口服投遞藥物是最能被患者接受的給藥方式，然而疏水性藥物在口服後容易在腸道內自我聚集而無法有效的被吸收，因此其生體可利用率（bioavailability）普遍較低。治療胰臟癌的化療用藥—紫杉醇（paclitaxel, PTX）為一疏水性藥物，目前以靜脈注射給予治療，但未能標靶累積於腫瘤部位而造成許多副作用。因此，本研究透過腸道氣泡破裂介導形成的甘露糖修飾奈米油珠載體口服投遞紫杉醇。應用製藥上泡騰片（effervescent tablet）的產泡原理，疏水性藥物可透過奈米油珠載體攜帶並有效地分散在腸道之中；由D-甘露糖（D-mannose）與癸胺（decylamine）合成之N-癸基-D-甘露糖胺（N-decyl-D-mannosylamine, DMA）具有界面活性劑的特質，透過凝集素辨識實驗證實添加DMA可修飾甘露糖基團於奈米油珠載體表面，使奈米油珠載體擁有標靶甘露糖受體的特性。利用大鼠胰臟癌模型評估此系統的抗腫瘤功效，甘露糖修飾之奈米油珠載體可以藉由腸道中的甘露糖結合凝集素（mannose binding lectin, MBL）延長其在腸道的滯留時間，進而增進腸上皮細胞及微皺摺細胞對其之胞移作用（transcytosis），促進藥物載體吸收進入淋巴循環系統，避開肝臟的首渡效應（first pass effect），並藉由甘露糖基團將藥物載體標靶累積在腫瘤部位，除了毒殺腫瘤細胞，也同時調節腫瘤微環境，提升抗腫瘤效果，且有良好的生物安全性。這樣的口服抗癌治療方式可改善患者的生活品質，亦可標靶累積藥物於腫瘤部位以提升治療效果，具有臨床上應用之潛力。

The oral route is preferred for drug administration. However, orally taken hydrophobic drugs form insoluble aggregates upon exposure to bodily fluids in the gastrointestinal tract and cannot be effectively absorbed, so their bioavailability is low. Paclitaxel (PTX), a chemotherapy for pancreatic cancer, is a hydrophobic drug and that is delivered by intravenous (i.v.) injection. Without a targeting drug delivery system, PTX may accumulate in normal cells, causing many side effects. In this study, an oral drug delivery system that spontaneously initiates an effervescent reaction to form mannose-decorated nanoemulsions is developed to deliver PTX. By bursting of bubbles, PTX could be encapsulated in the formed nanoemulsions and be effectively dispersed in the intestinal tract. N-decyl-D-mannosylamine (DMA) synthesized from D-mannose and decylamine serves as a surfactant. A lectin recognition assay reveals that the mannose groups can be exposed on the surface of the nanoemulsions following the addition of DMA. The exposed mannose groups can bind to the mannose binding lectin (MBL) in the intestinal mucosa, promoting the transcytosis of enterocytes and microfold (M) cells. Furthermore, the mannose-decorated nanoemulsions can target mannose receptors that are expressed on stromal cells, specifically accumulating in the tumorous tissues. The system significantly improves pancreatic cancer treatment outcomes with good biosafety in the rats with an orthotopically created pancreatic cancer. This oral anticancer therapy not only has great efficacy, but also has potential for clinical application, improving the patients' quality of life.

摘要 I
Abstract II
目錄 III
圖表目錄 V
第一章 緒論 1
1.1 口服投遞藥物 1
1.2 胰臟與胰臟癌 3
1.3 疏水性抗癌藥物紫杉醇 4
1.4 腸道氣泡破裂介導形成的奈米油珠載體 6
1.5 甘露糖、甘露糖受體與甘露糖胺 8
1.6 實驗架構 10
第二章 材料與方法 12
2.1 材料 12
2.2 合成N-癸基-D-甘露糖胺（N-decyl-D-mannosylamine, DMA） 12
2.3 DMA之結構鑑定 13
2.4 DMA修飾之奈米油珠載體特性 13
2.4.1 穿透式電子顯微鏡（TEM） 13
2.4.2 凝集素辨識（Lectin recognition assay） 13
2.5 DMA劑量選擇 14
2.6 腸道氣泡破裂介導的甘露糖修飾乳化膠囊製備 14
2.7 實驗細胞與動物 14
2.8 動物原位胰臟癌模型建立 15
2.9 動物體內疏水性藥物的吸收 15
2.10 動物體內疏水性藥物的定性分布 15
2.11 原位胰臟癌治療效果及生物安全性 16
第三章 實驗結果與討論 17
3.1 N-癸基-D-甘露糖胺（DMA）之合成與鑑定 17
3.1.1 傅立葉轉換紅外線光譜（FTIR） 17
3.1.2 核磁共振（NMR） 17
3.1.3 質譜儀（MS） 21
3.2 甘露糖修飾奈米油珠載體特性 21
3.2.1 穿透式電子顯微鏡（TEM） 21
3.2.2 凝集素辨識（Lectin recognition assay） 22
3.3 DMA劑量選擇 23
3.4 動物體內疏水性藥物的吸收 25
3.5 動物體內疏水螢光藥物的定性分布 26
3.6 原位胰臟癌治療效果 28
3.7 生物安全性 30
第四章 結論 31
參考文獻 32

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