發展牛血清蛋白包覆磁性奈米粒子作為藥物傳遞載體於光動力治療之應用

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研究生：	胡淳育 Hu, Chun-Yu
論文名稱：	發展牛血清蛋白包覆磁性奈米粒子作為藥物傳遞載體於光動力治療之應用 Development of Albumin Coated Iron Oxide Nanoparticles as Drug Delivery Vehicles in Photodynamic Therapy
指導教授：	黃郁棻 Huang, Yu-Fen
口試委員:	黃志清姜文軒
學位類別：	碩士 Master
系所名稱：	原子科學院 - 生醫工程與環境科學系 Department of Biomedical Engineering and Environmental Sciences
論文出版年：	2014
畢業學年度：	103
語文別：	中文
論文頁數：	110
中文關鍵詞：	牛血清蛋白、中空孔洞磁性奈米粒子、光敏劑
外文關鍵詞：	bovine serum albumin, porous hollow Fe3O4 nanoparticles, photosensitizer
相關次數：	點閱：2 下載：0
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光動力治療 (Photodynamic therapy, PDT)，是一種結合光敏劑(photosensitizer, PS)、光及氧之非侵入式治療且已廣泛應用於臨床癌症應用上。由於現階段的光敏劑大多為疏水性結構，在生物體應用上受限於溶解性不佳等問題而影響其治療之效率。故本研究利用具有三維結構與水溶性佳等特性之牛血清蛋白，與疏水性的光敏劑 (Protoporphyrin IX, PpIX)間，具有良好親和性以改善溶解性等問題，再者以微乳化合成方式包覆疏水性中空孔洞磁性鐵奈米粒子，以開發新型診斷治療制劑。動態光散射分析儀 (Dynamic light scattering, DLS)與穿透式電子顯微鏡 (Transmission electron microscope, TEM)鑑定結果顯示，此奈米複合體(BSA:PpIX:PHNPs)為團簇結構，其平均水合半徑為152.9 ± 29.0 nm。從吸收與螢光光譜鑑定結果證實此載體可有效裝載PpIX，並可長時間穩定於複雜生理緩衝環境。透過老鼠前列腺癌細胞之存活率分析顯示，以632 nm波長Xe燈照射30分鐘條件下，載體上之光敏劑可有效生成單態氧與自由基，達到毒殺癌細胞之目的；未照光組別無顯著的細胞毒性產生。此複合材料在本體系中進一步扮演磁共振造影對比劑的顯影功能，利用表面的血清蛋白與水分子良好的交互作用，可提升其影像對比度。
在生物體應用上，許多文獻記載奈米載體上修飾聚乙二醇分子可有效降低奈米載體與血清的交互作用、減少被內皮網狀系統的巨噬細胞所吞噬及延長於血液循環中的時間等，提升其治療之效率。故本研究利用Methoxy PEG succinimidyl carboxymethyl ester上的NHS-Ester與血清蛋白上的一級胺反應形成具有PEG修飾之血清蛋白。此血清蛋白亦可與PpIX間具有良好親和性，透過微乳化方式開發一聚乙二醇修飾之奈米藥物載體。研究結果證實載體修飾PEG的比例不同，可調控巨噬細胞吞噬之作用。
光動力治療也可搭配化學性療法以提升其治療效率。本研究可開發雙藥物於單一載體作為化學-光動力之結合治療，利用血清蛋白與中空孔洞奈米粒子，在微乳化方式，將化學治療藥物Dox及光敏劑PpIX有效裝載 (BSA:Dox:PpIX:PHNPs)。從光譜鑑定顯示BSA:Dox:PpIX:PHNPs具有良好的藥物裝載率(Dox: 82%及PpIX:98%)，再者細胞存活率分析證實結合化學-光動力治療可成功改善單藥物載體之治療效率。
本研究之奈米複合體系統透過簡單而且快速的合成方式，成功裝載疏水性光感物質PpIX，改善其生物體內溶解性不佳等問題，再者可利用PEG修飾或者搭配化學性藥物的結合治療下，提升生物體應用及治療之效率。

