結合化學治療和基因治療，使其於癌症治療中產生協同效應達到誘導增強治療的功效，為了實現這一目標本研究設計不同長度之三嵌段共聚物PEG-b-PDMAEMA-b-PDPA與隨機共聚物PEG-b-(PDMAEMA-r-PDPA)，用於將阿黴素（DOX）和Bcl-2小分子干擾核糖核酸（siRNA）靶向同時遞送到三陰性乳癌細胞中。探討其自組裝構型差異與不同鏈長之共聚物，對於藥物載送效果的影響，以及探討共同負載之兩種藥物間的協同效應。由實驗結果得知，三嵌段共聚物具有較佳的藥物包覆能力，而其中具有最長PDMAEMA鏈段之共聚物PEG113-b-PDMAEMA55-b-PDPA59（LB）有著最佳的載送效果。PEG113-b-PDMAEMA55-b-PDPA59（LB）之阿黴素包覆效率能夠達到80%，於pH= 7.4與5.0的環境下分別進行體外釋放，24小時阿黴素之累積釋放率分別達到24%與 68%，而若延長至96小時，則可達40%與接近100%的累積釋放率。而在氮磷比為20的條件下，PEG113-b-PDMAEMA55-b-PDPA59（LB）負載小分子干擾核糖核酸之包覆效率能高達94%，使其於pH= 7.4與5.0的環境下釋放了24小時後，其累積釋放率分別為14.6%與59%，由以上實驗之差距可以得知，PEG113-b-PDMAEMA55-b-PDPA59（LB）奈米載體具有相當靈敏之酸鹼響應。重要的是，於三陰性乳癌細胞（MDA-MB-231）之細胞活性實驗中，PEG113-b-PDMAEMA55-b-PDPA59（LB）載體包覆Bcl-2小分子干擾核糖核酸以及阿黴素之毒殺效果，比只包覆阿黴素之載體多出了約20%，證實兩者藥物有顯著的協同效應，也證實PEG113-b-PDMAEMA55-b-PDPA59（LB）微胞能夠成功地將雙藥負載運送至細胞中。期許未來能夠提供作為結合基因治療與化療藥物之複合治療載體平台，並用於三陰性乳癌的靶向治療，對治療方面有所貢獻 。

The combination of chemotherapy and gene therapy is known to induce the enhanced therapeutic efficacy in the cancer therapy, which is called synergistic effect. In this study, triblock copolymer（PEG-b-PDMAEMA-b-PDPA）and random copolymer（PEG-b-(PDMAEMA-r-PDPA)）with different composition has been designed as the co-delivery platforms, which targeted simultaneous delivery of doxorubicin (DOX) and Bcl-2 small interfering RNA (siRNA) into breast cancer cells. The efficiency of drug encapsulation was optimized by changing the chain length, composition and self-assembled configuration of copolymer. The experimental results show that the triblock copolymer has better drug-carrying capacity than the random copolymer. The copolymer PEG113-b-PDMAEMA55-b-PDPA59（LB） with the longest PDMAEMA segment is the best carrier. The drug loading efficiency of DOX could achieve around 80%, and the condensation efficiency of siRNA was 94% under N/P = 20. Co-loading of Bcl-2 siRNA and DOX wouldn't affect the high carry efficiency. In vitro drug cumulative release rate of DOX was 40% and nearly 100% at the environment of pH=7.4 and 5.0 in 96 hrs. In 24 hours, the cumulative release rate of siRNA could reach 14.6% and 59% in the environment of pH=7.4 and 5.0. The significant difference between the two environments demonstrated that these nanoparticles have a very sensitive pH response. And it could be used as a good platform for the combination of chemotherapy and gene therapy.
Importantly, by the results of cell viability, the codelivery of Bcl-2 siRNA and DOX showed significantly enhanced toxicity in MDA-MB-231 breast cancer cells around 20% more than the codelivery of control siRNA and DOX in 50 nM of siRNA. Therefore, a significant synergistic effect between Bcl-2 siRNA and DOX has been observed. PEG113-b-PDMAEMA55-b-PDPA59（LB） micelles thus confirmed to be able to carry the dual drug into the cells. These results indicate DOX/Bcl-2 siRNA co-delivery system by PEG113-b-PDMAEMA55-b-PDPA59（LB） is promising for targeted treatment of breast cancer.

