製備包覆靛氰綠及阿黴素之聚乳酸甘醇酸-聚乙二醇交聯標靶奈米粒子用於乳癌光/化學治療之研究

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姓名

張達盛(Da-Sheng Chang) 查詢紙本館藏

畢業系所

生物醫學工程研究所

論文名稱

製備包覆靛氰綠及阿黴素之聚乳酸甘醇酸-聚乙二醇交聯標靶奈米粒子用於乳癌光/化學治療之研究
(Fabrication and Characterization of HER2-Target Indocyanine Green-Doxorubicin-Loaded PLGA-PEG Nanoparticles for Chemo-/Photo-Therapy of Breast Cancer Cells)

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摘要(中)

本研究以微乳液法製作包覆抗癌藥物阿黴素(Doxorubicin)與光敏試劑靛氰綠(Indocyanine Green；ICG)之聚乳酸甘醇酸(Poly(Lactic-co- Glycolic Acid)；PLGA)-聚乙二醇(Polyethylene glycol；PEG)並於表面接枝人類上皮生長因子2(human epidermal growth factor receptor 2；HER2)單株抗體之新穎生物可降解性標靶奈米藥物載體(HER2-target ICG-DOX-Loaded PLGA-PEG Co-polymeric Nanoparticles;；HIDPNPs)，並測試該載體對於乳癌細胞進行複合式癌症治療之可行性。本研究首先以傅立葉轉換紅外線光譜儀與核磁共振儀確認PLGA及PEG共聚高分子合成效果，完成載體製備後再以螢光表現抗體及BCA蛋白質檢測證明HER2抗體於產品表面之存在與生物活性。經過動態光散射儀器分析HIDPNPs之平均粒徑與表面電位分別為266  4.3 nm和-12  4.48 mV；對於DOX及ICG的包覆率分別約為35%及79%；包藥率則分別約為0.15%及0.34%。再由UV-Vis分光光度計分析降解率得到48小時內HIDPNPs在4℃及37℃環境下所包覆的ICG降解率比單純溶解於水中之ICG分別低11%及54%；48小時內HIDPNPs在4℃及37℃環境的DOX釋放率分別為13%及26%。以激發波長808 nm搭配強度為 6 W/cm2的近紅外光雷射照射HIDPNPs奈米載體，結果發現ICG包覆濃度大於1μM下照射90秒內溶液溫度上升超過40℃並且可維持高溫長達5分鐘，另外藉由SOSG檢測單態氧濃度發現於5分鐘內的單態氧生成量和HIDPNPs的濃度成正比關係，在包含相等於4μM ICG的HIDPNPs其單態氧生成量比在相同濃度下單純ICG水溶液高出約3倍。藉由偵測被細胞攝取後的HIDPNPs其所發射的ICG螢光強度發現MDA-MB-453(HER2+)的螢光值明顯大於MCF-7 (HER2-)，如此證明了HIDPNPs對HER2表現的細胞具有主動靶向的功能。將HIDPNPs和MDA-MB-453乳癌細胞而共同培養12小時再以近紅外光雷射照射5分鐘後，經由計算得知包覆4μM ICG及3μM DOX的HIDPNPs之毒殺細胞效率比單純使用ICG或DOX分別高了1.5 (P < 0.05)及2.6 (P < 0.05)倍，此一結果證明HIDPNP可以有效的減少化療劑量並且搭配光療法以增加或維持乳癌治療效果，因此有望發展成為一種治療癌症的材料。

摘要(英)

Breast cancer has long been recognized as one of the most lethal gynecological disease for women due to high drug resistance and serious side effects during treatment. To resolve these issues, a multi-functional human epidermal growth factor receptor 2 (HER2)-targeted Indocyanine green (ICG)-Doxorubicin (DOX)-encapsulated poly( lactide- co-glycolide) -poly(ethylene glycol) copolymeric nanoparticles (HIDPNPs) was developed in this study. The mean size and surface charge of the HIDPNPs are 266 ± 4.26 nm and -12  4.48 mV, respectively, through measurements using dynamic light scattering technique. The encapsualtion efficiencies of ICG and DOX in HIDPNP are 79% and 35%, respectively, while the drug loading rates for ICG and DOX are 0.34% and 0.15%, respectively. The degradation rate of encapsulated ICG remarkably decreases 11% and 54% at 4 and 37oC, respectively, within 48 h as compared with freely dissolved ICG in PBS. The DOX release rates are 13% and 26% at 4 and 37oC, respectively, within 48 h. Through the detection of ICG-induced fluorescence, we found that the uptake efficiency of HIDPNPs in MDA-MB-453 cells (HER2+) was significantly higher than that in MCF7 cells (HER2-), showing that the HIDPNP enables to specifically target HER2-expressing cells. In terms of the therapeutic functionality of the agent, our data show that upon NIR laser exposure, the temperature of medium containing HIDPNPs with ≥ 1-μM equivalent ICG concentration enabled to reach > 40oC within 90 sec and its amount of singlet oxygen yielded significantly enhanced ≥ 3 folds after 5-min laser treatment. The capacity of HIDPNP in cancer cell killing was further verified by using MDA-MB-453 as the model cell that the motality of the cells which were treated by HIDPNPs including 4 and 3 μM of ICG and DOX, respectively for 12 h and followed by 5-min NIR laser irradiation significantly enhanced 1.5- (P < 0.05) and 2.6 folds (P < 0.05) as compared to the group treated with ICG or DOX alone, respectively. Overall, the HIDPNP which enables to provide both chemo and photo therapeutic effects exhibits a high potential for use in breast tumor destruction.