Photodynamic therapy (PDT) requires combination of a photosensitizer (PS), light and oxygen; it is a non-invasive therapeutic modality which is widely used in cancer clinical trial. Most existing PSs are hydrophobic in nature. PDT’s oxidative damage is significantly reduced by the low efficiency of reactive oxygen species (ROS) production. Owing to the high binding affinity of serum albumin toward Protoporphyrin IX (PpIX), bovine serum albumin (BSA) was applied as a carrier for PDT drug in the current study.The high aqueous solubility of BSA makes it an ideal candidate to stabilize hydrophobic porous hollow Fe3O4 nanoparticles (PHNPs). This process is done through one step oil-in-water emulsion under optimal ultrasonication condition.
The morphology and particle size of the BSA:PpIX:PHNPs were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The resultant nanocluster demonstrated a narrow size distribution with a mean hydrodynamic diameter of 152.9 ± 29.0 nm. Spectroscopic measurement confirmed high PpIX-loading efficiency, which was biocompatible and stable in various buffers. Furthermore, in vitro cytotoxicity of BSA:PpIX:PHNPs was tested in Tramp C1 cells via MTT assay and significant improvement in therapeutic efficacy was achieved with 30 min-red laser (632 nm) irradiation. This result was also consistent with an increase of ROS generation in cancer cells and was demonstrated using flow cytometry. In addition, BSA:PpIX:PHNPs exhibit high transverse relaxivity in MRI as the contrast agents (CAs).PEGylated nanoparticles have been proposed as enabling evasion by RAW 264.7 cells and reducing blood plasma protein adsorption. In this work, methoxy PEG succinimidyl carboxymethyl ester was covalently attached to BSA and followed by NHS ester-amine reaction in phosphate buffer (pH 8). PEG-BSA and hydrophobic porous hollow Fe3O4 nanoparticles (PHNPs) were stabilized through one step oil-in-water emulsion under optimal ultrasonication condition. Our results demonstrate that PEGylation of BSA:PpIX:PHNPs can modulate cellular uptake by RAW 264.7 cells.BSA:PpIX:PHNPs have shown great potential both in drug delivery and photodynamic therapy.Herein, we developed a doxorubicin (Dox)-loaded BSA:PpIX:PHNPs to facilitate combined chemotherapy and photodynamic therapy in one system. BSA:Dox:PpIX:PHNPs, show high loading efﬁciency of Dox and PpIX. Comparing in vitro cytotoxicity assays of BSA:Dox:PHNPs & BSA:PpIX:PHNPs with BSA:Dox:PpIX:PHNPs, we demonstrated that BSA:Dox:PpIX:PHNPs have higher therapeutic efﬁcacy during photodynamic therapy. The ability of BSA:Dox:PpIX:PHNPs to combine local speciﬁc chemotherapy with external photodynamic therapy signiﬁcantly improves therapeutic efﬁcacy of cancer treatment.Our findings suggest that albumin coated magnetic nanoparticles exhibit great potential as a diagnostic & therapeutic system in cancer therapy.

