臺灣博碩士論文加值系統

惡性腫瘤當前為全球死亡之主要原因，現今發展之各種癌症檢測技術皆具其特點與不足之處，而近紅外光對組織之低干擾與損害，故可針對較深層之組織進行治療，於生物醫學之應用深具潛力，其中癌症腫瘤之診斷與治療已成為當前研究中非常活躍之領域。本研究以近紅外光為主軸分成兩部分，發光二極體之封裝與癌症治療。
第一部分研究之近紅外光奈米粒子則以中孔洞二氧化矽球(mesoporous silica nanoparticle; MSN)作為模板，將鎵酸鋅螢光粉(ZnGa2O4:Cr3+,Sn4+; ZGOCS)燒結於孔洞中，避免顆粒因高溫而聚集，使其達奈米之大小，同時亦增加其分散性，並藉由鉻與錫離子共摻雜比例及前驅液濃度之調整，達最佳化之發光強度，於微米晶片之封裝測試上具良好光轉換效率之表現。
第二部分設計之奈米診斷治療系統可分為奈米複合材料與奈米載體。奈米複合材料由中孔洞二氧化矽層包覆之奈米金棒(mesoporous silica shell coated gold nanorod; AuNR@mS)與魚精蛋白包覆之上轉換奈米粒子(upconversion nanoparticle; UCNP)以靜電吸附作用結合。而奈米氣泡(nanobubble)則作為奈米載體，藉由高滲透長滯留效應，穩定地將奈米複合材料運送至癌細胞中進行顯影與治療。奈米氣泡具超音波之顯影功能，已廣泛運用於臨床醫療中，藉由包埋奈米複合材料，可與上轉換奈米粒子之螢光顯影達多重影像之功能。上轉換奈米粒子作為能量轉移之媒介，將近紅外光808 nm雷射之能量轉移至奈米金棒使其產生光熱效應，並透過自身綠色螢光觸發附載於孔洞中之光敏劑Merocyanine 540使其產生活性氧物質，抑制腫瘤生長，具良好之熱殺與毒殺效果。

The leading causes of death in the world is malignant tumors. In nowadays, various cancer detection technologies are developed with their own advantages and shortcomings. However, near-infrared (NIR) light has the highest potential because of the low absorption of blood and tissues avoiding the damage of heat which provides the treatments with deeper penetration. It revealed the importance of cancer treatments in the biomedical field. My master thesis is focused on NIR light and would like to be divided into two parts of the light-emitting diode (LED) package and cancer treatment.
In the first part, the NIR nanoparticles (ZnGa2O4:Cr3+,Sn4+) synthesized are loaded with mesoporous silica nanoparticle. The aggregation of phosphors is avoided with good dispersibility by the template method. However, the photoluminescence intensity is increased via tuning the doping ratio of chromium and tin ions and the concentration of the precursor solution. Moreover, the package test shows good performance and light conversion efficiency. In the second part, the designed nanosystem is composed of the mesoporous silica shell coated gold nanorod, the protamine coated upconversion nanoparticle and nanobubble. After embedded the upconversion nanocomposites, the multiple images can be approached with fluorescence and ultrasound. The upconversion nanoparticle transfers energy from 808 nm laser source to the gold nanorod performing the photothermal effect. The photosensitizer is also triggered via green fluorescence of upconversion nanoparticle which can generate reactive oxygen species to inhibit tumor growth showing the good curable effect in cancer treatment.

口試委員會審定書 I
誌謝 II
摘要 III
Abstract IV
目錄 V
圖目錄 IX
表目錄 XIV
英文縮寫表 XV
第一章 緒論 1
1.1 紅外光之簡介 1
1.1.1 近紅外光窗口 2
1.1.2 發光二極體 4
1.1.3 光學診斷與治療 5
1.2 超音波之簡介 7
1.2.1 超音波之醫學成像 7
1.2.2 超音波之顯影劑 8
1.2.3 超音波治療 9
1.3 奈米材料之簡介 10
1.3.1 奈米材料之定義與特性 10
1.3.2 小尺寸效應 12
1.3.3 表面效應 12
1.3.4 量子尺寸效應 13
1.4 光反應之多功能奈米粒子 14
1.4.1 長餘輝奈米粒子 14
1.4.2 奈米氣泡 16
1.4.3 上轉換奈米粒子 17
1.4.4 奈米金棒 19
1.4.5 奈米複合材料之應用 20
1.5 生物醫學之LED應用 23
1.6 光照治療 23
1.6.1 光熱治療 23
1.6.2 光動力治療 25
1.7 研究動機與目的 27
第二章 實驗步驟與儀器分析原理 29
2.1 化學藥品 29
2.2 實驗步驟 33
2.2.1 近紅外光奈米粒子之合成 33
2.2.2 近紅外光驅動上轉換奈米複合系統 34
2.2.2.1 中孔洞二氧化矽層包覆奈米金棒之合成 34
2.2.2.2上轉換奈米粒子之合成 35
2.2.2.3 奈米複合材料之合成 36
2.2.2.4 奈米複合系統之組裝 36
2.2.2.5 光熱與光動力效應測試 37
2.2.2.6 共軛焦顯微鏡之影像 37
2.2.2.7 細胞生物相容性與毒殺測試 38
2.2.2.8 細胞影像與光動力治療之毒殺效果 38
2.2.2.9 活體實驗 39
2.2.2.10 組織化學染色與免疫染色 39
2.3 儀器原理 40
2.3.1 超音波均質機(sonicator) 40
2.3.2 超音波診斷儀(ultrasound scanner) 41
2.3.3 奈米粒徑與界面電位量測儀(dynamic light scattering and zeta potential analyzer) 42
2.3.4 穿透式電子顯微鏡(transmission electron microscope; TEM) 44
2.3.5 掃描式電子顯微鏡(scanning electron microscope; SEM) 45
2.3.6 光致放光光譜儀(photoluminescence spectrometer) 46
2.3.7 雷射掃描共軛聚焦顯微鏡(laser scanning confocal microscopy; LSCM) 48
2.3.8 X光粉末繞射儀(X-ray powder diffraction microscopy; XRD) 49
2.3.9 紫外光/可見光吸收光譜儀(UV/Vis absorption spectroscopy) 50
2.3.10 傅立葉轉換紅外光譜儀(Fourier-transform infrared spectrometer; FTIR) 50
2.3.11 比表面積與孔隙度分析儀(specific surface area and porosimetry analyzer) 51
2.3.12 流式細胞儀(flow cytometer) 52
第三章 結果與討論 53
3.1應用於次毫米發光二極體之近紅外光奈米粒子 53
3.1.1近紅外光奈米粒子之晶體結構鑑定與形貌分析 53
3.1.2 近紅外光奈米粒子之表面性質鑑定 57
3.1.3 近紅外光奈米粒子之光學性質鑑定 59
3.1.3 近紅外光奈米粒子之封裝測試 61
3.2 應用於近紅外光診斷治療之上轉換奈米複合系統 63
3.2.1 奈米金棒之結構形貌與光學性質探討 63
3.2.2 三層核殼結構上轉換奈米粒子之結構形貌與光學性質探討 64
3.2.3 奈米複合材料結構形貌與光學性質之探討 68
3.2.4 奈米複合系統之影像與穩定性探討 71
3.2.5 奈米複合材料之光熱與光動力效應探討 74
3.2.6 奈米複合系統細胞相容性與細胞毒殺效果 76
3.2.7 奈米複合系統之細胞影像與毒殺效果探討 77
3.2.8 奈米複合系統之活體治療效果與組織切片探討 79
第四章 結論 82
參考文獻 84
著作目錄清單 92

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