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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳進庭(Chin-Tin Chen) | |
| dc.contributor.author | Chien-Yu Chen | en |
| dc.contributor.author | 陳芊伃 | zh_TW |
| dc.date.accessioned | 2023-03-19T23:16:44Z | - |
| dc.date.copyright | 2022-07-22 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-07-15 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/85447 | - |
| dc.description.abstract | 腫瘤缺氧(tumor hypoxia)在癌症進展中扮演關鍵角色，並且是造成腫瘤細胞抗藥性的重要機制之一，這不但是目前癌症治療的一大挑戰，也是預後不良的指標。由於腫瘤缺氧區域氧氣含量不足、癌細胞生長緩慢且血流供應較差，傳統的化學療法、放射線療法對於缺氧的腫瘤細胞往往療效有限，因此發展針對缺氧區域的治療方式有其必要性。缺氧活化前驅藥物(hypoxia-activated prodrug)能針對缺氧細胞產生選擇性毒性，而Tirapazamine (TPZ)即為其中一種，其在缺氧環境下能活化產生自由基，造成DNA斷裂而引發細胞死亡，此特性使TPZ被廣泛研究作為對抗腫瘤缺氧的治療方式。然而，TPZ在體內的半衰期短、容易被代謝，且在腫瘤中的累積量不足，因此臨床效果不如預期。因此在本研究中，以發展改善TPZ在體內的穩定性，增加腫瘤累積藥量，並且有利於臨床使用的劑型為目標。 本研究中利用銅離子與TPZ進行錯合，以促進TPZ的包覆。銅離子TPZ錯合物[Cu(TPZ)2]為疏水性物質，為增加Cu(TPZ)2的溶解度，我們進一步選用白蛋白(albumin)與Cu(TPZ)2形成奈米粒子(nanoparticles)，並優化白蛋白奈米粒子的製備過程，接著於in vitro實驗分析其儲存穩定性、血清穩定性、以及細胞毒殺效果。之後我們進一步以戊二醛(glutaraldehyde)將白蛋白奈米粒子交聯，改善其血清穩定性。最後在in vivo中初步探討ANP-Cu(TPZ)2的療效。 | zh_TW |
| dc.description.abstract | Tumor hypoxia remains one major challenge in treating solid tumor as it contributes to cancer progression and drug resistance. Conventional radiotherapy and chemotherapy have shown limited efficacy in treating hypoxia regions within solid tumor, indicating the importance of tumor hypoxia in cancer therapy. Tirapazamine (TPZ), a hypoxia-activated prodrug (HAP), produces toxic radicals that cause DNA breaks under hypoxic conditions. Despite its potential in selective cytotoxicity against hypoxic cells in tumor, clinical efficacy of TPZ is unsatisfactory due to its short half-life and rapid metabolism, rendering insufficient tumor accumulation. These obstacles indicate the need of better drug delivery system. Herein, we developed cupric-TPZ albumin nanoparticles [ANP-Cu (TPZ)2] with size of approximately 130 nm and high entrapment efficiency. Cupric ions were used to complex with TPZ to increase its hydrophobicity. Hydrophobic Cu(TPZ)2 was then encapsulated with albumin. In vitro analyses have shown that ANP-Cu(TPZ)2 display good storage stability and cytotoxicity. The serum stability of ANP-Cu(TPZ)2 was further improved by glutaraldehyde crosslinking. The therapeutic efficacy was further evaluated in mice bearing synergistic C26 tumor. | en |
| dc.description.provenance | Made available in DSpace on 2023-03-19T23:16:44Z (GMT). No. of bitstreams: 1 U0001-1307202217351200.pdf: 2084770 bytes, checksum: 3e33c6c0d71839e9de6a07ae235e6fe8 (MD5) Previous issue date: 2022 | en |
