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研究生:薛家雯
研究生(外文):Chia-Wen Hsueh
論文名稱:探討參雜鈰或銪的碳酸鈣於聲動力療法上對於癌症治療之效果
論文名稱(外文):Using CaCO3 doped with Ce or Eu-mediated Sonodynamic Therapy (SDT) for Cancer Treatment
指導教授:林峯輝
指導教授(外文):Feng-Huei Lin
口試日期:2017-06-16
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:醫學工程學研究所
學門:工程學門
學類:綜合工程學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:58
中文關鍵詞:超音波聲致發光自由基參雜鈰碳酸鈣參雜銪碳酸鈣
外文關鍵詞:ultrasoundsonoluminescencefree radicalscerium-doped calcium carbonateeuropium-doped calcium carbonate
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聲動力療法是以超音波為激發源來激發聲敏感藥物從而達到治療癌症的目的。當聲敏 感藥物於超音波作用之下,隨著聲波的震盪會發生超音波空化效應,於此同時往往伴隨著大 量的能量並以光的形式釋放,此放射現象稱為聲致發光(Sonoluminescence),進而激發藥物 並產生自由基與活性氧族來毒殺癌細胞。相較於其他癌症治療方法,聲動力療法的副作用較 低、過程較不具侵入性且超音波的裝置簡單成本較低,除此之外,其也克服了光動力療法在 穿透深度上的限制。本研究將會使用具有脈衝性質的方波來激發材料。在材料方面,是以具 有好的生物相容性與低生物毒性之碳酸鈣為主體材料,並參雜具發光性質之稀土族元素:鈰 或銪,作為本研究欲激發的聲敏感藥物。期望此材料經超音波激發後得以產生自由基與活性 氧族來毒殺癌細胞達到治療癌症的效果。
利用含有硝酸鈰或硝酸銪的硝酸鈣溶液與含有 PVA 與 Tween 80 之碳酸鈉溶液合成製備 參雜鈰或銪碳酸鈣,PVA 與 Tween 80 的添加可使材料形成多孔狀來增加表面積並加快反應 速率。材料分析方面,利用 XRD 確認材料主要為碳酸鈣的球霰石相(Vaterite),於 SEM 下 來看,參雜鈰的碳酸鈣顆粒大小約 2-4 μm,孔洞大小約 0.5-1 μm 左右;而參雜銪的碳酸鈣顆 粒大小約 3-5 μm,孔洞大小約 1 μm 左右。並以 EDX 確認材料參有鈰與銪,接著利用亞甲基 藍可降解的反應確認自由基的產生。
經 WST-1 及 LHD 測試,其結果符合 ISO10993 之規範,證明兩種材料皆具好的生物相容 性。在體外試驗結果中,兩種材料的聲動力療法組別相較於單照射超音波組別或純材料組別, 對癌細胞都有明顯的毒殺效果。在動物實驗方面,小鼠在實驗過程中皆具正常之動物行為, 從結果來看,每個組別的小鼠腫瘤皆呈現增大的趨勢,而兩種材料的聲動力療法組別增大的 趨勢較為緩慢,說明其具有抑制腫瘤增大的效果。
Sonodynamic therapy is a potential modality for the cancer treatments, which uses ultrasound to excite the sonosensitizers to kill the cancer cells. The treated sonosensitizers will have ultrasound cavitation effects and cause to an amount of energy which will lead to the generation of light, and this emission is termed as sonoluminescence. It further induce free radicals and reactive oxygen species to kill the cancer cells. Comparing with the other treatments, SDT is less invasive, its apparatus is so simple that having less cost and it also lowers the side effects, moreover, it has better ability of penetration in our body than light as a result of being able to treat deeply located cancers. As for the used ultrasound, instead of the utilization of the continuous sine wave that are common in sonodynamic therapy, the square wave having pulsed property will be chosen in this research due to the better cavitation ability in pulsed ultrasound. About the sonosensitizers used in this research, we used calcium carbonate that has good biocompatibility and no bio-cytotoxicity as the host material, and doped with the rare-earth elements: cerium or europium which has remarkable luminescent properties. We hope that the prepared sonosensitizers will be successfully induced ROS and free radicals by ultrasound to kill the cancer cell as the excellent and developed alternative treatment of cancer.
Spherical porous cerium-doped or europium-doped calcium carbonate have been successfully synthesized by adding calcium nitrate including cerium nitrate or europium nitrate into sodium carbonate with PVA and Tween 80. The existence of PVA and Tween 80 will help materials be porous phase to enhance the rate of reaction. As for the analysis of materials, we used XRD to confirm the synthesized materials is mainly composed of the vaterite which is one of the phase of calcium carbonate. Under the SEM, the particle size of cerium-doped calcium carbonate is about 2-4 μm, and the size of the holes is about 0.5-1 μm; while the particle size of the europium-doped calcium carbonate is about 3-5 μm, and the size of hole is about 1 μm. After that, using the EDX to confirm that the materials are prospectively doped with cerium or europium. Finally, the generation of the free radicals was detected through the methylene blue test.