關鍵字(中)

★ 奈米藥物載體
★ 聚乳酸甘醇酸
★ 聚乙二醇
★ 光-化學治療
★ 阿黴素
★ 靛氰綠
★ 乳癌

關鍵字(英)

★ Nanoparticle
★ Poly(lactic-co-glycolic acid)
★ Polyethylene glycol
★ Photo-Chemo therapy,
★ Doxorubicin
★ Indocyanine green
★ Breast cancer

論文目次

目錄
摘要 i
ABSTRACT iii
誌謝 v
目錄 vi
圖目錄 x
表目錄 xiv
第一章緒論 1
第二章原理與文獻探討 3
2-1 奈米科技 3
2-2 乳癌 5
2-3 癌症的治療 7
2-4 化學藥物治療 9
2-5 溫熱療法 11
2-6 光療法 13
2-6-1 光熱治療(Photothermal therapy；PTT) 14
2-6-2 奈米材料的光熱治療 15
2-6-3 光動力治療(Photodynamic therapy；PDT) 17
2-6-4 靛氰綠 (Indocyanine Green，ICG) 20
2-7 生醫材料 24
2-7-1 高分子生醫材料 25
2-7-2 Poly(lactide-co-glycolide )簡介 28
2-7-3 Poly(ethylene glycol)之性質與應用 29
2-8 藥物載體 29
2-8-1 奈米藥物載體製備與包覆原理 30
2-8-2 奈米藥物載體的細胞吞噬機制 32
2-8-3 奈米藥物載體的藥物釋放系統 34
第三章研究材料與方法 38
3-1 實驗藥品 38
3-2 實驗及分析儀器 40
3-2-1 UV-Vis分光光度計(UV-Vis Spectrophotoscope) 40
3-2-2 動態雷射粒徑分布暨界面電位儀 41
3-2-3 808 nm Fiber Coupled Laser 43
3-2-4 倒立式螢光顯微鏡 43
3-2-5 其他實驗儀器 45
3-3 實驗設計架構 46
3-4 實驗步驟 47
3-4-1 合成PLGA-b-PEG高分子 47
3-4-2 製備包覆 ICG、DOX之PLGA-PEG奈米載體 48
3-4-3 奈米載體表面修飾HER2 antibody 48
3-5 HIDPNPs特性分析 49
3-5-1 HIDPNPs 抗體接枝分析 49
3-5-2 HIDPNPs粒徑及表面電位分析 50
3-5-3 HIDPNPs構型分析 50
3-5-4 DOX及ICG的包覆率、包藥率分析 50
3-5-5 HIDPNPs穩定性分析 51
3-6 HIDPNPs光治療功能分析 52
3-6-1 HIDPNPs光熱功能檢測 52
3-6-2 HIDPNPs光動力功能檢測 52
3-7 細胞實驗 53
3-7-1 細胞培養 53
3-7-2 細胞染色 54
3-7-3 HIDPNPs細胞毒性分析 56
3-7-4 HIDPNPs細胞專一性能力分析 57
3-8 HIDPNPs細胞毒殺能力分析 57
3-9 統計分析 58
第四章結果與討論 59
4-1 PLGA-PEG 共聚物交聯分析鑑定 59
4-2 HIDPNPs製備及其性質量測 61
4-2-1 HIDPNPs表面抗體修飾分析 61
4-2-2 HIDPNPs粒徑及電位分布 62
4-2-3 HIDPNPs 型態分析 63
4-2-4 HIDPNPs包覆率及包藥率之量測 64
4-2-5 HIDPNPs奈米載體的穩定性分析 65
4-3. HIDPNPs 光治療功能分析 67
4-3-1 HIDPNPs 奈米載體光熱分析 67
4-3-2 HIDPNPs 奈米載體光動力分析 68
4-4 HIDPNPs 照光釋放藥物之檢測 69
4-5 HIDPNPs對乳癌細胞的專一性測試 70
4-6 HIDPNPs對乳癌細胞的生物毒性測試 71
4-7 HIDPNPs對乳癌細胞的細胞毒殺測試 72
4-8 結論 76
第五章未來展望 77
參考文獻 78
附錄 95

