根據衛生署統計自民國71年起，癌症已蟬聯35年國人十大死因之首，每年皆奪去4萬多人的性命。癌症不但破壞了病患的日常生活，也連帶影響了家人的生活品質。而龐大的醫療費用支出更是拖垮健保制度的原兇之ㄧ 。在所有癌症類別中，頭頸癌因手術切除風險大，因此目前主要的頭頸癌治療方式分為放射治療與化學治療，但皆有其副作用且T/N比不高。
奈米藥物尺寸小，直徑約 100~200 奈米，癌細胞容易吸收，且可透過增強滲透及滯留的作用(enhanced permeability and retention, EPR)聚集於腫瘤附近，因此可減少對人體正常組織的傷害，因此本實驗設計以奈米顆粒當作藥物載體包覆硼酸，並應用於硼中子捕獲治療(Boron Neutron Capture Therapy, BNCT)。目前用於硼中子捕獲治療的藥物為 Borophenylalanine (BPA), Sodium borocaptate (BSH)，及硼酸。BPA 以必要胺基酸phenylalanine為主結構，因此易被癌細胞吸收。然而近年的研究發現當腫瘤吸收足夠的 BPA 後，多餘的 BPA 將排出至血液中，由附近正常細胞所吸收，因而造成正常細胞的受損。BSH為單一分子含 12 個硼原子的含硼藥物，然而其在癌症細胞的留存濃度與一般細胞無太大差異。而硼酸則當作含硼藥物測量之控制組。
本實驗提出並綜合兩合理的方案，試圖解決上述難題。ㄧ、利用奈米載體的特性聚集於腫瘤部位，提升 T/N ratio。二、效仿BPA原理，將癌細胞必需胺基酸phenylalanine 接枝於奈米載體外層。並應用於硼中子捕獲治療。

According to the statistics of the Department of Health, since the 71 years of the Republic of China, cancer has been the first of the top 10 causes of death among the 35-year nationals and killed more than 40,000 lives each year. Cancer not only destroyed the daily life of patients, but also affected the quality of life of their families. And the huge medical expenses are the ones that destroy the health insurance system. In all cancer categories, head and neck cancer due to the risk of surgical resection, so the current treatment of head and neck cancer is divided into radiation therapy and chemotherapy, but both of them have their side effects and T / N ratio is not high.
Nanomedicine is small in size and about 100-200 nm in diameter. It is easily absorbed by cancer cells and can accumulate near the tumor through enhanced permeability and retention (EPR), thereby reducing damage to normal human tissues Therefore, this experiment designed the nanoparticles as a drug carrier coated with boric acid, and applied to boron neutron capture therapy (Boron Neutron Capture Therapy, BNCT). Currently used for boron neutron capture treatment of drugs Borophenylalanine (BPA) , Sodium borocaptate (BSH), and boric acid. BPA is the essential amino acid phenylalanine-based structure, it is easily absorbed by cancer cells. However, recent studies have found that when the tumor absorbs enough BPA, excess BPA will be excreted into the bloodstream and taken up by nearby normal cells, causing normal cell damage. BSH is a boron-containing drug containing 12 boron atoms in a single molecule, however, its concentration in cancer cells is not much different from that in normal cells. Boric acid is used as a control group for boron-containing drug measurements.
The experiment proposed two reasonable solutions to try to solve the above problems. First, the use of nano-carrier characteristics gathered in the tumor site, improve the T / N ratio. Second, to follow the principle of BPA, the amino acid essential amino acids phenylalanine grafted to the outer layer of nanocarriers, then used in boron neutron capture therapy.

章節目錄
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 文獻討論 4
2.1 EPR效應[5] 4
2.1.1EPR效應原理及早期發展 4
2.1.2 SMANCS與新的癌症藥物傳遞概念 6
2.1.3奈米顆粒的長期循環 8
2.1.4 EPR模型 9
2.1.5 EPR之展望 10
2.2幾丁聚醣材料[85] 11
2.2.1幾丁聚醣與天然聚合物的吸引 12
2.2.2幾丁聚醣-褐藻膠複合物 12
2.2.3幾丁聚醣-角叉菜膠複合物 14
2.2.4幾丁聚醣-果膠複合物 15
2.2.5幾丁聚醣-黃原膠複合物 15
2.2.6 幾丁聚醣與合成聚合物之間的聚電解質錯合物 16
2.2.7幾丁聚醣之未來潛力 17
2.3 奈米藥物載體之Zeta potential對藥物傳遞系統的影響[121] 18
2.3.1 Zeta potential 之物理意義 18
2.3.2 Zeta potential之量測 19
2.3.3 Zeta potential與標靶藥物傳遞 19
2.3.4 Zeta potential對細胞吸收的影響 20
2.3.5 Zeta potemtial對皮膚給藥系統的影響 22
2.3.7 Zeta potemtial對腫瘤的標靶作用 23
2.3.8 Zeta potential在腦中的標靶作用 25
2.4 Boronphenylalanine(BPA)通過細胞膜之機制[193] 26
2.4.1細胞吸收分析 27
2.4.2 L運輸系統 28
2.4.3 A運輸系統 29
2.4.4 BPA之外排分析 30
2.4.5 BPA運輸系統 31
2.5硼中子捕獲治療治療口腔鱗狀上皮細胞癌之機制 34
2.5.1腫瘤抑制蛋白(p53蛋白) 34
2.5.2放射線對細胞的影響 34
2.5.3硼中子捕獲治療影響SAS細胞的機制[220] 35
2.6以電噴灑製備奈米藥物載體[223] 38
第三章 實驗設計與規劃 43
3.1實驗設計與架構 43
3.2 實驗藥品 45
3.3實驗步驟 48
3.3.1苯丙胺酸修飾幾丁聚醣[225] 48
3.3.2水膠製備 49
3.3.3幾丁聚醣溶液製備 49
3.3.4幾丁聚醣/褐藻膠奈米顆粒製備實驗步驟 49
3.3.5 加入PVA之新製程實驗流程 50
第四章 結果與討論 51
4.1 以phenylalanine修飾Chitosan 51
4.1.1氫譜 51
4.1.2碳譜 54
4.1.3 接枝率計算 56
4.2奈米顆粒 57
4.2.1 奈米顆粒表面電位 57
4.2.2 奈米顆粒尺寸 58
4.3 細胞毒性測試 58
4.4 藥物吸收量 60
4.5 SAS藥物吸收速率 61
4.8 含PVA藥物SEM圖 65
4.9 含PVA藥物毒性測試與照射 65
4.10 修飾後之幾丁聚醣包覆含PVA藥物進行BNCT 66
第五章 結論 68
第六章 未來工作 69
參考文獻 70

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