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作者(中文):陳彥勳
作者(外文):Chen, Yen-Hsun
論文名稱(中文):開發金屬錯合奈米藥物以擾動細胞內氧化還原平衡進行抗腫瘤治療
論文名稱(外文):Development of Metal-cooridinated Nanodrugs to perturb the Cellular Redox Balance for Anticancer Therapy
指導教授(中文):黃郁棻
指導教授(外文):Huang, Yu-Fen
口試委員(中文):李岳倫
黃志清
口試委員(外文):Lee, Yueh-Luen
Huang, Chih-Ching
學位類別:碩士
校院名稱:國立清華大學
系所名稱:生醫工程與環境科學系
學號:107012520
出版年(民國):109
畢業學年度:108
語文別:英文
論文頁數:117
中文關鍵詞:抗腫瘤治療奈米藥物氧化還原平衡
外文關鍵詞:anticancer therapynanodrugsredox balance
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先前研究顯示,癌細胞由於致癌性刺激、細胞代謝增加和粒線體功能損壞所引起的氧化壓力(Reactive oxygen species stress) 會持續增加。由於癌細胞對氧化刺激的耐受性較低於正常細胞,因此增加癌細胞內活性氧 (Reactive oxygen species, ROS) 似乎是一種有前途的癌症治療方法。本研究中,透設計兩種過金屬配位奈米藥物,破壞癌細胞內氧化還原平衡進行抗腫瘤治療。在第一項研究中,藉由金離子 (Au(III)) 與線嘌呤 (Adenine, A) 的自組裝錯合物 (Au:A) ,合成奈米粒子 (p(Au:A/ATP)),並於合成過程中加入抑制細胞內穀胱甘肽 (Glutathione, GSH) 合成之藥物,丁硫氨酸磺酰亞胺 (Buthionine sulfoximine, BSO),合成載負BSO之金屬配位奈米藥物 (B@p(Au:A/ATP))。藉由同時抑制細胞內GSH和硫氧還蛋白還原酶 (thioredoxin reductase, TrxR) 的協同作用,相對於單一種治療,此策略可有效抑制腫瘤。在第二項研究中,通過鄰苯二胺 (o-phenylenediamine, OPD) 水解聚合成具有標靶粒線體功能之碳奈米載體 (Carbonized polymer dot, CPD),並藉由胺基螯合鉑離子 (CPD-Pt(II)) 作為藥物傳遞系統。進入粒線體後,CPD-Pt(II)可消耗粒腺體內GSH含量,使其產生大量粒線體ROS (Mitochondria ROS, mROS),與傳統藥物順鉑 (Cisplatin) 相比,可進一步使癌細胞產生大規模ROS損傷,進而表現出良好的抑制腫瘤治療效果。
Growing evidence suggests that cancer cells continuously exhibit increased intrinsic reactive oxygen species (ROS) stress resulted from oncogenic stimulation, increased metabolic activity, and mitochondrial malfunction. Oxidative insult appears to be a promising approach to cancer treatment owing to the fact that cancer cells confer less tolerance to oxidative stress than normal cells. Herein, we introduced two novel strategies based on the design of metal-coordinated nanodrugs to direct the ROS-mediated cancer therapy. In the first study, a supramolecular synthesis route was presented for self-assembly of coordinated Au(III)adenine (Au:A) complexes into nanoparticles (NPs). By encapsulation of buthionine sulfoximine (BSO), a specific glutathione (GSH) synthesis inhibitor into the coordinated A-Au networks, the BSO-loaded NPs, exhibited a synergistic cancer cell killing performance through a simultaneous intracellular GSH depletion and thioredoxin reductase (TrxR) inactivation, demonstrating a superior tumor regression activity than the respective monotherapy. In the second study, a mitochondria-targeting nanocarrier, which was produced via the hydrolysis of o-phenylenediamine (OPD) into carbonized polymer dots (CPD) was presented for Pt(II)-anchoring and delivery. After entry into mitochondria, CPD-Pt(II) could deplete intramitochondrial GSH level, causing overwhelming mitochondrial ROS (mROS) generation. Further production of intracellular ROS also leads to extensive oxidative damage, which in turn results in successful tumor eradication as compared with traditional antineoplastic drugs, cisplatin.
摘要
目錄
第一章......1
第二章......10
第三章......31
第四章......54
附錄........55
參考文獻.....109
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