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研究生:鄭意靜
研究生(外文):Cheng, Yi-Jing
論文名稱:經由電漿施打的水溶液作為肺癌併發惡性肋膜積水的輔助治療
論文名稱(外文):Plasma-activated Medium as Adjuvant Therapy on Lung Cancer Malignant Pleural Effusion
指導教授:鄭雲謙
指導教授(外文):Cheng, Yun-Chien
口試委員:吳宗信麥如村
口試委員(外文):Wu, Jong-ShinnMai, Ru-Tsun
口試日期:2018-08-24
學位類別:碩士
校院名稱:國立交通大學
系所名稱:機械工程系所
學門:工程學門
學類:機械工程學類
論文種類:學術論文
論文出版年:2018
畢業學年度:107
語文別:中文
論文頁數:58
中文關鍵詞:低溫常壓電漿肺腺癌細胞非癌細胞癌症治療
外文關鍵詞:non-thermal atmospheric-pressure plasma jets (NTAPPJ)adenocarcinoma cellnon-cancer cellcancer therapy
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近研究顯示,低溫常壓電漿系統(Non-thermal atmospheric pressure plasma jet, NTAPPJ)可誘發腫瘤細胞凋亡而對正常細胞之影響小,是全世界癌症治療研究者致力發展的目標與未來生醫研究重要趨勢。本研究將整合電漿工程與生物醫學,運用在治療惡性肋膜積水上作為一個輔助療程。
由於肺腺癌合併肋膜轉移會在轉移處有局部病變,導致肋膜積水而壓迫正常肺組織,使患者產生呼吸困難症狀。過去被視為後期疾病,無法手術根治,且患者存活率低。傳統上,給予患者肋膜積水引流或以肋膜沾黏術減少肋膜積液產生等緩和治療為主,近年來新的醫療技術發明,熱化學肋膜腔灌注治療(Intrapleural perfusion hyperthermo-chemotherapy)及光動力療法(Photodynamic therapy)對肋膜腫瘤之控制及患者存活率有一定的提升,但對周遭之正常組織仍有一定的影響及全身的副作用,所以需找尋更安全的治療方式。本研究使用NTAPPJ可望解決此問題,研究顯示電漿與其施打過的水溶液(Plasma-activated medium, PAM)中含活性氧/氮化物質(Reactive oxygen/nitrogen species, RONS)迫使癌細胞自然凋亡,且含ROS和RNS存在時間短,相較於化療、放療對人體傷害更小。
實驗架設NTAPPJ系統並施打培養基(Roswell Park Memorial Institute medium, RPMI medium),量測PAM裡的RONS,並將PAM處理細胞,隨後量測細胞的活性、增殖、遷移能力。實驗初步結果顯示,隨著電漿的施打時間增加,PAM裡的RONS濃度會增加。另外,在細胞活性、增殖、遷移能力檢測裡,肺腺癌細胞對PAM的敏感度較非癌細胞高,且隨著PAM濃度上升,兩者活性明顯拉大。綜合以上的結果,將PAM應用在治療肺癌併發肋膜積水上是可期待的。
Recent studies show that non-thermal atmospheric pressure plasma jet (NTAPPJ) can cause selective apoptosis of tumor cells, which becomes a prospective tendency in cancer treatment. The interdisciplinary research, including plasma engineering and biomedical research, is expected to provide an adjuvant therapy on lung cancer with malignant pleural effusion (MPE).
Local lesion of adenocarcinoma cancerometastasis leads to inflammatory exudate infiltrating through pleura into chest. Due to lung under the compression of pleural effusion, patients developed dyspnea, chest pain, and cough. In the past, MPE associated lung adenocarcinoma was regarded as terminal cancer, meaning that there was no radical treatment and that survival rate was low. Traditionally, patients underwent palliative treatment, such as serial thoracentesis, pleural catheter, and pleurodesis. Along with ever-changing technology, new tools, like intrapleural perfusion hyperthermo-chemotherapy and photodynamic therapy (PDT), can inhibit tumor growth and improve survival rate. Nevertheless, they have an impact on surrounding healthy tissue or cause systemic side effects. As a result, another way to cure lung cancer with MPE is needed, and plasma medicine is preferred. Studies have shown that reactive oxygen/nitrogen species (RONS) of NTAPPJ and plasma-activated medium (PAM) induce tumor cells apoptosis and have short half-life. Comparing it with chemotherapy and radiation therapy, plasma medicine is harmless to patients.
