製備奈米級複合性高分子雙藥搭載系統於光動力─化學治療之應用

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研究生：	張祐誠 Chang, Yu Cheng
論文名稱：	製備奈米級複合性高分子雙藥搭載系統於光動力─化學治療之應用 Fabrication of chitosan-based nanoparticles as a dual-functional drug carrier in combinational chemo-photodynamic therapy
指導教授：	黃郁棻 Huang, Yu Fen
口試委員:	張建文姜文軒
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：	2015
畢業學年度：	103
語文別：	中文
論文頁數：	70
中文關鍵詞：	高分子藥物載體、光動力治療、結合性治療
外文關鍵詞：	nanocarriers, photodynamic therapy, combinational therapy
相關次數：	點閱：2 下載：0
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同時載附雙藥物的奈米級載體在癌症治療領域中為一個較近期的治療方案，由於不同藥物間本身相異的作用機制，在進行治療時期望能夠同時發揮各自的毒理機制，進而達到加成性甚至具有增效作用的效果。本研究主要著重於光動力結合化學性治療。光敏劑選擇玫瑰紅 (Rose Bengal) ，其具有良好的光敏化效率，本身因具有帶負電性的官能基，能夠和帶正電的高分子有著良好的靜電作用力；另一方面，紫杉醇 (Paclitaxel) 做為傳統的化學治療藥物的方案。本研究主要利用甲殼素 (Chitosan) 、聚乙烯醇 (Polyvinyl alcohol)、混合短鏈聚乙烯亞胺 (Polyethylenimine) 等高分子，利用油水乳化法將疏水性的紫杉醇及親水性的玫瑰紅同時包覆，聚乙烯亞胺之陽離子聚電解質特性，可藉由靜電吸引力，進一步提升於中性環境下對於玫瑰紅的裝載效率。搭配牛血清白蛋白本身具有聚兩性電解質的特性，於載體中做為非共價型交聯劑，可以使載體成分間原本藉由靜電作用力所牽引的特性獲得更進一步的提升，使整體結構更為緻密。最後利用電性相異的特性使透明質酸 (Hyaluronic acid)在高分子載體上進行表面吸附的動作，除了有效降低載體原本過高的表面正電性外，更可以做為標靶治療的潛力。最後利用雷射光激發，誘導載體內雙藥物同時引發光動力以及化學藥物的毒性產生，治療效果勝於裝載單一藥物之外，同時在未照光時，能確保能有效包覆藥物以降低藥物本身毒性造成健康細胞的影響。
綜合上述，本研究提出簡單而快速的方式，無須經過化學性修飾或高分子聚合等複雜的製程，只利用數種高分子及藥物的參雜，即能有效的利用靜電作用力達成裝載藥物的目的。透過一系列的細胞實驗測試，首先證實載體具標靶的潛力，相對於大部分載體利用被動標靶的傳遞方式，能夠更有效的利用細胞表面受體的胞吞途徑達到進一步的藥物累積；另外細胞毒性及自由基效率測試，除了呈現出雙藥物結合下的治療優勢外，相對於傳統的光動力治療，提供了一個顯著改善的方案。

Dual functional drug carrier has been a modern strategy in cancer therapy, because it is a platform to evaluate synergistic effect through combination therapy. In the present study, we combined properties of two drugs Paclitaxel (PTX) and Rose Bengal (RB) as a synergistic treatment of chemo-photodynamic therapy . In order to encapsulate these hydrophobic and hydrophilic drugs in one functional system, we fabricate polymeric nanocarriers (NCs) using tripolymer mixtures of chitosan (CTS), branched polyethylenimine (bPEI) and polyvinyl alcohol (PVA) through an oil-in-water emulsion method. The polycationic properties of CTS and bPEI permit effective entrapment of RB molecules. During assembly process, bovine serum albumin (BSA) was also added to condense cationic tripolymer mixtures into stable nanocarriers (BNCs). Eventually, hyaluronic acid (HA) was used as an ionic cross-linking agent through electrostatic interaction to lower down carrier’s zeta potential for suitable application in biological systems. Our results suggest an effective drug loading and high dispersion stability of HBNCs in different buffer solutions. Low leakage of drug molecules from the engineered HBNCs were also confirmed on the basis of dialysis experiments. Moreover, fluorescence microscopic images displayed a high intracellular uptake and localization of drug-loaded HBNCs toward Tramp-C1 cells. The photodynamic effect showed intracellular RB release after photo irradiation; its ROS generation was further evaluated by flow cytometry and alamar blue cytotoxicity assays. Together, our dual-drug carrier system assures enhanced cytotoxicity in cancer cells compared with single-loading drug alone. A dual-functional delivery platform was successfully established to improve the therapeutic efficacy in tumor cells.