圖目錄
圖 1. 2011年十大癌症發生率統計資料 2
圖 2.研究策略 2
圖 3.奈米科技於各領域之應用 3
圖 4.全球乳癌發生率統計分布 6
圖 5.全球乳癌死亡率統計分布 6
圖 6.亞洲各國乳癌發生率與死亡率統計結果 7
圖 7. Doxorubicin (DOX) 分子結構示意圖 11
圖 8. Doxorubicin-DNA複合物 (a) DOX分別以共價鍵及氫鍵等方式和DNA兩端的鳥嘌呤鍵結，(b) DOX螯合DNA示意圖 11
圖 9.溫度與時間對細胞存活率的影響 13
圖 10.人體中水分子、血紅素(Hb)以及攜氧血紅素(HbO2)於可見光-近紅外之光吸收圖 16
圖 11. (A)雷射照射時間與腫瘤的溫度變化圖，(B)腫瘤生長狀況圖 17
圖 12. (A) 光動力治療之分類；(B) 光動力治療之反應機制 18
圖 13.光感物質照光刺激氧氣形成單相氧造成細胞凋亡的作用機制 20
圖 14. (A) ICG結構圖；(B) ICG近紅外光吸收放射圖譜 21
圖 15. (A) 73ug/ml的ICG於不同的光照強度對溫度提升的效應；(B)不同濃度ICG光照後溫度的變化 21
圖 16. (A)不同濃度ICG之吸收光譜示意圖及(B)ICG於血液中濃度與螢光表現量關係圖 22
圖 17. ICG 濃度高低影響螢光表現量示意圖 22
圖 18. ICG與Phospholipids結合之螢光放射波長變化圖 23
圖 19. ICG溶液降解速率與光照、不同光源、溫度及濃度關係圖 23
圖 20.以HPLC分析ICG於無光照及光照後結構變化 24
圖 21. (A)PLA、PGA及PLGA之結構示意圖；(B)PLA/PGA共聚比和PLGA的降解關係 29
圖 22.奈米載體乳化製備 (A) 水相包油相(B)油相包水相 30
圖 23. 聚合物自組裝載體 31
圖 24.細胞吞噬作用 32
圖 25.細胞胞飲作用 32
圖 26.細胞受體介導和內吞作用 33
圖 27.藥物載體於細胞內之藥物釋放模式示意圖 34
圖 28.藥物載體於組織內之藥物釋放模式示意圖 34
圖 29.藥物擴散釋放 35
圖 30.載體澎潤釋放藥物 35
圖 31.滲透幫補藥物釋放 36
圖 32.載體溶蝕釋放藥物 36
圖 33.化學控制釋放 36
圖 34.可分解性支鏈載體 37
圖 35.可分解性骨架之載體 37
圖 36.可分解性支鏈載體 37
圖 37. UV-VIS光譜儀的外觀構造圖及架構圖 40
圖 38. 比爾定律吸收光路徑的示意圖 41
圖 39. Zetasizer Nano之外觀圖及測量示意圖 42
圖 40.近紅外光雷射裝置示意圖 43
圖 41. 螢光能階示意圖 44
圖 42. 倒立式螢光顯微鏡光路圖及實體圖 44
圖 43.實驗流程 46
圖 44. PLGA-PEG 反應流程 47
圖 45. IDPNPs合成流程 48
圖 46.奈米載體修飾抗體流程 49
圖 47. (A) MDA-MB-453細胞和(B)MCF-7細胞之可見光圖 54
圖 48. HER2 receptor 膠體電泳結果比較 54
圖 49. Calcein AM細胞染色示意圖 55
圖 50.以核磁共振圖譜(NMR)分析PLGA-PEG共聚物的結果 59
圖 51.以傅立葉轉換紅外光譜分析PLGA-PEG共聚物的結果 59
圖 52. (A)修飾與未修飾Anti-HER2抗體的奈米載體在接枝螢光抗體後之螢光表現量分析圖；(B)以FT-IR分析抗體修飾情形 62
圖 53. HIDPNPs與IDPNPs的粒徑分布與表面電性分布比較圖 62
圖 54. HIDPNPs奈米載體的型態分析 63
圖 55.HIDPNPs內DOX釋放率及ICG降解率量測結果 66
圖 56.HIDPNPs及純ICG之光熱檢測結果 68
圖 57.HIDPNPs及純ICG的光動力檢測結果 69
圖 58.經過近紅外光照射奈米載體之藥物釋放結果 70
圖 59. HIDPNPs專一性(A)DOX螢光及(B)ICG螢光結果 71
圖 60. HIDPNPs毒性測試結果 72
圖 61.(A)與MDA-MB-453共同培養4小時之HIDPNPs光化療、純ICG光療及純DOX化療毒殺細胞結果及(B)以倒立式顯微鏡觀察與MDA-MB-453共同培養4小時之HIDPNPs光化療、純ICG光療及純 DOX化療毒殺細胞細胞存活狀況(scale bar:50μm) 74
圖 62. (A)與MDA-MB-453共同培養12小時之HIDPNPs光化療、純 ICG光療及純DOX化療毒殺細胞結果(*P < 0.05)及(B)以倒立式顯微鏡觀察與MDA-MB-453共同培養12小時之HIDPNPs光化療、純ICG光療及純DOX化療毒殺細胞細胞存活狀況(scale bar:50μm) 75
表目錄
表 1. 乳癌分期 5
表 2. PLGA載體包覆藥物之比較 65

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指導教授

李宇翔(Yu-Hsiang Lee)

審核日期

2016-8-22

推文