臺灣博碩士論文加值系統

據近年衛福部統計，惡性腫瘤已多年蟬聯國人死亡率之首，其次為心臟疾病與腦血管疾病，故癌症之預防、診斷與治療已成為目前醫療重大課題之一。現今之癌症治療方法，仍以外科手術切除、化學治療與放射線治療等為主，但治療成效仍有改善空間。
故近年來，人類正積極研究新型輔佐性癌症療法，其中尤以光動力治療備受矚目，因其相較於傳統療法具低侵襲性、低副作用與可選擇性誘導腫瘤壞死之優點 。 本 研 究 主 要 為 合 成 鑭 系 元 素 摻 雜 之 上 轉 換 奈 米 粒 子 (lanthanide-doped upconversion nanoparticles; UCNPs)，並以石墨相氮化碳量子點(graphitic-carbon nitride quantum dots; g-C3N4 )為光感藥物之複合材料應用於近紅外光驅動之光動力治療，其中以高溫共沉澱法製備上轉換奈米粒子，並以鹽酸溶液去除表面配體轉成水相，進一步將聚賴氨酸(poly-L-lysine; PLL)修飾於材料表面使其帶正電，爾後以靜電組裝作用與氮化碳量子點結合。 本研究乃基於上轉換之特殊光學特性，可以連續波近紅外光雷射激發上轉換奈米粒子，將低能量之近紅外光轉換為高能量紫外光與可見光波段之螢光，而其所釋放之紫外光將誘導表面之 g-C3N4 ，於 365 nm 有最佳吸收，並進而釋放出綠色螢光與活性氧分子(reactive oxygen species; ROS)。再者，藉由調控不同濃度之PLL，使最大量之 g-C 3N4 光感藥物承載於上轉換粒子表面，可有效地將氧氣轉換為具細胞毒性之活性氧分子，誘導腫瘤細胞壞死與凋亡，達良好之光動力治療效果。

Based on the latest statistics from the Ministry of Health and Welfare, malignant tumor continues to be on top of disease, and then followed by the heart disease and cerebrovascular disease, so the diagnosis and medical treatment has become one of the major issues. Nowadays, cancer treatments still focus on surgical resection, chemotherapy and radiation therapy, but it still can be improved for the more effective treatment.
As a result, human beings have continued to investigate novel adjuvant cancer therapy in recent years, photodynamic therapy (PDT) is now becoming a widely used medical tool. Compared with the traditional therapy, photodynamic therapy is recognized as a minimally invasive procedure, also has little side effect and can selectively lead to tumor necrosis.
The purposes of this research is to fabricate a lanthanide-doped upconversion nanoparticles (UCNPs) nanocomposite by combining with graphitic carbon nitride (g-C 3 N 4 ) photosensitizer for near-infrared (NIR) light mediated PDT application. First, we synthesized upconversion nanoparticles by high temperature co-precipitation method, and then the ligand on the surface were removed via the treatment with hydrochloric acid to obtain water-dispersible nanoparticles. Furthermore, ligand-free upconversion nanoparticles modified with poly-L-lysine (PLL) in order to render the positive-charged group which can allow the attachment of the g-C 3N4 by electrostatic assembling.
Through the excitation of continuous wave NIR laser, upconversion nanoparticles can convert the low-energy NIR light to high energy ultraviolet (UV) or visible light. Owing to this unique optical property of upconversion nanoparticles, the UV light will further photoexcites g-C3N4 at 365 nm, emit the green light and release reaction oxygen species (ROS). Meanwhile, we also modified different concentration of PLL to achieve a moderate condition for high g-C3N4 loading and ensuring maximum energy transfer from UCNPs to g-C3N4 photosensitizer, so as to generate a significant amount of ROS, which can result in tumor cell necrosis and apoptosis for efficient PDT effect.