目錄
摘要    I
Abstract    III
致謝    V
目錄    VI
圖目錄    IX
表目錄    X
第一章  緒論    1
1.1 癌症與治療方案    1
1.1.1 淺談癌症及其治療方針    1
1.1.2 化學藥物治療    3
1.1.3 光動力治療    3
1.1.4 給藥型癌症治療所面臨的困境    4
1.2 奈米科技與生醫應用    5
1.2.1 奈米材料簡介    5
1.2.2 奈米材料於生醫應用    7
1.2.3 奈米載體於傳統化學治療的改善    8
1.2.4 奈米載體於傳統光動力治療的改善    9
1.2.5 標靶治療    10
1.2.6 雙重藥物結合性治療    11
1.2.6.1 光動力-化學結合性治療    13
1.3 高分子奈米材料於癌症治療的應用    14
1.3.1 高分子奈米藥物載體簡介    14
1.3.2 高分子奈米載體合成方法    16
1.4 研究動機與目的    17
第二章　實驗材料與方法    20
2.1 實驗藥品與儀器    20
2.1.1 實驗藥品    20
2.1.2 緩衝溶液配置    22
2.1.3 細胞培養與操作    23
2.1.4 儀器    23
2.2 藥物載體的合成與特性鑑定    25
2.2.1 高分子包覆雙藥物載體合成    25
2.2.2 藥物載體之特性鑑定    26
2.2.3 藥物載體於不同環境之穩定性探討    27
2.2.4 探討高分子比例間參數改變    27
2.3 藥物載體載附藥物後之特性探討    28
2.3.1 定量藥物載體之載附效率    28
2.3.2 藥物載體之藥物洩漏評估    28
2.4 藥物載體的光應答特性測試    29
2.4.1 藥物載體的自由基產率分析    29
2.4.2 藥物載體之光照後藥物釋放評估    29
2.4.3 藥物載體照光後吸收變化評估    30
2.5 藥物載體與目標細胞 Tramp-C1 的作用探討    30
2.5.1共軛交螢光顯微鏡分析照光後細胞內藥物釋放    30
2.5.2 流式細胞儀分析載體自由基產生之效率    31
2.5.3 流式細胞儀鑑定藥物載體標靶功能    32
2.5.4 細胞存活率分析    33
第三章　實驗結果與討論    34
3.1 藥物載體之合成與鑑定    34
3.1.1 高分子包覆雙藥物載體合成與鑑定    34
3.1.2 藥物載體於不同環境之穩定性探討    34
3.1.3 複合性高分子各成分組成之探討    35
3.2 藥物載體裝載藥物後之特性探討    36
3.2.1 藥物載體裝載藥物後之光譜鑑定    36
3.2.2 藥物載體之載附效率定量    36
3.2.3 藥物載體之藥物洩漏評估    37
3.3 藥物載體的光應答特性    37
3.3.1 藥物載體的自由基產率分析    37
3.3.2 藥物載體之光照後藥物釋放評估    38
3.3.3 藥物載體照光後吸收變化評估    38
3.4 藥物載體與目標細胞 Tramp-C1 的作用    39
3.4.1 顯微鏡分析細胞吞噬效率    39
3.4.2 共軛交螢光顯微鏡分析細胞吞噬效率及藥物釋放    40
3.4.3  HA專一性測試    40
3.4.4 流式細胞儀分析載體自由基產生之效率    41
3.5 細胞存活率分析    42
3.5.1 藥物載體之結合性治療    42
3.5.2 藥物載體於不同濃度下之治療效果分析    42
第四章　結論    44
第五章  未來展望    46
圖表說明    47
參考文獻    64

 
圖目錄
圖一： 奈米藥物載體於腫瘤之主動與被動傳遞與治療    2
圖二： 光動力治療的作用機制    4
圖三： 奈米藥物載體的發展史    7
圖四： 多種光敏劑藥物載體型式    9
圖五： 光內化治療的作用機制    10
圖六： 多種結合性治療示意圖    12
圖七： 高分子結合抗癌藥物作為治療的發展史    14
圖八： 油水乳化法製備雙藥物高分子載體於光動力治療示意圖    19
圖九： 油水乳化以及揮發法示意圖    25
圖十： 高分子藥物載體之穿透式電子顯微鏡影像    47
圖十一： 藥物載體之穩定性測試    48
圖十二： 藥物載體裝載藥物後之光譜鑑定    51
圖十三： 藥物載體之藥物洩漏評估    52
圖十四： 藥物載體之自由基產率測試    53
圖十五： 藥物載體光照後釋放情形    54
圖十六： 藥物載體光照後吸收光譜變化    55
圖十七： RB與bPEI照光後之吸收變化    56
圖十八： 吞噬藥物載體後之細胞螢光顯微鏡影像    57
圖十九： 光照前後細胞內藥物分布的共軛交螢光顯微鏡影像    58
圖二十： 細胞內競爭式反應顯微鏡影像    59
圖二十一： 流式細胞儀測試細胞內競爭式反應    60
圖二十二： 細胞內藥物載體自由基產率    61
圖二十三： 藥物載體對於目標細胞Tramp-C1的毒性測試    62
圖二十四： 藥物以及藥物載體在不同濃度下的細胞毒性    63

 
表目錄
表一： 目前市售藥物載體及裝載化學藥物之其載體型式    8
表二： 1970年代高分子與抗癌藥物型成的複合體於臨床的應用    15
表三： 固定高分子比例下不同NCs之配置    26
表四： 改變高分子比例之NCs配置    27
表五： 改變載體高分子間比例結果的特性鑑定    47
表六： 不同NCs間藥物裝載效率    48

                                

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