In the experiment, first and foremost, NTAPPJ system was set up and RPMI medium was treated with NTAPPJ. Then, RONS in PAM were detected. Last but not least, the cells were treated with PAM and their activity, proliferation and migration ability were measured. The preliminary results of the experiment showed that as the plasma application time increases, the concentration of RONS in the PAM increases with increasing plasma treatment time. Further, in the cell viability, proliferation, and migration assay, the lung adenocarcinoma cells were more sensitive to PAM than non-cancer cells. Based on the above results, the application of PAM in the treatment of lung cancer with MPE can be expected soon.
第一章、緒論 1
1.1.2 低溫常壓電漿簡介 1
1.1.3 活性氧/氮化物質對細胞之影響 2
1.1.5 非癌細胞簡介 3
1.1.6 化療(Chemotherapy)與標靶藥物治療(Targeted therapy) 3
1.1.7 胸腔放液穿刺術(Thoracentesis)與胸腔導管引流(Pleural catheter) 4
1.1.8 胸膜沾黏術(Pleurodesis) 4
1.1.9 熱治療結合化療藥物(Intrapleural perfusion hyperthermo-chemotherapy) 5
1.1.10 光動力療法(Photodynamic therapy) 5
1.2 文獻回顧 6
1.2.1 PAM透過降低生存信號分子(AKT激酶)對殺死膠質母細胞腦瘤細胞(Glioblastoma brain tumor cell)具有選擇性 6
1.2.2 在含有過氧化氫和/或亞硝酸鹽的培養基中或在電漿施打過後的培養基中對膠質細胞瘤的細胞存活之探討 6
1.4 論文架構 8
第二章、實驗原理與檢測儀器 9
2.2 光譜分析儀(Optical emission spectroscopy, OES) 10
2.3 酵素免疫分析儀(Enzyme-linked immuno-sorbent assay reader, ELISA reader) 10
2.4 水溶液中RONS量測 11
2.4.1 氫氧自由基量測 11
2.4.2 過氧化氫量測 12
2.4.3 亞硝酸根量測 13
2.5 細胞檢驗 14
2.5.1 細胞活性檢測 14
2.5.2 細胞增殖檢測 14
2.5.3 細胞遷移檢測 14
2.6 腫瘤微環境之蛋白質檢驗 14
2.6.1 生長因子FGF-1檢測 14
第三章、實驗方法 16
3.1 細胞取得與培養 16
3.2 低溫常壓氬氣電漿設備與實驗參數 17
3.3 實驗流程 19
3.4 量測實驗 20
3.4.1 光譜分析儀(OES) 20
3.4.2 水溶液中RONS量測 21
3.5 細胞檢驗 27
3.5.1 細胞活性檢測 27
3.5.2 細胞增殖檢測 28
3.5.3 細胞遷移檢測 29
3.6 臨床應用 29
3.6.1 不同電漿施打時間的PAM對細胞不同作用時間的比較 29
3.6.2 PAM與熱治療結合化療藥物的比較 30
3.7 腫瘤微環境之蛋白質檢測 30
3.7.1 生長因子FGF-1檢測 30
第四章、實驗結果與討論 32
4.3 水溶液中RONS量測 34
4.3.1 氫氧自由基量測 34
4.3.2 過氧化氫量測 35
4.3.3 亞硝酸根量測 37
4.4 細胞分析 38
4.4.1 細胞活性分析 38
4.4.2 細胞的形態變化 40
4.4.3 細胞增殖分析 41
4.4.4 細胞遷移分析 43
4.4.5 不同種細胞的活性分析 46
4.5 臨床應用 48
4.5.1 不同電漿施打時間的PAM對癌細胞不同作用時間的比較 48
4.5.2 PAM與熱治療結合化療藥物的比較 49
4.6 腫瘤微環境之蛋白質檢測 50
4.7 實驗總結與討論 50
第五章、結論與未來研究內容 52
5.1 結論 52
5.2 未來研究內容 53
參考文獻 54
附錄 57
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