| dc.description.tableofcontents | 目錄 致謝 i 中文摘要 ii Abstract iii 目錄 iv 表目錄 vii 圖目錄 viii 附圖表目錄 ix 第一章 緒論 1 1.1 腫瘤缺氧 (tumor hypoxia) 1 1.1.1 腫瘤缺氧與抗藥性 2 1.2 缺氧活化前驅藥物 (hypoxia-activated prodrugs, HAPs) 2 1.2.1 Tirapazamine (TPZ) 3 1.3 金屬與金屬化合物 4 1.3.1 銅離子與銅離子化合物 5 1.4 蛋白質奈米傳輸系統 (protein-based nanoparticulate delivery system) 6 1.4.1 白蛋白奈米粒子(albumin nanoparticle, ANP) 7 1.5 研究動機與目的 8 第二章 材料與方法 10 2.1 藥品 10 2.2 儀器 11 2.3 細胞培養 (Cell culture) 13 2.3.1 細胞株 13 2.3.2 細胞培養液 13 2.3.3 繼代培養方法 13 2.3.4 細胞解凍與冷凍方法 13 2.3.5 細胞計數 14 2.4 ANP-Cu(TPZ)2製備與純化 14 2.5 ANP-Cu(TPZ)2交聯(Crosslinking) 15 2.5.1 戊二醛(Glutaraldehyde, GLA)交聯 15 2.5.2 孟加拉玫瑰紅(Rose Bengal)交聯 15 2.6 白蛋白奈米粒子內TPZ定量 15 2.7 ANP-Cu(TPZ)2儲存穩定性分析 16 2.8 ANP-Cu(TPZ)2血清穩定性分析(serum stability) 16 2.9 細胞存活率檢測 – MTT assay 17 2.10 活體動物實驗 17 2.10.1 動物與腫瘤模式 17 2.10.2 TPZ合併Ce6光動力治療 18 2.10.3 TPZ合併Stilbene 5C 18 2.11 統計分析 18 第三章 結果 19 3.1 製備包覆Cu(TPZ)2的白蛋白奈米粒子 19 3.2 以熟成方式穩定ANP- Cu(TPZ)2 20 3.3 ANP-Cu(TPZ)2性質分析 21 3.4 ANP-Cu(TPZ)2儲存安定性分析 21 3.5 ANP-Cu(TPZ)2血清穩定性分析 21 3.6 In vitro毒殺效果分析 22 3.7 交聯白蛋白粒子 23 3.7.1 交聯後血清穩定性 23 3.7.2 交聯後in vitro毒殺效果 24 3.8 In vivo療效分析 24 3.8.1 ANP-Cu(TPZ)2與Ce6光動力治療併用 25 3.8.2 ANP-Cu(TPZ)2與Stilbene 5C併用 26 第四章 討論 27 4.1 以Cu2+與TPZ錯合形成Cu(TPZ)2 27 4.2 製備與優化ANP-Cu(TPZ)2 28 4.3 ANP-Cu(TPZ)2穩定性分析與優化 29 4.4 In vitro之ANP-Cu(TPZ)2療效初步分析 30 4.5 In vivo之ANP-Cu(TPZ)2療效分析 31 4.5.1 ANP-Cu(TPZ)2與Ce6 光動力治療併用 32 4.5.2 ANP-Cu(TPZ)2與Stilbene 5C併用 32 第五章 結論 36 第六章 未來展望 37 參考文獻 57 表目錄 表一 以TPZ:BSA不同莫耳比攪拌製備之ANP粒徑、PDI、外觀 38 表二 以不同混合方式製備之ANP粒徑、PDI、外觀 39 表三 ANP-Cu(TPZ)2與150 mM PBS共培養後之粒徑、PDI變化 40 表四 ANP-Cu(TPZ)2的性質分析 41 表五 以Rose Bengal或Glutaraldehyde交聯後之ANP-Cu(TPZ)2的性質分析 42 圖目錄 圖一 熟成溫度與時間對於ANP-Cu(TPZ)2粒徑的影響 43 圖二 熟成溫度與時間對於ANP-Cu(TPZ)2在150 mM PBS中培養 (A)2小時 (B)20小時後粒徑大小的影響44 圖三 ANP-Cu(TPZ)2於4℃下儲存30天內之 (A)粒徑與PDI (B)藥物留存率(%) 45 圖四 ANP-Cu(TPZ)2於10%與60% FBS中之血清穩定性分析 46 圖五 ANP-Cu(TPZ)2於 (A)Normoxia (B)Hypoxia下之細胞毒殺效果分析 47 圖六 ANP-Cu(TPZ)2於(A)Normoxia (B)Hypoxia下處理4小時之毒殺效果分析 48 圖七 ANP-Cu(TPZ)2於不同交聯處理後之血清穩定性分析 49 圖八 GLA-ANP-Cu(TPZ)2於(A)Normoxia (B)Hypoxia之細胞毒殺效果分析 50 圖九 TPZ與Ce6光動力治療併用後之 (A)小鼠腫瘤大小 (B)小鼠體重 51 圖十 TPZ與Stilbene 5C併用治療之 (A)小鼠腫瘤大小 (B)小鼠體重 52 附圖表目錄 附表一 GLA-ANP-Cu(TPZ)2 於in vivo 研究中之腫瘤外觀 (第一次給藥後8天) 53 附圖一 TPZ作用機制 54 附圖二 TPZ與Cu2+錯合結構 55 附圖三 ANP-Cu(TPZ)2製備與純化流程 56 | |
| dc.language.iso | zh-TW | |
| dc.subject | 缺氧 | zh_TW |
| dc.subject | Tirapazamine | zh_TW |
| dc.subject | 白蛋白奈米粒子 | zh_TW |
| dc.subject | Tumor hypoxia | en |
| dc.subject | Tirapazamine | en |
| dc.subject | Albumin nanoparticles | en |
| dc.title | 開發用於遞送Tirapazamine之白蛋白奈米載體 | zh_TW |
| dc.title | Development of Tirapazamine-Loaded Albumin Nanoparticles | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 110-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 蔡翠敏(Tsuimin Tsai),吳亘承(Hsuan-Chen Wu) | |
| dc.subject.keyword | Tirapazamine,白蛋白奈米粒子,缺氧, | zh_TW |
| dc.subject.keyword | Tirapazamine,Albumin nanoparticles,Tumor hypoxia, | en |
| dc.relation.page | 62 | |
| dc.identifier.doi | 10.6342/NTU202201451 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2022-07-18 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科技學系 | zh_TW |
| dc.date.embargo-lift | 2022-07-22 | - |
| 顯示於系所單位： | 生化科技學系 | |
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