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標題: | 研發以EpCAM為標的之藥物傳輸系統運用於大腸癌之治療 Development of Anti-EpCAM Targeted Drug Delivery Systems for Treatment of Colon Cancer |
作者: | Tsung-Wei Hou 侯宗緯 |
指導教授: | 吳漢忠(Han-Chung Wu) |
關鍵字: | 大腸直腸癌,上皮細胞黏附因子及其細胞外域,噬菌體顯現法,標的胜?,單鏈抗體,藥物傳輸系統,微脂體藥物, colorectal cancer,EpCAM,EpEX,phage display,peptide,scFv,drug delivery systems,liposomal drug, |
出版年 : | 2014 |
學位: | 碩士 |
摘要: | 上皮細胞黏附因子 (EpCAM),屬第一型的穿膜醣蛋白,幾乎存在於所有的腺狀細胞癌及鱗狀上皮細胞癌並有高度的表現量。過去文獻顯示,此蛋白也出現在癌幹細胞中,並有助於腫瘤的生長。其中又以大腸直腸癌,擁有極高度的EpCAM表現量與高居首位的表現頻率。在我們先前的研究指出,EpCAM在大腸癌幹細胞中具有調節腫瘤細胞起始的能力,又與癌症的惡性程度有密切的相關性。因此在本研究中,我們利用噬菌體展現胜肽庫 (phage-displayed peptide library) 及嗜菌體呈現之人類單鏈抗體庫 (phage-displayed human naïve scFv library) 篩選出一些可以與上皮細胞黏附因子之細胞外域 (EpEX) 結合的新穎胜肽配體或單鏈抗體,並以酵素結合免疫吸附分析、流式細胞儀、免疫螢光法及活體內腫瘤導向分析,驗證與EpEX結合之專一性和結合強度。其次,將EpEX標的胜肽或單鏈抗體接於螢光微脂體上,發現能提升微脂體對大腸癌細胞結合和內化的效率。此外,利用結合標的胜肽與包覆癌症藥物之微脂體,治療異體移植大腸癌細胞的免疫缺陷老鼠,可得到較佳的腫瘤抑制效果及療效。綜觀上述結果,此標的胜肽具有作為標靶藥物傳輸系統、治療大腸癌之潛力,根據對於腫瘤細胞標的專一性及降低化療藥物對正常組織細胞之毒性,進而延長整體病人臨床存活率是可以被期待的。 Epithelial cell adhesion molecule (EpCAM) is a type I transmembrane glycoprotein overexpressed in almost all adeno and squamous cell carcinoma. It has also been shown that EpCAM is expressed on cancer stem cells and contributes to tumor growth. Colon cancer has the highest frequency of high-level EpCAM expression. Our previous study indicates that EpCAM plays an important role in regulating cancer-initiating abilities in colon cancer stem cells and is correlated with tumor malignancy. In this study, we used a phage-displayed peptide library and a human naïve scFv library to isolate two novel peptides and scFvs that bind to EpCAM's extracellular domain (EpEX). The specificity and binding affinity of EpEX-selected peptides and scFvs were confirmed by ELISA, flow cytometry, immunofluorescence and in vivo tumor homing assays. Next, conjugation of EpEX-specific peptides or scFvs to liposomal SRB can potentially improve binding and internalization efficiency of liposomes to colon cancer cells. Furthermore, the therapeutic index and the survival rates of mice bearing human colon cancer xenografts treated with liposomal doxorubicin or vinorelbine were increased significantly by conjugating EpEX-specific peptide to the liposomal drug. These results revealed the potential benefit of EpEX-specific peptide at enhancing the therapeutic efficacy of targeted drug delivery in the treatment of colon cancer. According to afford tumor specificity and limitless toxicity for normal tissues, prolonging the survival of the patient in clinical scenarios is expected. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/16797 |
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顯示於系所單位: | 口腔生物科學研究所 |
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