臺灣博碩士論文加值系統

光動力療法 (Photodynamic therapy, PDT) 係使光感藥物選擇性的累積於特定組織或腫瘤細胞，施與特定波長之光能激發光感藥物使之發生光化學反應，產生具有細胞毒性的活性氧分子，對腫瘤局部造成損傷，以達到癌症治療的目的。本研究目的在探討脫鎂葉綠素搭配 660 nm 發光二極體照射對小鼠乳腺癌 4T1 細胞及 4T1 腫瘤Balb/c小鼠之 PDT 療效。首先觀察到脫鎂葉綠素 a 與 4T1 細胞共培養 2 小時，細胞內累積濃度可達最高點；接著發現隨著藥物濃度提升、共培養時間增加及光照能量增強，PDT 對 4T1 細胞的致死率也隨之增加。在共培養 2 小時，光照 2.55 J/cm2，脫鎂葉綠素 a 的半致死劑量 (LD50) 為 459.3 ± 28.9 ng/mL；光照 5.10 J/cm2，LD50 降為 320.2 ± 23.3 ng/mL。同樣的參數下，脫鎂葉綠素 b 的 LD50 分別為 303.8 ± 25.1 及 226.7 ± 5.4 ng/mL。TUNEL 分析可發現隨著共培養時間由 2 小時增長到 6 小時，凋亡細胞比例亦隨之增加。對小鼠進行劑量為 87.25 mg/kg 的急毒性測試，結果發現脫鎂葉綠素 a 注射 14 天內不會造成小鼠體重下降，主要器官的組織切片也無明顯損傷；同時，連續14天注射 2 mg/kg 脫鎂葉綠素 a 對腫瘤小鼠也無亞急毒性。進一步觀察尾靜脈注射脫鎂葉綠素 a在正常小鼠與 4T1 腫瘤小鼠體內的生物分佈狀態，發現注射 4 小時後，在正常鼠體內，以肝臟所累積的濃度最高；而在 4T1 腫瘤小鼠，則以腫瘤所累積的濃度最高。每天注射 2 mg/kg 脫鎂葉綠素 a，以10.2 J/cm2 光照進行 PDT 可顯著抑制4T1 腫瘤小鼠腫瘤組織的生長；組織染色分析驗證 PDT 組出現較多的凋亡細胞及腫瘤組織損傷。綜上所述，脫鎂葉綠素 a 能選擇性的累積在腫瘤組織，並對小鼠乳腺癌 4T1 細胞具有光敏毒性，結合光照能抑制乳癌小鼠腫瘤組織的生長。

Photodynamic therapy (PDT) is an alternative modality for cancer treatment. Tumor site is damaged by cytototoxic reactive oxygen species (ROS) produced by the activated photosensitizer selectively accumulated in cancerous cells and specific tissues after light irradiation with specific excitation wavelength. The aim of this study was to the efficacies of pheophytin mediated PDT combined with 660 nm light emitting diodes (LEDs) against murine mammary gland adenocarcinoma 4T1 cells and 4T1 tumor bearing Balb/c mice. First of all, the maximal concentration of pheophytin a in 4T1 cells was found 2 hrs after incubation with the photosensitizer. Cell viability decreased as the photosensitizer concentration, incubation time and light dose increased. When incubated with pheophytin a for 2 hrs, half lethal dose (LD50) for 4T1 cells was 459.3 ± 28.9 ng/mL with 2.55 J/cm2 irradiation and 320.2 ± 23.3 ng/mL with 5.10 J/cm2 irradiation. For pheophytin b, LD50 was 303.8 ± 25.1 and 226.7 ± 5.4 ng/mL with 2.55 and 5.10 J/cm2 irradiation, respectively. TUNEL assay revealed that the percentage of apoptotic cells increased as the increase of incubation time with pheophytin a. Acute toxicity was studied in mice with single dose injection of 87.25 mg/kg pheophytin a. It was found that bodyweight of mice did not decline and no major organs damage was observed in tissue section within 14 days post photosensitizer administration. No subacute toxicity was seen in 4T1 tumor bearing mice after daily injection of 2 mg/kg pheophytin a. Biodistribution of pheophytin a in normal and 4T1 tumor bearing mice were analyzed after intravenous injection through the tail vein. At 4 hr post-injection, pheophytin a accumulated most in the liver of the normal mice, whereas it accumulated most at tumor site of tumor bearing mice. Tumor growth was inhibited in 4T1 tumor-bearing mice with daily intravenous injection of pheophytin a at the concentration of 2 mg/kg and light dose of 10.2 J/cm2. Histochemical staining further showed that more apoptotic cells and more tumor tissue damage post-PDT. To sum up, this study demonstrated that pheophytin a is selectively accumulated in tumor tissue, possesses phototoxicity against urine mammary gland adenocarcinoma 4T1 cells, and effectively inhibits tumor growth when combined with red light irradiation.