摘要    I
Abstrate    III
致謝    V
目錄    VI
圖目錄    XI
表目錄    XIII
第一章    緒論    1
1光動力治療於癌症之應用    1
1.1癌症治療    1
1.2光動力治療之作用機制    1
1.3光動力治療之優勢    3
1.4光動力治療的起源與歷史    4
1.5光感物質之臨床應用    6
1.6光敏感劑PpIX    7
1.7光動力療法於癌症治療之限制    7
2奈米材料與生醫應用    8
2.1奈米材料簡介    8
2.2奈米材料於生醫應用    9
2.3磁性奈米材料於生醫之應用    11
2.3.1磁性奈米材料之合成    11
2.3.2磁性奈米粒子之特性與應用    13
2.4血清蛋白之奈米藥物載體之應用與發展    15
2.4.1血清蛋白    15
2.4.2人類血清蛋白之藥物傳遞系統    16
2.4.3奈米藥物載體    17
2.5蛋白質修飾磁性奈米粒子合成及其應用    19
2.5.1合成蛋白質-磁性奈米之複合型材料    19
2.5.2蛋白質修飾磁性奈米粒子之特性與應用    22
3研究動機與目的    24
第二章　實驗材料與方法    28
1 實驗藥品與儀器    28
1.1 實驗藥品    28
1.2 緩衝溶液配置    29
1.3 細胞培養與操作    30
1.4 儀器    31
2 中空孔洞奈米粒子之合成與特性鑑定    33
2.1 合成鐵核/四氧化三鐵殼核奈米粒子    33
2.2合成中空四氧化三鐵奈米粒子    33
2.3合成中空孔洞的四氧化三鐵奈米粒子    34
2.4 中空四氧化三鐵奈米粒子之定量分析    35
2.5 中空四氧化三鐵奈米粒子之特性鑑定    35
3藥物載體之合成與鑑定    36
3.1載體合成    36
3.2藥物載體合成    36
3.3藥物載體之鑑定    37
3.4藥物載體之穩定性測試    39
3.5藥物載體之溶液條件自由基偵測    41
3.6藥物載體細胞內自由基偵測    41
3.7藥物載體細胞內螢光顯微鏡偵測    42
3.8藥物載體之細胞存活率分析    42
4聚乙二醇修飾血清蛋白以提升水溶性及減少巨噬細胞的吞噬    43
4.1合成聚乙二醇修飾血清蛋白    43
4.2膠體電泳鑑定聚乙二醇修飾血清蛋白    43
4.3聚乙二醇藥物載體合成    44
4.4聚乙二醇藥物載體定量分析    44
4.5聚乙二醇藥物載體之動態光散射分析儀    45
4.6聚乙二醇藥物載體之自由基分析    45
4.7聚乙二醇藥物載體之細胞存活率分析    45
4.8螢光顯微鏡觀察聚乙二醇藥物載體    45
4.9 ICP-MS偵測巨噬細胞吞噬藥物載體之影響    45
第三章　實驗結果與討論    47
1中空孔洞四氧化三鐵之合成與特性鑑定    47
1.1鐵/四氧化三鐵殼核奈米粒子    47
1.2中空四氧化三鐵奈米粒子    47
1.3合成中空孔洞的四氧化三鐵    48
1.4 中空孔洞四氧化三鐵奈米粒子之飽和磁化量    48
2藥物載體之合成與鑑定    49
2.1血清蛋白與光感劑PpIX之作用    49
2.2合成載體    49
2.3合成藥物載體    50
2.4藥物載體之鑑定    50
2.4.1動態光散射分析儀    50
2.4.2吸收及螢光光譜偵測光感劑裝載率    51
2.4.3熱重分析儀    51
2.4.4超導量子磁化儀    52
2.4.5核磁共振顯影MRI及影像分析    52
2.5藥物載體之穩定性測試    53
2.5.1不同pH緩衝溶液之影響    53
2.5.2不同濃度的氯化鈉溶液之影響    53
2.5.3不同細胞培養液環境之影響    53
2.5.4長時間穩定性之影響    54
2.5.5藥物滲漏之影響    54
2.6藥物載體之自由基偵測    54
2.6.1溶液條件自由基偵測    54
2.6.2細胞內自由基偵測    55
2.7藥物載體之細胞內鐵染色偵測    55
2.8藥物載體之細胞內螢光顯微鏡偵測    55
2.9藥物載體之細胞存活率分析    56
3聚乙二醇修飾蛋白質以提升水溶性及減少巨噬細胞的吞噬    56
3.1膠體電泳鑑定聚乙二醇修飾之血清蛋白    56
3.2定量分析    57
3.3動態光散射分析儀    57
3.4溶液相自由基偵測    58
3.6 細胞存活率分析    58
3.5 螢光顯微鏡觀察巨噬細胞吞噬奈米載體之影響    59
3.7 ICP-MS測試巨噬細胞吞噬奈米載體之影響    59
4結合化學藥物於光動力治療以提升細胞毒殺率    60
4.1雙藥物載體之定量分析    60
4.2雙藥物載體之動態光散射分析儀    60
4.3雙藥物載體之溶液相自由基偵測    61
4.4雙藥物載體之細胞內自由基偵測    61
4.5雙藥物載體之細胞內螢光偵測    62
4.6雙藥物載體之細胞存活率分析    62
第四章 結論    64
圖表說明    65
參考文獻    90

                                

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