利用化學修飾菊苣纖維的口服載體包覆老藥新用作為肝癌組合式療法

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研究生：	林瑋晟 Wei-Cheng Lin
論文名稱：	利用化學修飾菊苣纖維的口服載體包覆老藥新用作為肝癌組合式療法 Dual repurposing drugs loaded in chemical-modified inulin as an oral administration drug carrier for liver cancer combination therapy.
指導教授：	白孟宜 Meng-Yi Bai
口試委員:	王毓淇 Yu-Chi Wang 鄭詠馨 Yung-Hsin Cheng
學位類別：	碩士 Master
系所名稱：	應用科技學院 - 醫學工程研究所 Graduate Institute of Biomedical Engineering
論文出版年：	2023
畢業學年度：	111
語文別：	中文
論文頁數：	95
中文關鍵詞：	菊苣纖維、口服載體、肝癌
外文關鍵詞：	Inulin, Oral administration, Liver cancer
相關次數：	點閱：205 下載：0
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上一筆

肝癌作為目前全球最為流行的癌症之一，一直是一個難以被治癒的疾病，從相關的文獻中可以知道無論是蕾莎瓦（Sorafenib）、樂衛瑪（Lenvatinib），這兩種晚期口服晚期抗癌藥物，都有明顯的副作用，且患者需要肝功能及體能良好才能使用該藥物，並且兩種藥物只能擇一使用，不能交互使用，因此在治療上有需多使用的困難以及治療效果不如預期的情形。
本研究希望透過新發現具有抗癌作用的老藥新用（Repurposing drug）的組合式療法，而不是使用已知的常見抗癌化療物作為目標，除了已知的藥物在毒性上有較久的臨床觀察，相關的安全性也較高，在法規的限制上也比新藥來的更易通過，然而本研究所使用的兩支老藥新用的藥品分別是耐克螺（Niclosamide）以及戒酒硫（Disulfiram）。不過這兩種藥都有一樣的問題，首先是親脂性高造成生物利用性低和嚴重的首度效應造成在胃部、腸道運輸的過程中造成大量的藥物失去活性，因此本研究選擇使用化學修飾菊苣纖維作為口服的兩性載體，該纖維的特性除了可以承受胃部的極端強酸還境之外，還可以被腸道吸收，因此本研究的化學修飾菊苣纖維包裹兩支老藥新用的口服顆粒，除了可以治療肝癌以外，還可以減輕患者在靜脈注射治療過程的痛苦以外，也可以降低感染的風險，避免手術置入人工血管或是中央靜脈導管的相關費用支出以及體力的消耗。

Hepatocellular carcinoma, being one of the most prevalent cancers worldwide, has posed significant challenges in terms of treatment due to its resistance to cure. Existing literature reveals that both Sorafenib and Lenvatinib, two orally administered advanced-stage anticancer drugs, exhibit notable side effects. Patients require well-functioning liver and overall health to tolerate these medications. Furthermore, the use of either Sorafenib or Lenvatinib is exclusive, prohibiting their combined administration. Consequently, therapeutic difficulties arise, leading to suboptimal treatment outcomes.
This study aims to explore a combination therapy approach using repurposed drugs with anticancer properties, rather than targeting conventional known anticancer chemotherapeutics. The selected repurposed drugs have established clinical observations of lower toxicity, increased safety, and easier regulatory clearance compared to novel drugs. The two repurposed drugs employed in this study are Niclosamide and Disulfiram. However, both drugs share a common challenge: their high lipophilicity results in reduced bioavailability and significant first-pass effects during gastric and intestinal transport. To address this issue, the study employs chemically modified inulin fibers as oral dual-functional carriers. These fibers not only withstand the harsh acidic environment of the stomach but are also absorbed in the intestines. Hence, the chemically modified inulin fiber encapsulates the repurposed drugs in oral granular form.
Beyond their efficacy against liver cancer, this approach offers additional advantages. It mitigates patient discomfort associated with intravenous injection treatments, reduces infection risks, and circumvents the expenses and physical toll of surgical implantation of artificial blood vessels or central venous catheters.

