為了增加硼中子捕獲治療中，現有藥物的T/N ratio，我們設計了可包覆含硼藥物的奈米藥物載體，利用奈米藥物的特性：體積小較容易被細胞吸收，與可藉由增強滲透及滯留的作用(enhanced permeability and retention, EPR)優先聚集於腫瘤附近來減少對身體帶來的副作用。
本研究使用電噴灑技術製備均勻性高的奈米藥物載體，成功設計出兩種奈米藥物載體，而其分別有不同的特性，一為利用褐藻酸鍶(Alginate strontium)包覆硼酸，外層以靜電力吸引的方式包覆幾丁聚醣(Chitosan)；另一為利用聚乙烯醇(Polyvinyl alcohol)鍵結硼酸，混以褐藻酸鍶形成緊密結構，外層以靜電力吸引的方式包覆幾丁聚醣。前者因其結構較為鬆散，內容藥物容易洩漏出來，所以適合應用於需要快速釋放的藥物；而後者之硼酸利用化學鍵緊緊抓住，因此不容易洩漏出來，因此可應用於長期釋放的藥物。而在硼中子捕獲治療中，後者的適用度較高，當奈米藥物載體抵達癌症部位時，外層的幾丁聚醣將因癌症部位的弱酸環境而崩解，內容藥物即可接收熱中子照射而釋放能量進而殺死癌症細胞。兩者的顆粒尺寸分別為164.8±39 nm與212.8±51 nm，而前者洩漏率高，約一天就洩漏50%的藥物；後者於兩天後僅洩漏約10%的藥物。應用於硼中子捕獲治療時，前者僅能造成約25%的癌症細胞死亡，然而後者最高能夠殺死80%的癌症細胞，且幾乎沒有細胞毒性。

In order to increase the T/N ratio of existing drugs in boron neutron capture therapy(BNCT), we designed a nano drug carrier for boron-containing drugs, using the characteristics of nano drugs: smaller size which is easily absorbed by cells, and can be benefit by the enhanced permeability and retention (EPR) preferentially accumulates in the vicinity of the tumor to reduce side effects to the body.
In this study, electrospray technology was used to prepare nano drug carriers with high uniformity. Two kinds of nano drug carriers were successfully designed, and they have different characteristics. One is to use alginate strontium to contain boric acid; the other is the use of polyvinyl alcohol to bond boric acid, mixed with strontium alginate to form a compact structure, and the outer layer of both carriers is chitosan. Because the former is loose in structure so the content drug is easy to leak out, it is more suitable for drugs that require rapid release; while the latter, boric acid is tightly grasped by chemical bonds and hard to leak out, so it can be applied to drugs that are released for a long time. In the BNCT, the latter has a higher applicability. When the nano drug carrier reaches the cancer site, the outer chitosan will disintegrate due to the weak acid environment of the cancer site, then serve the content drug with thermal neutron, and release energy to kill cancer cells. The particle sizes of the two are 164.8±39 nm and 212.8±51 nm, respectively. The former has a higher leak rate which leaks 50% of the drug in about one day; the latter only leaks about 10% of the drug after two days. For BNCT, the former can only cause about 25% of cancer cell death, but the latter is capable of killing up to 80% of cancer cells with little cytotoxicity.

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 5
2.1 硼中子捕獲治療 5
2.1.1 機制 6
2.1.2目前使用藥物 7
2.1.3 直接投藥的治療效果 8
2.1.4 以liposome包覆含硼藥物 10
2.2 奈米藥物釋放 15
2.2.1 EPR effect (enhanced permeability and retention effect) 16
2.2.2脂質體(liposome) 17
2.2.3 高分子奈米藥物載體 18
2.2.4 無機奈米藥物載體 19
2.3 奈米藥物載體投藥系統 20
2.4 物理方式製備奈米藥物載體 21
2.4.1 微流道成形 21
2.4.2 多重相乳化 26
2.4.3 電噴灑 27
2.5 褐藻酸 31
2.5.1 利用電噴灑製造褐藻酸微米顆粒 33
2.6 幾丁聚醣(chitosan) 36
2.6.1 靜電作用力形成幾丁聚醣及褐藻酸奈米網狀結構 36
2.6.2 利用褐藻酸與幾丁聚醣製造殼核奈米結構 37
2.7 聚乙烯醇(PVA)鍵結硼以提升硼含量 38
2.7.1 聚乙烯醇鍵結硼之結構與性質 38
2.7.2 PVA佐以Alginate與硼酸和氯化鈣形成顆粒 40
2.8 奈米藥物載體於體內累積 41
2.8.1 Liposome於體內累積 41
2.8.2 Alginate/chitosan奈米藥物於體內累積 42
第三章 實驗設計與規劃 45
3.1 實驗設計與架構 45
3.2 實驗藥品 47
3.3 實驗步驟 48
3.3.1 以褐藻酸鍶包覆硼酸為核心之奈米藥物載體 48
3.3.2 以聚乙烯醇鍵結硼為核心之奈米藥物載體 51
3.3.3 聚乙烯醇鍵結硼為核心之奈米藥物載體理論劑量計算 53
3.3.4 提升奈米藥物載體包覆率 54
第四章 結果與討論 56
4.1 以褐藻酸鍶包覆硼酸為核心之奈米藥物載體 56
4.1.1 奈米載體顆粒尺寸 56
4.1.2 chitosan殼層厚度 58
4.1.3 奈米藥物載體包覆率 59
4.1.4 奈米藥物洩漏率 60
4.2 細胞實驗 60
4.2.1 藥物毒性測試 60
4.2.2 硼中子捕獲治療測試 61
4.3 以聚乙烯醇鍵結硼為核心之奈米藥物載體 64
4.3.1 奈米顆粒性質 64
4.3.2 洩漏率 66
4.4 細胞實驗 68
4.4.1 藥物毒性測試 68
4.4.2 硼中子捕獲治療測試 69
第五章 結論 72
References 73

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