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研究生:莊文凱
研究生(外文):Wen-Kai Chuang
論文名稱:轉換奈米粒子/蛋白暈狀體形成微氣泡對比劑方法之研究
論文名稱(外文):Study on Translating the Nanoparticle-Protein Corona into Microbubble Contrast Agents
指導教授:林政鞍張恒雄
指導教授(外文):Cheng-An J. LinWalter H. Chung
學位類別:碩士
校院名稱:中原大學
系所名稱:醫學工程研究所
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:2011
畢業學年度:99
語文別:中文
論文頁數:80
中文關鍵詞:微氣泡超音波對比劑血清白蛋白螢光金奈米團簇奈米粒子
外文關鍵詞:ultrasound contrast agentfluoroescent gold nanoclustermicrobubblenanoparticleserum albumin
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本研究欲建立簡單、快速之奈米粒子多功能化整合帄台,因此採用被廣泛研究也是大量
存在於人體內之材料—白蛋白,做為各種奈米粒子整合之介面。白蛋白以靜電吸附之方式,
吸附至帶有羧基官能基之奈米粒子與奈米團簇表面,形成暈狀結構而稱之粒子-白蛋白暈狀體,
為提升奈米粒子生物相容性與接枝能力之保護層與媒介。利用穿透式電子顯微鏡可明顯觀察
出各種奈米粒子帶有暈狀外型,而得以證實暈狀體之形成,且各種粒子、白蛋白與各粒子之
白蛋白暈狀體,皆使用各式光譜進行量測,並比較暈狀體合成前、後蛋白之結構、粒子之表
面電漿共振與光激發螢光等表現有無差異。本研究使用超音波乳化法將奈米粒子(或團簇)-白
蛋白暈狀體轉換為蛋白型微奈米氣泡,以醫用影像超音波驗證其帶有超音波影像對比之功用,
並且使用共軛交顯微鏡觀察氣泡之構型與光學特性,以確認氣泡之形成以及粒子嵌入氣泡與
否。研究結果可將多種或多數奈米粒子以白蛋白為基材形成氣泡,使奈米粒子更集中而提升
其特性表現,也賦予多種奈米粒子具有複合之潛力。

A general platform for nanoparticles functionalization as well as integration had been
demonstrated in the thesis. The albumin was chosen due to its’ abundance of the most amount
proteins in human serum. The albumin can spontaneously adsorb onto nanoparticles or nanoclusters
surface by electrostatic force, where nanoparticles contain plenty of carboxylic groups on their
surface. The corona shape was then formed upon the successful adsorption between nanoparticles
and albumins, resulting in a so-called complex of nanoparticle-protein corona. The proteins shell
can be improved the biocompatibility and formed as protection media for nanoparticles. The
nanoparticles within a corona-shaped shell was observed by transmission electron microscopy, and
provided the information that nanoparticle-protein corona can be formed. Different nanoparticles,
albumin and their protein corona were analyzed by spectra, TEM, surface plasma resonance effect
and photoluminescence comparing to the bared ones. Furthermore, sonochemical microemulsion
was utilized to fabricate the microbubbles from nanoparticle- protein corona. The echogenic
properties of microbubbles were tested by medical ultrasound image system, confirming if the
microbubble can increase the contrast of ultrasound image. Herein, the morphology and optical
feature of microbubbles were also observed and detected by confocal laser scanning microscopy,
demonstrating that the microbubbles can be formed with inserted nanoparticles shells. Be a
coordinator between kinds of nanoparticles, albumin and its bubble integrated different functions of
nanoparticles and created a variety of oncoming application.