Through ISO10993 WST-1 and LDH test, both of materials are shown to be biocompatible. And the cancer cells killing in sonodynamic therapy group is significantly effective from the view of the result in in-vitro test. We also get the similar result in the in-vivo study, the tumor size in each group all enlarge in the end of the experiment, however, that of the sonodynamic therapy group get increasing slightly.
目錄
口試委員會審定書……………………………………………………………… i
誌謝……………………………………………………………………………… ii
中文摘要………………………………………………………………………….. iii
英文摘要………………………………………………………………………….. iv
目錄……………………………………………………………………………… vi
圖目錄……………………………………………………............................. x
表目錄…………………………………………………………………………… xii
公式目錄………………………………………………………………………… xii
附錄……………..……………………………………………………………… xii
名詞縮寫目錄…………………………………………………………………… xii
第一章 序論…………………………………………………………………….. 1
1.1 前言…………………………………………………………………….. 1
1.2 癌症…………………………………………………………………….. 2
1.3 治療方法……………………………………………………………….. 3
1.3.1 手術 (Surgery) ………………………………………………….. 3
1.3.2 化學療法 (Chemotherapy).……………………………………… 3
1.3.3 放射線療法 (Radiation therapy) ………………………………... 3
1.3.4 免疫療法 (Immunotherapy) …………………………………….. 4
1.3.5 熱治療 (Hyperthermia) ……………………………………..….... 4
1.3.6 光動力療法 (Photodynamic therapy) …………………………… 5
1.3.7 聲動力療法 (Sonodynamic therapy) ……………………………. 5
1.4 聲動力療法……………………………………………………………… 5
1.4.1 超音波 (Ultrasound)………………………………………….. 5
1.4.2 聲敏感藥物(Sonosensitizers)…………………………………. 7
1.5 研究目的………………………………………………………………… 7
第二章 理論基礎……………………………………………………………….. 9
2.1 聲動力療法之機制……………………………………………………… 9
2.1.1 超音波空化效應 (Ultrasound cavitation)………………………… 9
2.1.2 聲化學物質 (Sonochemical effects)……………………………… 10
2.1.3 超音波誘導細胞凋亡 (Ultrasound-induced apoptosis)…..... 10
2.2 材料-參雜銪和鈰之碳酸鈣…………………………………………….. 12
2.2.1 主體材料-碳酸鈣………………………………………………… 12
2.2.2 稀土元素-銪和鈰………………………………………………… 12
2.3 細胞吞噬作用(Phagocytosis)…………………………………….. 13
第三章 實驗方法………………………………………………………………. 14
3.1 實驗儀器………………………………………………………………... 14
3.2 實驗藥品………………………………………………………………... 15
3.3 實驗架構………………………………………………………………... 16
3.4 材料製備與分析………………………………………………………... 17
3.4.1 材料製備方法……………………………………………………. 17
3.4.2 X光繞射分析儀…………………………………………………. 17
3.4.3 掃描式電子顯微鏡………………………………………………. 18
3.4.4 能量散射光譜分析儀……………………………………………. 19
3.4.5 亞甲基藍測試……………………………………………………. 19
3.5 生物相容性試驗………………………………………………………... 20
3.5.1 細胞培養…………………………………………………………. 20
3.5.2 材料萃取液之製備………………………………………………. 21
3.5.3 WST-1 細胞活性………………………………………………… 21
3.5.4 LDH 細胞毒性…………………………………………………… 22
3.6 超音波裝置……………………………………………………………... 23
3.7 體外實驗……………………………………………………………....... 24
3.7.1 WST-1 細胞活性………………………………………………… 24
3.7.2 LDH 細胞毒性…………………………………………………… 24
3.7.3 細胞形貌之觀察.………………………………………………… 25
3.7.4 Live & Death測試……………………………………………….... 25
3.8 動物實驗………………………………………………………………... 26
3.8.1有效性試驗………………………………………………………... 26
3.8.2安全性試驗………………………………………………………... 27
第四章 結果與討論……………………………………………………………. 28
4.1 材料分析………………………………………………………………... 28
4.1.1 X光繞射分析……………………………………………………... 28
4.1.2 材料表面型態分析………………………………………………. 29
4.1.3 材料成分分析……………………………………………………. 30
4.1.4 自由基生成測試…………………………………………………. 31
4.2 生物相容性……………………………………………………………... 32
4.2.1 WST-1細胞活性測試……………………………………………. 32