摘要 I
Abstract III
謝誌 V
目錄 VI
圖目錄 X
表目錄 XIII
式目錄 XIV
第一章 　文獻回顧 1
1-1 癌症（Cancer） 1
1-1-1 乳癌 3
1-2 常見治療乳癌之方式 4
1-2-1 手術治療 4
1-2-2 放射治療 4
1-2-3 化學治療 5
1-2-4 荷爾蒙治療 7
1-3 基因型藥物治療癌症（Gene-based Therapeutics） 8
1-3-1 質體去氧核糖核酸（plasmid DNA, pDNA） 8
1-3-2 小分子干擾核糖核酸（small-interfering RNA, siRNA）與微型核糖核酸（microRNA, miRNA） 9
1-4 奈米載體應用以治療癌症 12
1-4-1 增強通透與滯留效應（Enhanced Permeability and Retention Effect, EPR） 12
1-4-2 腫瘤微環境（Tumor Microenvironment） 14
1-4-3 核內體逃脫（Endosomal Escape） 15
1-5 刺激響應型高分子奈米載體（Stimuli-Responsive Polymeric Nanocarrier） 18
1-5-1 酸鹼響應型高分子微胞奈米載體（pH-Responsive Polymeric Nanocarrier） 19
1-5-2 氧化還原響應型高分子奈米載體（Redox-Responsive Polymeric Nanocarrier） 21
1-5-3 其他響應型高分子微胞奈米載體（Other Responsive Polymeric Nanocarriers） 22
1-6 多功能小分子2,3-二溴馬來醯亞胺（2,3-Dibromomaleimide, DBM） 24
1-6-1 可逆反應之高選擇性 24
1-6-2 功能性修飾（螢光修飾以及高分子修飾） 25
1-7 原子轉移自由基聚合反應（Atom Transfer Radical Polymerization, ATRP） 29
1-8 研究動機 33
第二章 酸鹼響應之二合一奈米藥物平台其基因與化療藥物之材料與實驗方法 35
2-1 材料設計 35
2-2 三嵌段共聚物與隨機共聚物之合成與鑑定 36
2-2-1 聚乙烯醇引發劑（PEG-Br）之合成 36
2-2-2 Poly（ethylene glycol）-b-poly（2-（dimethylamino）ethyl methacrylate）-b-poly（2-（diisopropylamino）ethyl methacrylate）（PEG-b-PDMAEMA-b-PDPA）三嵌段共聚物之聚合反應 37
2-2-3 Poly（ethylene glycol）-b-（poly（2-（dimethylamino）ethyl methacrylate）-r-poly（2-（diisopropylamino）ethyl methacrylate））（PEG-b-(PDMAEMA-r-PDPA)）隨機共聚物之聚合反應 39
2-3 三嵌段共聚物與隨機共聚物之材料特性及刺激響應分析 41
2-3-1 高分子之臨界微胞濃度（Critical Micelle Concentration, CMC） 41
2-3-2 高分子之酸鹼性質滴定 41
2-3-3 高分子對酸鹼值之靈敏度測定 41
2-3-4 高分子奈米微胞製程 41
2-3-5 高分子奈米微胞粒徑分析 42
2-3-6 高分子奈米微胞酸鹼響應分析 43
2-3-7 高分子奈米微胞表面電位量測 43
2-4 三嵌段共聚物與隨機共聚物之阿黴素包覆及釋放 44
2-4-1 製備包覆阿黴素之高分子奈米微胞與分析 44
2-4-2 包覆阿黴素之高分子微胞前後之螢光強度 46
2-4-3 製作阿黴素於不同pH磷酸緩衝液之減量線 46
2-4-4 包覆阿黴素之高分子奈米微胞在酸鹼響應下之釋放 46