摘要 ............................................................................................................................. I
A b s t r a c t .................................................................................................................. II
致謝 ........................................................................................................................... III
目錄 ........................................................................................................................... VI
圖目錄 .................................................................................................................... VIII
表目錄 ....................................................................................................................... X
第一章 前言 ........................................................................................................ 1
1.1. 研究背景 .............................................................................................................................. 1
1.1.1. 奈米粒子之表面特性 ............................................................................................................. 1
1.1.2. 白蛋白之特性與應用 ............................................................................................................. 1
1.1.3. 多模態奈米複合材料與微氣泡 ............................................................................................. 3
1.2. 研究目的 .............................................................................................................................. 6
第二章 研究方法 ............................................................................................. 7
2.1. 研究架構 .............................................................................................................................. 7
2.2. 蛋白暈狀體之文獻回顧與製備方法 .................................................................................. 8
2.2.1. 製備蛋白暈狀體之文獻背景 ................................................................................................. 8
2.2.2. 製備蛋白暈狀體之材料與方法 ........................................................................................... 11
2.2.2.1. 有機相量子點之兩性高分子披覆 ................................................................................... 11
2.2.2.2. 量子點-白蛋白暈狀體製備 ............................................................................................. 11
2.2.2.3. 紅螢光金奈米團簇之合成 ............................................................................................... 12
2.2.2.4. 奈米團簇-白蛋白暈狀體製備 ......................................................................................... 13
2.2.2.5. 磁奈米粒子-白蛋白暈狀體製備 ..................................................................................... 13
2.2.3. 分析蛋白暈狀體之材料與方法 ........................................................................................... 15
2.2.3.1. 膠體電泳分析(Agarose gel electrophoresis) .................................................................. 15
2.2.3.2. 紫外光-可見光吸收光譜分析(UV-VIS absorption spectra) ........................................ 15
2.2.3.3. 螢光光譜分析(Photoluminescence spectra) .................................................................. 15
2.2.3.4. 原子力顯微鏡(Atom force microscopy) ........................................................................ 15
2.2.3.5. 圓二色光譜(Circular dichroism,CD) .......................................................................... 16
2.2.3.6. 穿透式電子顯微鏡(Transmission electron microscopy,TEM) ................................. 16
2.3. 轉換奈米粒子-蛋白暈狀體至微氣泡之文獻回顧與方法 .............................................. 17
2.3.1. 製備蛋白型微氣泡之文獻背景 ........................................................................................... 17
2.3.2. 轉換奈米粒子-蛋白暈狀體至微氣泡之材料與方法 .......................................................... 18
2.3.3. 分析微氣泡之材料與方法 ................................................................................................... 19
2.3.3.1. 共軛焦雷射掃描顯微鏡(Confocal laser scanning microscope,CLSM) .................... 19

2.3.3.2. 光學顯微鏡影像 ............................................................................................................... 19
2.3.3.3. 影像超音波(Image ultrasound) ...................................................................................... 19
2.3.3.4. 紫外光激發之外觀 ........................................................................................................... 19
第三章 結果與討論 ..................................................................................... 20
3.1. 奈米粒子-白蛋白暈狀體之結果與討論 .......................................................................... 20
3.1.1. 膠體電泳分析結果 ............................................................................................................... 20
3.1.2. 紫外光-可見光吸收光譜分析結果 ...................................................................................... 21
3.1.3. 螢光光譜分析結果 ............................................................................................................... 22
3.1.4. 圓二色光譜分析結果 ........................................................................................................... 23
3.1.5. 原子力顯微鏡影像 ............................................................................................................... 25
3.1.6. 穿透式電子顯微鏡影像 ....................................................................................................... 34
3.2. 微氣泡之結果與討論 ........................................................................................................ 42
3.2.1. 共軛交顯微鏡分析 ........................................................................................................ 42
3.2.2. 倒立式螢光顯微鏡影像 ................................................................................................ 45
3.2.3. 醫用超音波影像分析 .................................................................................................... 46
3.2.4. 紫外光激發之氣泡外觀 ................................................................................................ 47
第四章 結論 ...................................................................................................... 49
參考文獻 ............................................................................................................... 51
附錄一 六奈米金- 白蛋白暈狀體......................................................... 57
附錄二 各式奈米粒子於圓二色光譜定量之結果 .................... 61
附錄三 金奈米粒子標準品之AFM 掃描結果 ............................ 63
附錄四 膠體電泳之洋菜膠體製備 ..................................................... 66
附錄五 超音波影像之洋菜膠仿體製備 .......................................... 67
附錄六 化學藥品 ........................................................................................... 68
附錄七 儀器設備 ........................................................................................... 70

