile: 10%-25%的濃度梯度,能作為分離至純化製備高純度GHBSP胜肽的製備條件。而使用非水溶性GMBS能於DMF有機溶媒相中,室溫下反應2小時,能成功鍵結修飾GHBSP胜肽。最後於細胞存活率與細胞凋亡實驗結果得知,皆事先對Neuro-2A細胞株投與不同濃度的GHBSP胜肽,並不能降低對不同濃度staurosporine所引發的細胞毒性與凋亡。 總結而論,我們成功建立本實驗室建立固相胜肽合成法的合成系統,並搭配HPLC與ESI-MASS合成出高純度之目標胜肽-GHBSP胜肽。於有機溶媒反應相,能以非水溶性具專一反應端之連結子GMBS成功鍵結修飾GHBSP胜肽,而形成具與與硫醇基 (thiol group)專一反應端的胜肽。然而GHBSP胜肽面對staurospoirne於Neuro-2A神經細胞株所引起的細胞毒性與細胞凋亡的體外試驗,並無展現神經保護的活性,其原因仍需未來更進一步的研究。 | zh_TW |
dc.description.abstract | The increasing amount of biological pharmaceutical research and development over the past years has led us to see its importance in the drug developing . Erythropoietin (EPO) is a biological pharmaceutical agent, clinically used for the treatment of anemia induced by chronic kidney disease (CKD), chemotherapy, radiotherapy and pregnancy. In more recent years, EPO has been reported of its tissue-protective effects. EPO can be synthesized locally by many tissues in response to metabolic stress, triggering multiple mechanisms of tissue protection, including brain tissue protection. However, because EPO cannot cross the blood brain barrier, the clinical dosages used for EPO as a neuro-protection agent are much higher than needed for treating anemia; which raises concerns about the thrombosis side effects.
Therefore, development of a neuro-protective EPO analogue lacking the erythropoietic activity is needed, to solve the limitations of EPO as neuro-protection agent in clinical application. helix B surface peptide (HBSP) is a neuro-protective EPO mimetic, derived from the helix B of EPO. In this study, we would like to establish a preparation system for a HBSP, and modify this peptide with site-specific reaction linkers. Solid phase peptide synthesis is a well-developed technology in peptides synthesis. Firstly, we used this technique to synthesize the HBSP peptide, modifying an additional glycine at the peptide N-terminal (GHBSP) to avoid glutamine spontaneously undergoing cyclization. Secondly, we used a high-performance liquid chromatography (HPLC) system to prepare and purify GHBSP peptide. The solid phase was Jupiter proteo C12 column; the mobile phase included water containing 0.1 % TFA (trifluoroacetic acid) and acetonitrile containing 0.1 % TFA in a gradient program, flow rate at 1 and 4 mL/min; UV detection was at 215 nm. Afterwards, we did qualitative analysis by electrospray ionization mass spectrometry (ESI-MASS). Subsequently, the GHBSP peptide was modified by a water-soluble linker, sulfo-SMPB (sulfosuccinimidyl 4-[p-maleimidophenyl] butyrate) and a water-unsoluble linker, GMBS (N-[γ-maleimidobutyryloxy]succinimide ester). Finally, we choose the mouse brain neuroblastoma cell line (Neuro-2A) for in vitro neuro-protection model, using MTT (3-[4,5-dimethylthylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay and PI (propidium iodide)-stain cell to estimate cell toxicity and apoptosis. Preparation results of our study showed that we could prepare high purity of GHBSP peptide in gradient program (0-20 min, 10 %-25 % acetonitrile containing 0. 