口試委員會審定書 i
謝誌 ii
摘要 iii
Abstract iv
目錄 v
圖目錄 viii
表目錄 xi
第一章 緒論 1
1.1 奈米材料之簡介 1
1.2 奈米材料之定義與特性 1
1.2.1 小尺寸效應 3
1.2.2 表面效應 4
1.2.3 量子尺寸效應 5
1.3 上轉換奈米粒子之簡介 5
1.3.1上轉換奈米粒子之組成 7
1.3.2.1 主體材料 8
1.3.2.2 敏化劑 9
1.3.2.3 活化劑 10
1.3.3 980 nm與808 nm激發之上轉換奈米粒子 11
1.3.4 上轉換奈米粒子之表面修飾 13
1.3.5 上轉換奈米粒子之核殼結構 14
1.3.6 上轉換奈米粒子之放光機制 15
1.3.6.1 激發態吸收 15
1.3.6.2 能量轉移上轉換 16
1.3.6.3 光子雪崩 16
1.4 石墨相氮化碳之簡介 17
1.5 光動力治療 19
1.5.1 光感物質 21
1.6上轉換奈米粒子應用之文獻回顧 22
1.7 研究動機與目的 25
第二章 實驗步驟與儀器分析原理 27
2.1 化學藥品 27
2.2 實驗步驟 29
2.2.1 氮化碳量子點之合成 29
2.2.2 NaYF4:Yb/Tm上轉換奈米粒子之合成 29
2.2.3 NaYF4:Yb/Tm@NaYF4:Yb/Nd之上轉換奈米粒子合成法 30
2.2.4 以聚賴氨酸修飾之上轉換奈米粒子合成法(NaYF4:Yb/Tm-PLL) 31
2.2.5 氮化碳與上轉換奈米粒子之複合材料合成法 (NaYF4:Yb/Tm-PLL@g-C3N4) 32
2.2.6 細胞毒性之測試(cytotoxicity assay) 32
2.2.7 細胞顯影 33
2.2.8 溶液與細胞中之單基態氧(singlet oxygen species; ROS)測試 33
2.2.9 光動力治療之測試 34
2.3 儀器原理 35
2.3.1 穿透式電子顯微鏡(transmission electron microscope; TEM) 35
2.3.2 X光粉末繞射儀(X-ray powder diffraction microscopy; XRD) 38
2.3.3 紫外光/可見光吸收光譜儀(UV/Vis absorption spectroscopy) 40
2.3.3.1 π、σ與n電子間之躍遷 42
2.3.3.2 電荷轉移吸收 43
2.3.3.3 d軌域與f軌域間電子之躍遷 43
2.3.4 傅立葉轉換紅外光譜儀(Fourier-transform infrared spectrometer) 44
2.3.5 光激發放光光譜儀(photoluminescence spectrometer) 47
2.3.5.1 振動弛豫(vibrational relaxation) 49
2.3.5.2 內部轉換(internal conversion) 49
2.3.5.3 螢光發射(fluorescence emission) 50
2.3.5.4 系統間跨越(intersystem crossing) 50
2.3.5.5 磷光發射(phosphorescence emission) 50
2.3.5.6 外部轉換(external conversion) 51
2.3.6 介面電位分析儀 (zeta potential analyzer) 51
2.3.7 雷射掃描共軛聚焦顯微鏡(laser scanning confocal microscopy) 54
第三章 結果與討論 57
3.1 980 nm雷射激發上轉換奈米粒子與氮化碳量子點複合材料之光動力治療應用 57
3.1.1 上轉換奈米粒子之合成與鑑定 57
3.1.1.1 上轉換奈米粒子之XRD圖譜 58
3.1.1.2 上轉換奈米粒子之TEM影像與FTIR官能基鑑定 59
3.1.1.3上轉換奈米粒子之雷射PL圖譜 61
3.1.2 石墨相氮化碳量子點之合成與鑑定 62
3.1.2.1 石墨相氮化碳量子點之UV/Vis吸收圖譜與PL圖譜 63
3.1.2.2 石墨相氮化碳量子點之TEM影像 64
3.1.2.3 石墨相氮化碳量子點之介面電位分析 65
3.1.3 UCNP-PLL@g-C3N4奈米複合材料之相關鑑定 66
3.1.3.1 UCNP-PLL@g-C3N4奈米複合材料之TEM影像 68
3.1.3.2 UCNP-PLL@g-C3N4奈米複合材料之介面電位分析與FT-IR官能基鑑定 68
3.1.3.3 UCNP-PLL@g-C3N4奈米複合材料之雷射PL圖譜 70
3.1.3.4 UCNP-PLL@g-C3N4奈米複合材料之螢光壽命量測分析 71
3.1.4 奈米複合材料於光動力治療之結果與討論 72
3.1.4.1 細胞毒性之測試 73
3.1.4.2 奈米複合材料於溶液中ROS含量之測試 75
3.1.4.3 奈米複合材料於OECM-1細胞中ROS含量之測試 79
3.1.4.4 奈米複合材料於光動力治療之細胞凋亡機制探討 82
3.1.4.5 奈米複合材料於體內實驗(in vivo)之光動力活性 84
3.2 808 nm雷射激發上轉換奈米粒子與氮化碳量子點複合材料之光動力治療應用 85
3.2.1 上轉換奈米粒子之合成與鑑定 85
3.2.1.1 808 nm上轉換奈米粒子之XRD圖譜 86
3.2.1.2 808 nm上轉換奈米粒子之TEM影像 87
3.2.1.3 808 nm上轉換奈米粒子之PL圖譜 88
3.2.1.4 808 nm UCNP-PLL@g-C3N4奈米複合材料之相關鑑定 89
3.2.1.5 808 nm UCNP-PLL@g-C3N4奈米複合材料之TEM影像 91
3.2.1.6 808 nm UCNP-PLL@g-C3N4奈米複合材料之介面電位與雷射PL圖譜 93
3.2.2 奈米複合材料於光動力治療之結果與討論 95
3.2.2.1 細胞毒性之測試 95
3.2.2.2 奈米複合材料於溶液中ROS含量之測試 96
第四章 結論 98
參考文獻 99

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