目錄
摘要 I
Abstract II
目錄 V
圖目錄 VIII
表目錄 IX
縮寫表 X
第一章 緒論 1
1.1 前言 1
1.2 文獻回顧 3
1.2.1. 光動力療法之歷史 3
1.2.2. 光動力療法於乳癌治療和葉綠素衍生物之應用 5
1.2.3. 葉綠素衍生物於光動力療法之應用 8
1.3 研究動機及目的 12
第二章 理論基礎 13
2.1 光動力療法之三大要素 13
2.1.1. 光 13
2.1.2. 氧氣 14
2.1.3. 光感藥物 14
2.2 光動力療法的標靶特性 16
2.2.1. 光感藥物對腫瘤組織的選擇性 16
2.2.2. 治療部位的光照操作 17
2.3. 光動力治療的藥物動力學 17
2.3.1. 藥物吸收 18
2.3.2. 藥物分佈 18
2.3.3. 藥物代謝 18
2.3.4. 藥物排除 19
2.4. 光動力治療造成細胞死亡機制 19
第三章 材料與方法 21
3.1. 研究架構 21
3.2. 小鼠乳腺癌細胞培養 23
3.2.1. 細胞培養藥物配製 23
3.2.2. 細胞培養 24
3.3. 光動力治療-葉綠素衍生物 26
3.3.1. 葉綠素衍生物藥物配製 27
3.3.2. 光源硬體設備 27
3.3.3. PDT 之細胞實驗方法 29
3.3.4. PDT 之動物實驗方法 29
3.4. 細胞存活率分析 30
3.4.1. MTT assay 之藥物配製 30
3.4.2. 細胞存活率之實驗步驟 30
3.5. 細胞對脫鎂葉綠素 a 的藥物攝取量試驗 30
3.6. 偵測 DNA 片段化之細胞實驗 31
3.7. 實驗動物來源及飼養 34
3.8. 脫鎂葉綠素 a 之動物體內毒性測試 34
3.8.1. 急性毒性測試 34
3.9. 小鼠乳癌腫瘤模型 35
3.10. 組織切片及染色 35
3.10.1. 組織處理 36
3.10.2. 組織脫水及包埋 36
3.10.3. 組織切片 37
3.10.4. 組織切片染色 38
3.11. 脫鎂葉綠素 a 在小鼠體內之生物分佈 39
3.12. 小鼠乳癌腫瘤模型光動力療效評估 40
3.13. 組織切片中凋亡細胞染色 41
3.14. 統計分析 42
第四章 結果 43
4.1. 脫鎂葉綠素 PDT 對 4T1 細胞之細胞存活率測試 43
4.2. 4T1 細胞對脫鎂葉綠素 a 的藥物攝取量試驗 48
4.3. 4T1 細胞在脫鎂葉綠素 a-PDT 後之DNA 片段化定量 50
4.4. 脫鎂葉綠素 a 之動物體內毒性測試 52
4.5. 小鼠乳癌腫瘤模型 53
4.6. 脫鎂葉綠素 a 在小鼠體內之生物分佈 57
4.7. 小鼠乳癌腫瘤模型光動力療效 60
4.8. 小鼠乳癌腫瘤模型光動力療效的累積藥物毒性評估 68
第五章 討論 73
5.1. 脫鎂葉綠素 a 及 b PDT 對 4T1 細胞之光毒性反應 73
5.2. 4T1 細胞及乳癌小鼠對脫鎂葉綠素 a 的攝取量 73
5.3. 脫鎂葉綠素 a 對小鼠的急毒性及累積藥物毒性評估 75
5.4. 小鼠的乳癌誘發 75
5.5. 脫鎂葉綠素 a 對乳癌小鼠的光動力療效評估 76
5.6. 脫鎂葉綠素 a 光動力治療後造成 DNA 片段化情形評估 77
第六章 結論與未來展望 78
參考文獻 80
附錄表 90

圖目錄
圖 3-1 脫鎂葉綠素-PDT 對乳癌光動力效應之研究架構 22
圖 3-2 脫鎂葉綠素 a 及 b 之化學結構式 26
圖 3-3 脫鎂葉綠素 a 之螢光光譜圖 27
圖 3-4 LED 光板實際圖 28
圖 3-5 高功率 LED 實際圖 28
圖 4-1 脫鎂葉綠素 a-PDT 對 4T1 細胞之細胞存活率影響 46
圖 4-2 脫鎂葉綠素 b-PDT 對 4T1 細胞之細胞存活率影響 47
圖 4-3 脫鎂葉綠素 a 濃度與螢光之標準曲線圖 48
圖 4-4 4T1 細胞在不同時間點對脫鎂葉綠素 a 的攝取量 49
圖 4-5 4T1 細胞經脫鎂葉綠素 a-PDT 後之 DNA 片段化情形 51
圖 4-6 脫鎂葉綠素 a 注射後之小鼠體重變化趨勢 52
圖 4-7 成功誘發之乳癌腫瘤小鼠外觀及體溫變化 54
圖 4-8 正常小鼠之皮下組織切片圖 55
圖 4-9 4T1 腫瘤小鼠之皮下腫瘤切片圖 56
圖 4-10 脫鎂葉綠素 a 於正常小鼠及腫瘤小鼠體內之生物分佈狀態 59
圖 4-11 腫瘤小鼠體重變化 61
圖 4-12 小鼠腫瘤體積生長變化 63
圖 4-13 腫瘤組織經 PDT 後之細胞凋亡情形 67
圖 4-14 腫瘤小鼠肝臟組織染色切片圖 70
圖 4-15 腫瘤小鼠腎臟組織染色切片圖 72

表目錄
表 3-1 小鼠乳腺癌細胞株資料表 24
表 3-2 Cell death detection ELISAPLUS 試劑藥品表 32
表 3-3 Cell death detection ELISAPLUS 試劑藥品配置方式 32
表 3-4 In situ cell death detection kit, POD 試劑藥品表 41
表 4-1 脫鎂葉綠素 PDT 對 4T1 細胞之半致死劑量 45

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