圖目錄
圖 1 流程分為蛋白暈狀體製備與微/奈米氣泡合成........................................................................ 7
圖 2 血清白蛋白於各pH 值環境之構形61 ..................................................................................... 9
圖 3 大小條件影響奈米粒子與蛋白吸附構形56 ........................................................................... 10
圖 4 膠體電泳結果經白光照射(左)紫外光照射(右)。 ................................................................ 20
圖 5 紫外光-可見光吸收光譜,黑色虛線為牛血清白蛋白 ......................................................... 21
圖 6 螢光粒子與其白蛋白暈狀體之螢光光譜 ............................................................................... 22
圖 7 牛血清白蛋白於350 nm 激發光之螢光光譜........................................................................ 23
圖 8(A) (○)α-helix,(●) β-sheet,(▽) β-turn,(▼) P2 (poly-L-proline in 0.1 M acetic acid) 82。
(B)未正規化之白蛋白暈狀體圓二色光譜圖。 ...................................................................... 24
圖 9 最小值正規化之圓二色光譜 ................................................................................................... 25
圖 10 牛血清白蛋白之AFM 掃描影像與橫切面振幅曲線 ......................................................... 27
圖 11 紅螢光金團簇之AFM 掃描影像與橫切面振幅曲線 ......................................................... 28
圖 12 紅螢光金團簇-白蛋白暈狀體之AFM 掃描影像與橫切面振幅曲線 ................................ 29
圖 13 綠螢光量子點之AFM 掃描影像與橫切面振幅曲線 ......................................................... 30
圖 14 綠螢光量子點-白蛋白暈狀體之AFM 掃描影像與橫切面振幅曲線(小粒徑) ................. 31
圖 15 綠螢光量子點-白蛋白暈狀體之AFM 掃描影像與橫切面振幅曲線(大粒徑) ................. 32
圖 16 氧化鐵奈米粒子之AFM 掃描影像與橫切面振幅曲線 ..................................................... 33
圖 17 氧化鐵-白蛋白暈狀體之AFM 掃描影像與橫切面振幅曲線 ............................................ 34
圖 18 牛血清白蛋白經負染後之TEM 影像 ................................................................................. 36
圖 19 紅螢光金奈米團簇(Au@DHLA)之TEM 影像 ................................................................... 36
圖 20 紅螢光金奈米團簇-白蛋白暈狀體之TEM 影像 ................................................................ 37
圖 21 Minghui Hu(2007)合成4.4 nm 之金奈米粒子與Ad 12 瘤蛋白自組裝之TEM 影像84 ... 37
圖 22 綠螢光量子點之TEM 影像 ................................................................................................. 38
圖 23 綠營光量子點-白蛋白暈狀體之TEM 影像 ........................................................................ 38
圖 24 氧化鐵奈米粒子之TEM 影像 ............................................................................................. 39
圖 25 氧化鐵奈米粒子-白蛋白暈狀體之TEM 影像 .................................................................... 40
圖 26 紅螢光金奈米團簇-白蛋白暈狀體負染前之TEM 影像 .................................................... 41
圖 27 紅螢光金奈米團簇-白蛋白負染後之TEM 影像 ................................................................ 41
圖 28 紅螢光奈米金團簇-白蛋白暈狀體合成之白蛋白微氣泡 .................................................. 43
圖 29 綠螢光量子點-白蛋白暈狀體合成之白蛋白微氣泡 .......................................................... 43
圖 30 白蛋白與螢光蛋白以超音波乳化法合成之微氣泡結構49 ................................................ 44
圖 31 脂質型微氣泡包覆油相藥物或氣體之結構85 .................................................................... 44
圖 32 各式氣泡於倒立式螢光顯微鏡之影像 ................................................................................ 46
圖 33 醫用超音波影像於洋菜膠仿體之造影結果 ........................................................................ 47
圖 34 紫外光(365 nm)於洋菜膠仿體下方光激發微氣泡之外觀 ................................................. 48
圖 35 金奈米粒子(6 nm)與其白蛋白暈狀體之吸收光譜圖 .......................................................... 57
圖 36 金奈米粒子(6 nm)-白蛋白暈狀體之TEM 影像 ................................................................. 58
圖 37 金奈米粒子(6 nm)之TEM 影像 .......................................................................................... 58
圖 38 金奈米粒子(6 nm)-白蛋白暈狀體,發現有中白蛋白吸附量少之粒子,且未完整貼附至
粒子表面。 ............................................................................................................................... 59
圖 39 水帄式膠體電泳經白光照射(左)紫外光照射(右) .............................................................. 60
圖 40 以牛血清白蛋白定量之圓二色光譜 ..................................................................................... 61
圖 41 金奈米粒子(60 nm)之AFM 掃描影像與切面曲線 ............................................................ 63
圖 42 金奈米粒子(40 nm)之AFM 掃描影像與切面曲線 ............................................................. 63
圖 43 金奈米粒子(20 nm)之AFM 掃描影像與切面曲線 ............................................................ 64
圖 44 金奈米粒子(10 nm)之AFM 掃描影像與切面曲線 ............................................................ 64
圖 45 金奈米粒子(5 nm)之AFM 掃描影像與切面曲線 .............................................................. 65
圖 46 金奈米粒子(2 nm)之AFM 掃描影像與切面曲線 .............................................................. 65
圖 47 自製模具側面觀與仿體俯視觀 ............................................................................................ 67
圖 48 自製模具與仿體俯測觀 ........................................................................................................ 67

表目錄
表格 1 以量子點為例,奈米粒子改質策略以及多數帶有羧基的表面特性3 ............................. 2
表格 2 2009 年統計各類型上市超音波對比劑41 ............................................................................ 5
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