1 % TFA). Keeping reaction under room temperature for 2 hours would successfully modify GHBSP with GMBS linker in DMF (N,N-Dimethylformamide) organic solvent. However, the results of MTT assay and PI-stain indicated that pre-treatment with different concentrations of GHBSP peptide could not affect the level of staurosporine induced cell toxicity and apoptosis in Neuro-2A cell line. In conclusion, we have established a solid phase peptide synthesis system for the synthesis of GHBSP in our laboratory, and produced high purity of GHBSP peptide, using HPLC and ESI-MASS. We also achieved peptide conjugation by a thiol-targeted, site-specific reaction to water-unsoluble GMBS linker in organic solvent. However, the GHBSP peptide showed no neuro-protection against staurosporine induced cell toxicity and apoptosis in Neuro-2A cell line. Further studies may be needed to investigate the lack of neuro-protection. | en |
dc.description.provenance | Made available in DSpace on 2021-06-07T23:54:11Z (GMT). No. of bitstreams: 1 ntu-102-R00423006-1.pdf: 1984687 bytes, checksum: c0ab8da47959ee9b05002c58893e6292 (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 目錄
圖目錄 iv 表目錄 v 縮寫表 vi 中文摘要 vii Abstract ix 第一章 緒論 1 1.1生物製劑的發展 1 1.1.1紅血球生成素的臨床運用與限制 1 1.1.2擬紅血球生成素生物製劑的開發 2 1.2大分子藥物的遞送策略 4 1.2.1細胞穿透胜肽 (cell-penetrating peptide, CPP) 5 1.2.2連結子 (linker)的鍵結修飾 5 1.3固相胜肽合成法(solid phase peptide synthesis, SPPS) 6 第二章 實驗目的 8 第三章 實驗材料與方法 10 3.1實驗材料 10 3.1.1細胞培養 10 3.1.2胜肽合成與製備 12 3.1.3連結子之鍵結反應 14 3.1.4細胞存活與凋亡分析 14 3.2細胞培養 15 3.3合成擬紅血球生成素胜肽GHBSP 15 3.3.1固相胜肽合成法 15 3.3.2定性分析 16 3.4高效液相層析純化與製備 16 3.4.1純化與製備條件 17 3.4.2定性分析 17 3.4.3純度分析 18 3.4鍵結連結子與GHBSP胜肽 19 3.4.1反應條件 19 3.4.2純化 19 3.4.3定性分析 19 3.5生物活性分析 20 3.5.1細胞存活實驗 20 3.5.2細胞凋亡實驗 20 3.6統計分析 21 第四章 實驗結果 22 4.1固相胜肽合成法合成系統的建立 22 4.2開發完成高純度GHBSP胜肽分離與製備條件 22 4.3最佳化連結子鍵結修飾之反應條件 23 4.4 GHBSP胜肽的生物活性 24 4.4.1細胞存活實驗 24 4.4.1細胞凋亡實驗 25 第五章 討論 26 5.1影響固相胜肽合成法產率的因素 26 5.2影響連結子鍵結修飾的條件 27 5.3序列修飾對GHBSP的影響 27 5.4生物活性的測定模式 28 5.5本研究的實驗限制 30 第六章 結論 31 第七章 參考文獻 55 圖目錄 圖 1. 固相胜肽合成法(solid phase peptide synthesis)之原理圖 32 圖 2. 合成產物定性分析ESI-MASS spectrometry之圖譜 33 圖 3. GHBSP胜肽的高效液相層析分離圖譜(以第二批次為例) 34 圖 4. 目標產物-GHBSP胜肽定性分析ESI-MASS spectrometry之圖譜 35 圖 5. 以LC-MASS針對合成樣品中目標產物-GHBSP定性分析之圖譜 36 圖 6. GHBSP胜肽運用高效液相層析製備之圖譜(以第二批次為例) 37 圖 7. 第一批GHBSP胜肽之純度分析 38 圖 8. 第二批GHBSP胜肽之純度分析 39 圖 9. sulfo-SMPB連結子之反應式 40 圖 10. GMBS連結子之反應式 41 圖 11. 以Sulfo-SMPB鍵結修飾產物定性分析ESI-MASS spectrometry之圖譜 42 圖 12. 以GMBS鍵結修飾產物定性分析ESI-MASS spectrometry之圖譜 43 圖 13. 不同濃度GHBSP胜肽對Neuro-2A細胞株存活率之影響I 44 圖 14. 不同濃度GHBSP胜肽對Neuro-2A細胞株存活率之影響II 45 圖 15. 不同濃度GHBSP胜肽對不同濃度staurosporine引起Neuro-2A細胞株細胞毒性之影響-I 46 圖 16. 不同濃度GHBSP胜肽對不同濃度staurosporine引起Neuro-2A細胞株細胞毒性之影響-II 47 圖 17. 不同濃度GHBSP胜肽對高濃度100 nM staurosporine引起Neuro-2A細胞株細胞凋亡之影響 49 圖 18. 不同濃度GHBSP胜肽對低濃度30 nM staurosporine引起Neuro-2A細胞株細胞凋亡之影響 51 表目錄 表 1. 合成產物以氮氣作為霧化氣流ESI-MASS spectrometry之定性分析條件 52 表 2. 目標產物-GHBSP胜肽以氮氣作為霧化氣流ESI-MASS spectrometry之定性分析條件 52 表 3. 以氮氣作為霧化氣流之LC-MASS針對合成樣品中目標產物-GHBSP定性分析條件 53 表 4. 以氮氣作為霧化氣流之ESI-MASS spectrometry針對使用Sulfo-SMPB鍵結修飾產物的定性分析條件 53 表 5. 以氮氣作為霧化氣流之ESI-MASS spectrometry針對使用GMBS鍵結修飾產物的定性分析條件 54 | |
dc.language.iso | zh-TW | |
dc.title | 以具專一反應端之連結子修飾神經保護性擬血球生成素胜肽之製備系統 | zh_TW |
dc.title | A preparation system for a neuroprotective erythropoietin mimetic peptide modified with site-specific reaction linkers | en |
dc.type | Thesis | |
dc.date.schoolyear | 102-1 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 梁碧惠,郭錦樺 | |
dc.subject.keyword | 固相胜?合成,紅血球生成素,HBSP,連結子,神經保護性, | zh_TW |
dc.subject.keyword | solid phase peptide synthesis,erythropoietin,HBSP,linker,neuro-protection, | en |
dc.relation.page | 70 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2013-10-01 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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