胰臟癌為難以治癒的癌症之一，雖然現今已經提出多種治療方式，但治療效果仍不如預期。本篇研究提出一個口服藥物遞送平台能自行產生二氧化碳（carbon dioxide，CO2）氣泡載體。此載體系統主要包含五種化合物：親水性藥物吉西他濱（gemcitabine，GEM）、親脂性藥物紫杉醇（paclitaxel，PTX）、癸酸（capric acid）、碳酸氫鈉（sodium bicarbonate，SBC）與檸檬酸（citric acid）等。利用此氣泡載體同時投遞PTX和GEM，並藉由氣泡的爆破來提升藥物於腸道的吸收性。GEM是一種具有抗腫瘤作用的核苷酸類似物，而PTX為一細胞有絲分裂抑制劑，二者皆為臨床胰臟癌第一線用藥，臨床上皆是以靜脈注射（intravenous，i.v.）投遞。脂質癸酸大量的存在於天然椰子油與動物乳奶中，碳酸氫鈉與檸檬酸為製藥上泡騰片（effervescent tablet）的主要成分。將所有化合物充分混合後裝載於膠囊中，並在膠囊外鍍上一層腸溶衣層（enteric coating）。經口服後，膠囊外的腸溶衣層在胃酸裡並不會受到影響，在小腸中性、弱鹼的環境下崩解釋放所攜帶的化合物。膠囊內的檸檬酸遇到腸液後會開始解離釋放出氫離子，產生出一暫時性的酸性環境並促使碳酸氫鈉裂解產生二氧化碳氣泡，而腸液中膽鹽（bile salt）具有界面活性劑的特性可幫助穩定CO2的氣泡結構，並以其形成的氣泡載體攜帶癸酸與親脂性藥物PTX。在口服投遞後，PTX會透過腸道內的淋巴循環系統進行吸收循環，最後再回到血液循環系統。而GEM則是直接透過一般的血液循環系統吸收，最後兩種藥物會累積在胰臟腫瘤組織中。在藥物動力學的實驗裡也證實口服藥物的組成成分相較於靜脈注射的組別有更低的毒性、更輕微的副作用卻有更高的生物可使用率，而口服投遞的組別也能有更好的抑制腫瘤生長、轉移等效果。本實驗數據證實了，我們所提出的口服藥物遞送平台能有效地抑制癌腫瘤的生長及其轉移，具有潛力改善胰臟癌的治療效果。

The therapeutic outcome of pancreatic cancer remains unsatisfactory, despite many attempts to improve it. To address this challenge, an oral drug delivery system that spontaneously initiates an effervescent reaction to form gas-bubble carriers is proposed. These carriers concurrently deliver lipophilic paclitaxel （PTX） and hydrophilic gemcitabine （GEM） in the small intestine. The bursting of the bubbles promotes the intestinal absorption of the drugs. The antitumor efficacy of this proposed oral drug delivery system is evaluated in rats with experimentally created orthotopic pancreatic tumors. The combined administration of equivalent amounts of PTX and GEM via the intravenous （i.v.） route, which is clinically used for treating pancreatic cancer, serves as a control. Following oral administration, the lipophilic PTX is initially absorbed through the intestinal lymphatic system and then enters systemic circulation, whereas the hydrophilic GEM is directly taken up into the blood circulation, ultimately accumulating in the tumorous pancreatic tissues. A pharmacokinetic study reveals that the orally delivered formulation has none of the toxic side-effects that are associated with the i.v. injected formulation； changes the pharmacokinetic profiles of the drugs； and increases the bioavailability of PTX. The oral formulation has a greater impact than the i.v. formulation on tumor-specific stromal depletion, resulting in greater inhibition of tumor growth with no evidence of metastatic spread. As well as enhancing the therapeutic efficacy, this unique approach of oral chemotherapy has potential for use on outpatients, greatly improving their quality of life.

摘要 ................. 1
Abstract........ 2
Contents .................. 3
一、 緒論................................ 5
1.1胰臟與胰臟癌............................... 5
1.2口服投遞藥物 ............................... 6
1.3 PTX ................................... 7
1.3.1 PTX作用機制....................................... 8
1.3.2 PTX副作用與投遞難題 ............................... 8
1.4 GEM ................................................ 9
1.4.1 GEM作用機制 ........................................ 9
1.4.2 GEM副作用與治療效率的降低 ............................... 10
1.5氣泡爆破式載體 .......................................... 11
1.6實驗架構 ....................................... 14
二、 材料與方法 .............................................. 16
2.1 材料 ............................................... 16
2.2脂質奈米乳化載體 ........................................ 16
2.2.1藥物載體組成成分最佳化 ................................. 16
2.2.2載體產泡能力及結構 ..................................... 16
2.3 劑型製備 ..................................... 17
2.4動物實驗 ......................................... 17
2.4.1原位胰臟癌腫瘤模型建立 ............................. 17
2.4.2藥物劑量最佳化 .................................... 18
2.4.3藥物吸收途徑 .................................... 18
2.4.4藥物吸收生體分布 .................................... 18
2.4.5 PTX、GEM之藥物動力學實驗 .............................. 19
2.4.6抗腫瘤藥效 ......................................... 20
2.4.7正電子發射電腦斷層掃描 ............................... 22
三、 實驗結果與討論 ........................................... 23
3.1脂質奈米油珠載體 ........................................... 23
3.1.1藥物載體產泡成分最佳化.................................. 23
3.1.2載體產泡能力及結構 ..................................... 23
3.2動物實驗 ............................................. 26
3.2.1藥物劑量最佳化 ....................................... 26
3.2.2藥物吸收途徑 ........................................... 27
3.2.3藥物吸收生體分布 ....................................... 28
3.2.4 PTX、GEM之藥物動力學實驗 ............................. 30
3.2.5動物胰臟癌模型治療效果 ................................ 32
3.2.6免疫組織染色 ......................................... 33
3.2.7正電子發射電腦斷層掃描 .............................. 35
四、 結論 ................................................. 37
五、參考文獻 ............................................... 38

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