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研究生:劉忠翰
研究生(外文):Jhong-Han Liu
論文名稱:藥物劑量與復原時間影響光動力療法疫苗之功效的系統性研究
論文名稱(外文):Systematic Study of the Dependence of PDT Vaccine Efficacy on PDT Dosage and Recovering Time
指導教授:陳賜原
指導教授(外文):Szu-Yuan Chen
學位類別:碩士
校院名稱:國立中央大學
系所名稱:物理學系
學門:自然科學學門
學類:物理學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:中文
論文頁數:14
中文關鍵詞:光動力療法癌症疫苗外排體免疫原性細胞凋亡
外文關鍵詞:Photodynamic therapycancer vaccineexosomeimmunogenicity apoptosis
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光動力療法是近十年來癌症治療研究中一個很有潛力的領域,傳
統的光動力療法為:先將光敏化藥物注射至體內,在腫瘤區域照射對應
波段的光,激發光敏化藥物產生單態氧(singlet oxygen)以直接破壞腫瘤細胞。近期研究發現,體外培養癌症細胞或手術將活體內的腫瘤
細胞直接取出,在體外進行加藥及照光的步驟,可製作出癌症疫苗,
將此疫苗注射入體內會刺激免疫反應,進而達到治療和預防癌症的效果。

目前對於此疫苗激活免疫系統的機制尚未完全明朗,但研究指出
受刺激的細胞釋放熱休克蛋白70的量與疫苗效果呈正相關,另外,細
胞受到光動力療法刺激後會產生帶有熱休克蛋白70與癌細胞膜表面抗
體的外排體(exosome),此外排體上的熱休克蛋白70會吸引巨噬細胞吞
噬外排體並釋放TNF-α。

本實驗旨在使用mouse lewis lung carcinoma(LL/2)癌症細胞與chlorin e6 (Ce6)光敏化藥物製備癌症疫苗,研究改變不同Ce6劑量與光動力療法處理後的等待時間對於癌症細胞表現熱休克蛋白70的改變,以最佳化疫苗的效果。並藉由收集外排體誘導巨噬細胞釋放TNF-α以驗證疫苗刺激免疫反應的效果。
Over past decade, Photodynamic therapy(PDT) is one of most potential way in cancer research. In classic PDT, photosensitizer(PS) is injected into tumor region, then expose to specic wavelength of light to excite PS to induce singlet oxygen dealing damage directly on tumor cell. Recent study shows that treating PDT on surgical resection tumor or culture tumor cell ex-vivo make cancer vaccine which stimulate immune system to cure and prevent caner.

The mechanism of PDT-treated vaccine is not clear, but research shows that the level of heat shock protein 70(hsp70) expression in cancer cell after PDT treated is correlate with their immunogenicity. In addition, after PDT treated, cancer cell release exosome, a kind of membrane-bound nanovesicle, induce macrophage to release TNF-α as an indicator of macrophage activation.

In this research, we choose mouse lewis lung carcinoma and chlorin e6 to develop cancer vaccine. We change concentration of Ce6 and recovering time after PDT to optimize vaccine by detecting cell surface hsp70, and induce macrophage release TNF-α by exosome to test immunogenicity of vaccine.
中文摘要................................................. i
英文摘要............................................... ii
謝誌.......................................... iii
目錄................................................................................................. iv
圖目錄.............................................................................................. v
一、緒論............................................................................ 1
二、材料與實驗方法.......................................................... 3
2.1 細胞培養. . . . . . . . . . . . . . . . . . . . . . . 3
2.2 光動力療法. . . . . . . . . . . . . . . . . . . . . . 3
2.3 光動力疫苗製備流程. . . . . . . . . . . . . . . . . 4
2.4 細胞表面hsp70量測. . . . . . . . . . . . . . . . . . 4
2.5 細胞表面hsp70量測流程. . . . . . . . . . . . . . . 4
2.6 細胞存活率量測流程. . . . . . . . . . . . . . . . . 5
2.7 由TNF-α檢測免疫反應效果. . . . . . . . . . . . . 5
2.8 Exosome製備. . . . . . . . . . . . . . . . . . . . . 5
2.9 TNF-α誘導與溶液製備. . . . . . . . . . . . . . . 6
2.10 TNF-α ELISA量測. . . . . . . . . . . . . . . . . 6
三、結果與討論................................................................. 7
3.1 不同Ce6劑量的光動力療法誘導hsp70的變化. . . . 7
3.2 不同復原時間下光動力療法誘導hsp70的變化. . . . 8
3.3 疫苗外排體誘導巨噬細胞產生TNF-α量測. . . . . 9
四、結論與未來展望..........................................................10
4.1 結論. . . . . . . . . . . . . . . . . . . . . . . . . . 10
4.2 未來展望. . . . . . . . . . . . . . . . . . . . . . . 10
文獻.................................................................................................12
附錄一..............................................................................................14
[1] Mladen Korbelik. Cancer vaccines generated by photodynamic therapy. Photochem. Photobiol. Sci., 10(5):664{669, 2011.
[2] Sandra O Gollnick, Lurine Vaughan, and Barbara W Henderson. Generation of eective antitumor vaccines using photodynamic therapy. Cancer research, 62(6):1604{1608, 2002.
[3] Mladen Korbelik and Jinghai Sun. Photodynamic therapy-generated vaccine for cancer therapy. Cancer Immunology, Immunotherapy, 55(8):900{909, 2006.
[4] Mladen Korbelik, Jinghai Sun, and Ivana Cecic. Photodynamic therapy{induced cell surface expression and release of heat shock proteins: relevance for tumor response. Cancer research,65(3):1018{1026, 2005.
[5] Xiaohong Chen, Qun Tao, Hai Yu, Lihuang Zhang, and Xuetao Cao. Tumor cell membrane-bound heat shock protein 70 elicits antitumor immunity. Immunology letters, 84(2):81{87, 2002.
[6] Virginia L Vega, Monica Rodrguez-Silva, Tiany Frey, Mathias Gehrmann, Juan Carlos Diaz, Claudia Steinem, Gabriele Multho, Nelson Arispe, and Antonio De Maio. Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. The Journal of Immunology, 180(6):4299{4307,2008.
[7] Huang-Ge Zhang and William E Grizzle. Exosomes: a novel pathway of local and distant intercellular communication that facilitates the growth and metastasis of neoplastic lesions. The American journal of pathology, 184(1):28{41, 2014.
[8] M Korbelik, B Stott, and J Sun. Photodynamic therapy-generated vaccines: relevance of tumour cell death expression. British journal of cancer, 97(10):1381{1387, 2007.
[9] Abhishek D Garg, Dmitri V Krysko, Peter Vandenabeele, and Patrizia Agostinis. Damps and pdt-mediated photo-oxidative stress:exploring the unknown. Photochemical &; Photobiological Sciences,10(5):670{680, 2011.
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