在已發展國家中，癌症為造成人類死亡的主要原因之一，因此目前在對於癌症的治療發展是非常迫切且必要的。癌症的治療分為非常多種，其中最常見的就是化學療程、放射治療、標靶藥物治療，在大部分的療程都會造成人體的正常組織的傷害。因此有許多研究開始使用奈米顆粒作為藥物載體，因奈米顆粒可保護藥物，且因腫瘤附近血管不正常之增生，且內皮細胞排列不緊密，因此會形成結構缺陷，而此血管間隙會依腫瘤種類不同範圍大概為100~780nm，可使尺寸在100~200nm的奈米顆粒進入腫瘤細胞，進而減少癌症治療上對於人體的傷害，因此本研究設計一可調控殼層孔洞大小之奈米藥物載體，具應用於多種癌症治療方式之潛力，而在本研究中主要應用於前驅藥物治療(directed enzyme prodrug therapy)以及硼中子捕獲治療(Boron Neutron Capture Therapy)。
在前驅藥物治療中，利用奈米載體包覆酵素，且調控載體孔洞尺寸介於酵素及前驅藥物之間，再藉由EPR effect 而聚集於腫瘤附近的血管中，之後再投入前驅藥物使其與奈米載體內的酵素反應而形成具有毒性的藥物，進而殺死腫瘤細胞。
目前硼中子捕獲治療主要使用之含硼藥物為boronophenylalanine (BPA), sodium borocaptate (BSH) 以及硼酸，其中BPA之結構與腫瘤之必需氨基酸Phenylalanine結構類似，因此可被腫瘤吸收，但在近年來研究發現此藥物不僅會被腫瘤吸收，也會被一般腦細胞吸收，造成一般腦細胞之損害；BSH為另一常用之含硼藥物，但其於癌細胞之留存濃度不高；硼酸一般被認為在人體內擴散無特徵分佈，因此常被作為含硼藥物測量之控制組。現今硼中子捕獲治療所遇到最大的貧頸為含硼藥物無法有效的聚集於病灶，使得腫瘤細胞與一般細胞之硼濃度比(T/N ratio)無法提高，因此本研究目的及為設計一含硼藥物之奈米藥物載，使含硼藥物藉由奈米藥物載體聚集於腫瘤，提升T/N ratio。

Cancer is the first leading cause of death in developed countries and the second one in developing countries, accounting for around 13% of all deaths in 2008. Conventional cancer therapy, chemotherapy, the agents are distributed non-specifically where they affect both normal and cancerous cells. Nanoparticles drug delivery carriers, by using both passive and active targeting strategies, can enhance the intracellular concentration of drugs in cancer cells while avoiding toxicity in normal cells.
In previous researches, nanoparticles drug delivery carriers focus more on directly chemo drug carrying and delivering, however, the leakage of drug during circulation and unwanted organ/tissue targeting/accumulating pose serious side effects on the therapy [3]. Therefore, instead of carrying cancer drug directly, by carrying enzyme for directed enzyme prodrug therapy (DEPT) or boric acid for BNCT in demand may solve the aforementioned issues. Because in DEPT enzymes are caged and protected inside the nanoparticles for digesting non-toxic pre-drug into cancer drug and then released into tumor cite by diffusion and in BNCT alpha particles have high linear energy transfer and short path lengths (5-9um), in terms of theory, the boron-10-loaded drugs are accumulated in tumor cells that supply a selective way to destroy malignant cells and have little effect on normal cells.
In this study, alginate-based nanoparticles was employed to carry boric acid for its good biocompatibility and diffusivity. To enhance the protection of the drug being attacked from immune system including macrophage and antibodies but not deteriorate the drug diffusion properties too much, chitosan were engineered to coating on the alginate particle surface as a tunable pore size shell. Most importantly, the fabrication processes designed in this study are both aqueous base with enzyme compatibility.

摘要 I
Abstract III
誌謝 IV
目錄 V
圖目錄 VIII
第一章 緒論 1
1.1 研究背景前言 1
1.2 研究動機 2
第二章 文獻探討 4
2.1 奈米藥物釋放[1] 4
2.1.1脂質體（liposome） 6
2.1.2高分子奈米藥物載體 6
2.1.3無機奈米藥物載體 7
2.2 奈米藥物載體投藥系統 8
2.2.1前驅藥物[9,10] 8
2.3 硼中子捕獲治療 12
2.3.1機制 12
2.3.1目前使用藥物 13
2.3.2以liposome包覆含硼藥物 14
2.4 物理方式製備奈米藥物載體 20
2.4.1　多重相乳化 20
2.4.2　電噴灑[34] 22
2.5 幾丁聚醣(chitosan) 25
2.5.1　靜電作用力形成幾丁聚醣顆粒及褐藻膠顆粒奈米網狀結構 26
2.6 褐藻酸[37] 26
2.6.1 利電噴灑製造褐藻酸微米顆粒 [38] 27
2.6.1 利用褐藻酸與幾丁聚醣製造殼核奈米結構[39] 31
第三章 實驗設計與規劃 33
3.1 實驗設計與架構 33
3.1.1應用於前驅藥物治療之奈米藥物 34
3.1.2應用於硼中子捕獲治療之chitosan/alginate奈米顆粒 39
3.2 實驗藥品 41
3.2.1 實驗化學藥品 41
3.3 實驗步驟 43
3.3.1 PLGA-NHS製備 43
3.3.2水膠製備 43
3.3.3幾丁聚醣溶液製備 44
3.3.4幾丁聚醣/PLGA奈米顆粒實驗步驟 44
3.3.5幾丁聚醣/褐藻膠奈米顆粒實驗步驟 45
第四章 結果與討論 46
4.1 chitosan/PLGA殼核結構表現形貌及尺寸 46
4.2 chitosan/alginate殼核結構奈米顆粒特徵 47
4.2.1 chitosan/褐藻膠殼核結構表現形貌及尺寸 47
4.2.2 chitosan/褐藻膠殼核結構孔洞大小調控 52
4.2.3 chitosan/褐藻膠殼核結構pH stability測試 53
4.3幾丁聚醣/褐藻膠殼核奈米酵素載體殼層之酵素活性測試 56
4.5幾丁聚醣/褐藻膠殼核奈米載體應用於硼中子捕獲治療之結果 58
4.5.1奈米硼酸載體包覆率測試 58
4.5.2硼中子捕獲治療藥物毒性測試 60
4.5.3 幾丁聚醣/褐藻膠殼核奈米載體接枝EpCam antibody 61
4.5.4硼中子捕獲治療細胞測試 64
第五章 結論 70

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