2-5 小分子干擾核糖核酸之高分子複合體製備與釋放情形 48
2-5-1 小分子干擾核糖核酸之微胞複合體製備與分析 48
2-5-2 微胞複合體釋放在酸鹼響應下之釋放 48
2-6 細胞實驗分析 50
2-6-1 基因沉默（gene silencing） 50
2-6-2 細胞存活率（viability） 51
2-6-3 細胞吞噬實驗（uptake experiment） 52
第三章 酸鹼響應之二合一奈米藥物平台其基因與化療藥物之結果與探討 53
3-1 三嵌段共聚物與隨機共聚物合成 53
3-2 三嵌段共聚物與隨機共聚物之材料特性與刺激響應分析 55
3-2-1 高分子之臨界微胞濃度（Critical Micelle Concentration, CMC） 55
3-2-2 高分子之酸鹼性質 57
3-2-3 高分子奈米微胞對於酸鹼性變化之靈敏度 59
3-3 三嵌段共聚物與隨機共聚物奈米微胞之粒徑分析與刺激響應分析 61
3-3-1 高分子奈米微胞粒徑大小與表面電位 61
3-3-2 高分子奈米微胞之穩定性 62
3-4 以三嵌段共聚物與隨機共聚物形成奈米微胞攜帶阿黴素 64
3-4-1 包覆阿黴素之高分子奈米微胞製備以及負載效率之計算 64
3-4-2 包覆阿黴素之高分子微胞前後粒徑大小與螢光強度 66
3-5 小分子干擾核糖核酸之高分子微胞複合體（polyplexes）之包覆效率 69
3-6 以包覆效率最佳之材料PEG113-b-PDMAEMA55-b-PDPA59（LB）共同負載阿黴素與小分子干擾核糖核酸 72
3-6-1 PEG113-b-PDMAEMA55-b-PDPA59（LB）高分子奈米微胞粒徑之酸鹼影響 72
3-6-2 PEG113-b-PDMAEMA55-b-PDPA59（LB）包覆阿黴素於不同酸鹼下釋放情形 74
3-6-3 PEG113-b-PDMAEMA55-b-PDPA59（LB）之小分子干擾核糖核酸微胞複合體於不同酸鹼值下之釋放情形 76
3-6-4 PEG113-b-PDMAEMA55-b-PDPA59（LB）共同負載阿黴素與小分子干擾核糖核酸之微胞複合體粒徑大小與表面電位分析 78
3-7 以PEG113-b-PDMAEMA55-b-PDPA59（LB）載負阿黴素與小分子干擾核糖核酸之細胞分析 79
3-7-1 基因沉默（gene silencing） 79
3-7-2 細胞存活率（viability） 81
3-7-3 細胞吞噬實驗（uptake experiment） 84
3-8 結論 86
第四章 具馬來醯亞胺核心之還原與酸鹼響應的高分子液胞用於藥物控制釋放 88
4-1 實驗設計 88
4-2 實驗過程中之問題與解決方式 90
4-2-1 溶劑對化合物之影響與解決方法 91
4-2-2 還原劑效果與解決方法 94
4-2-3 鍵擊反應之產物的鑑定方式 96
4-2-4 立體障礙結構之影響與解決方法 97
4-3 AB2-type雙嵌段共聚物之合成與鑑定 99
4-3-1 聚乙二醇甲醚-疊氮化物（PEG113-N3）之合成59 99
4-3-2 N-propargyl-2,3-dibromomaleimide 之合成48 100
4-3-3 3,4-bis((2-hydroxyethyl)thio)-1-(propynyl)pyrroledione, alkyne-DTM- (SCH2CH2OH)2 之合成 101
4-3-4 PEG113-Mal-（SCH2CH2OH）2藉由鍵擊反應之合成 102
4-3-5 PEG113-Mal-（SCH2CH2OBiBB）2之巨雙頭起始劑合成步驟 103
4-3-6 PEG113-Mal-（PDPA30）2之合成步驟 105
4-4 結論與未來展望 107
藥品與儀器 108
參考文獻 112
附錄 122

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