摘要    3
Abstract    4
致謝    5
目錄    6
第一章 緒論    1
1.1研究背景    1
1.2研究動機與目的    1
1.3論文架構    3
第二章 文獻回顧    4
2.1菊苣纖維（Inulin）    4
2-1-1菊苣纖維之結構與物化性質    4
2-1-2菊苣纖維（Inulin）在生醫材料領域的應用    4
2-2乙醯化菊苣纖維（Acetyl Inulin, INAc）    5
2-2-1乙醯化    5
2-3 Niclosamide    6
2-3-1 Niclosamide之結構與物化性質    6
2-3-2 Niclosamide在醫療領域的應用    7
2-3-3 Niclosamide臨床應用之難處    7
2-4 Disulfiram    8
2-4-1 Disulfiram之結構與物化性質    8
2-4-2 Disulfiram在醫療領域的應用    8
2-4-3 Disulfiram臨床應用之難處    9
2-5 電噴灑系統（Electrospray）    9
2-5-1電噴灑系統    9
2-5-2電噴灑之設置    9
2-5-3影響電噴灑系統之主要因素    10
2-6口服藥物系統（Oral administration）    11
2-6-1口服藥物介紹    11
2-6-2口服藥物載體之應用及其困難    12
2-7肝癌（Hepatocellular carcinoma）    13
2-7-1肝癌的介紹    13
2-7-2肝癌治療的困難    14
第三章 實驗內容    15
3-1實驗設計    15
3-2實驗材料與儀器    15
3-2-1材料    15
3-2-2儀器設備    16
3-3乙醯化菊苣纖維製備步驟    16
3-4試驗分析    17
3-4-1 傅里葉紅外線光譜儀（Fourier Transform Infrared Spectroscopy, FTIR）    17
3-4-2核磁共振光譜法（Nuclear Magnetic Resonance, NMR）    17
3-4-3掃描式電子顯微鏡（Scanning Electron Microscopy, SEM）    18
3-4-4微孔盤光譜分析儀（Plate Reader）    19
3-5細胞實驗測試    19
3-5-1四甲基偶氮唑鹽（MTT）試劑    19
3-5-2細胞毒性測試步驟    19
3-5-3 ROS測試（DCFH-DA）    20
3-5-4細胞ROS測試步驟    20
3-5-5 細胞中基因表現量（NF-κB）    21
3-5-6細胞中NF-κB基因表現測試步驟    21
3-5-7細胞轉移實驗-滑痕測試    22
3-5-8細胞轉移實驗步驟    22
3-5-9細胞內微絲（Actin filament）染色    23
3-5-10細胞內微絲（Actin filament）染色步驟    23
3-6動物實驗    24
3-6-1肝癌動物模型    24
3-6-2抗癌實驗流程    25
第四章 結果    25
4-1乙醯化菊苣纖維製備步驟    25
4-2定性分析    26
4-2-1 傅里葉紅外線光譜儀（Fourier Transform Infrared Spectroscopy, FTIR）    26
4-2-2核磁共振光譜法（Nuclear Magnetic Resonance, NMR）    27
4-2-3官能基取代率（Substitution Rate）    27
4-3電噴灑實驗（Electrospray）    28
4-3-1不同溫度的收集板對顆粒的影響    28
4-3-2不同溶劑比例對顆粒的影響    29
4-3-3不同乙醯化菊苣纖維濃度對顆粒的影響    29
4-3-4不同電噴灑距離對顆粒的影響    29
4-4細胞實驗測試    29
4-4-1細胞毒性測試（MTT assay）    29
4-4-2 ROS累積情形（DCFH-DA）    29
4-4-3細胞中癌症基因表現量（NF-κB）    30
4-4-4抗轉移實驗（滑痕測試）    30
4-4-5細胞內微絲染色（Phalloidin staining）    30
4-5動物實驗    30
4-5-1肝癌動物模型    30
4-6-2抗癌實驗流程    30
第五章 討論    31
5-1 乙醯化菊苣纖維    31
5-2不同參數對電噴灑實驗的影響    31
5-3口服藥物載體的細胞毒性    32
5-4口服藥物載體自由基累積和基因的表現    32
5-5口服藥物抗轉移能力及細胞內微絲變化    32
5-6口服藥物載體的抗癌動物模型    32
第六章 結論與未來展望    32
6.1結論    32
6.2未來展望    32
第七章 參考文獻    33



                                

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