4.2.2 LDH 細胞毒性測試……………………………………………… 32
4.3 體外試驗……………………………………………………………… 34
4.3.1 WST-1 細胞活性………………………………………………… 34
4.3.2 LDH 細胞毒性…………………………………………………… 34
4.3.2細胞形貌之觀察...………………………………………………… 34
4.3.3 Live & Death測試………………………………………………... 37
4.4 動物實驗……………………………………………………………….. 40
4.4.1 體重變化…………………………………………………………. 40
4.4.2 腫瘤大小變化……………………………………………………. 40
4.4.3 組織切片分析……………………………………………………. 45
4.4.4 血清分析…………………………………………………………. 52
第五章 總結……………………………………………………………………. 53
參考文獻…………………………………………………………………….…… 54
附錄ㄧ……………………………………………………………………….…… 58
圖目錄
圖 1-1 民國104年十大死因…………………………………………………….. 1
圖 1-2 西元2012年世界十大死因……………………………………………… 2
圖 1-3 腫瘤示意圖……………………………………………………………….. 2
圖 1-4 超音波各頻率之醫療應用……………………………………………….. 6
圖 2-1 超音波空化效應………………………………………………………….. 9
圖 2-2 聲化學物質的產生…………………………………………………….... 10
圖 2-3 超音波誘導細胞凋亡…………………………………………………… 11
圖 2-4 鈣離子誘導細胞凋亡…………………………………………………. 11
圖 2-5 能階轉換圖……………………………………………………………. 12
圖 2-6 螢光粉示意圖…………………………………………………………. 13
圖 2-7 內噬作用之不同型態...…………………………………………………. 13
圖 3-1 實驗架構與流程圖…………………………………………………...... 16
圖 3-2 材料合成示意圖……………………………………………………...... 17
圖 3-3 布拉格定律……………………………………………………………. 18
圖 3-4 能量散射光譜分析示意圖……………………………………………. 19
圖 3-5 測定吸光值之示意圖…………………………………………………. 20
圖 3-6 WST-1試劑反應示意圖…………………………………………………. 21
圖 3-7 LDH試劑反應示意圖…………………………………………………. 22
圖 3-8 超音波裝置架設圖……………………………………………………. 23
圖 3-9 LIVE/DEATH試劑作用機制……………………………………………. 26
圖 4-1參雜鈰的碳酸鈣與參雜銪的碳酸鈣之X光繞射圖譜……………… 28
圖 4-2 以SEM觀察參雜鈰的碳酸鈣………………………………………….. 29
圖 4-3 以SEM觀察參雜銪的碳酸鈣………………………………………….. 29
圖 4-4 EDS 對參雜鈰的碳酸鈣之分析圖譜及元素組成百分比……… 30
圖 4-5 EDS 對參雜銪的碳酸鈣之分析圖譜及元素組成百分比………… 30
圖 4-6 亞甲基藍測試…………………………………………………………… 31
圖 4-7 生物相容性之細胞活性測試………………………………..………... 32
圖 4-8 生物相容性之細胞毒性測試………….………………..……………... 33
圖 4-9 體外試驗-細胞活性測試………………………………………………... 34
圖 4-10 體外試驗-細胞毒性測試………………………………………………. 35
圖 4-11 施予超音波前細胞型態……………………………………………... 36
圖 4-12 LIVE/DEATH螢光染色圖..…………………………………………... 38
圖 4-13 活細胞定量分析圖…………………………………………………... 39
圖 4-14小鼠體重變化百分比圖………………………………………………... 40
圖 4-15 控制組之腫瘤大小外觀紀錄...……………………………….……... 41
圖 4-16參雜鈰碳酸鈣組之腫瘤大小外觀紀錄……………………………... 41
圖 4-17參雜銪碳酸鈣組之腫瘤大小外觀紀錄……………………………... 42
圖 4-18純超音波組之腫瘤大小外觀紀錄…………………………………... 42
圖 4-19參雜鈰碳酸鈣聲動力療法組之腫瘤大小外觀紀錄……………... 43
圖 4-20參雜銪碳酸鈣聲動力療法組之腫瘤大小外觀紀錄…………... 43
圖 4-21 小鼠腫瘤體積大小變化百分比圖...………………………………... 44
圖 4-22 心臟組織切片圖……………........…………………………………... 46
圖 4-23 肝臟組織切片圖……………........…………………………………... 47
圖 4-24 脾臟組織切片圖……………........…………………………………... 48
圖 4-25 肺臟組織切片圖……………........…………………………………... 49
圖 4-26 腎臟組織切片圖……………........…………………………………... 50
圖 4-27 腫瘤組織切片圖……………........…………………………………... 51 表目錄
表 1-1聲敏感藥物………………………………………………………………... 7
表 3-1 實驗儀器………………………………………………………………. 14
表 3-2 實驗藥品………………………………………………………………. 15
表 3-4動物實驗組別…………………………………………………………… 27
表 3-5血清生化分析…………………………………………………………… 52


公式目錄
式 1-1 超音波能量公式…...………………………………………………..…... 6
式 3-1 布拉格定律………...………………………………………………..…... 18
式 3-2 比爾定律………...………………………………………………………. 20
式 3-3 生物活性換算百分比公式……………………………………………. 21
式 3-4 生物毒性換算百分比公式……………………………………………. 22
式 3-5 腫瘤體積計算公式……………………...………………………………. 26

附錄
附錄一 ………………...………………………………………………………. 58
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