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系統識別號 U0026-0303201917395900
論文名稱(中文) 探討零價鐵奈米藥物誘導的癌細胞鐵死亡機制與再敏化策略
論文名稱(英文) Investigation of the Zero-valent Iron-based Nanotherapeutics for Ferroptosis Induction and Resensitization Strategy in Cancer Cells
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 107
學期 2
出版年 108
研究生(中文) 黃光靖
研究生(英文) Kuang-Jing Huang
學號 S58024012
學位類別 博士
語文別 英文
論文頁數 97頁
口試委員 指導教授-謝達斌
共同指導教授-吳尚蓉
召集委員-王憶卿
召集委員-蘇五洲
召集委員-蔡曜聲
口試委員-陳家俊
口試委員-李新城
口試委員-鄭豐裕
中文關鍵字 零價鐵奈米粒子  鐵死亡  芬頓反應  粒線體脂質過氧化  穀胱甘肽過氧化物酶 
英文關鍵字 zero-valent iron nanoparticles  ferroptosis  Fenton reaction  mitochondrial lipid peroxidation  glutathione peroxidase 
學科別分類
中文摘要 奈米材料已廣泛應用於生物醫學領域,包括生物感測、組織工程、免疫調節以及當作癌症藥物的運輸載體。近年來,一些奈米材料已被發現在不需攜帶化療藥物的情況下即具有內生性的抗癌潛力,例如碳60富樂烯、奈米鑽石……等。然而,隨著這些無修飾奈米材料受到越來越多的關注,癌症對於奈米藥物的抗藥性逐漸成為奈米醫學領域的關鍵問題。儘管奈米醫學抗藥性對於其最終的臨床試驗和優化癌症治療策略至關重要,至今文獻中仍然很少討論此問題。我們先前的研究發現了鐵核金殼 (Fe@Au)奈米粒子具有選擇性毒殺癌細胞的能力,並能造成粒線體功能缺失,其未氧化的零價鐵(ZVI)核心是導致細胞毒性的主要成分,但大腸直腸癌與一些頭頸癌細胞株對此奈米粒子具有較高的耐受性。在本研究中,我們製備不同種類的零價鐵奈米粒子並對7種頭頸癌細胞株進行系統性的細胞毒性篩檢。其中OEC-M1、OC3和SCC9被發現為零價鐵敏感性細胞系。HSC-3、SAS、KOSC-3和OC2則一致地顯示出對這些零價鐵奈米粒子有高度耐受性。在零價鐵奈米粒子的治療中,游離的二價鐵離子主要引發芬頓反應,並隨後誘導出過量的自由基進而攻擊癌細胞。然而,對零價鐵有耐受性的癌細胞可以限制其自由基的激增。零價鐵奈米粒子的抗癌能力是透過自由基依賴性的細胞死亡但不伴隨典型細胞凋亡的產生。我們進一步證實鐵死亡是調控零價鐵奈米粒子治療效果和其抗藥性的中樞機制。在敏感性癌細胞中,零價鐵誘導的鐵死亡特徵為粒線體脂質過氧化和其胞器中穀胱甘肽過氧化物酶(GPx)蛋白的降低。但是具抗性的癌細胞可以減弱零價鐵誘導的氧化壓力和GPx減少。他們還具有較強的粒線體呼吸能力,進而抵抗零價鐵奈米粒子造成的線粒體膜電位損失。成對的零價鐵奈米粒子抗性與敏感性癌細胞株之轉錄組分析和定量聚合酶連鎖反應結果(qPCR)顯示具零價鐵抗性的細胞株表達了一系列與鐵死亡抗性相關的基因組,包括增強的NADPH水平、更高的對於活性氧物質的解毒能力,以及對鐵死亡誘導劑(FINs)的敏感性降低。最後,我們發現某些鐵死亡誘導劑能夠再敏化這些具零價鐵抗性的癌細胞,且不會損害健康的正常細胞。這些研究結果表明鐵死亡機制可以作為零價鐵奈米藥物和其再敏化策略的重要分子標靶。我們預期這項研究將優化我們對於精準化奈米醫學的設計,以及幫助開發能預測癌細胞對臨床結果易感性的伴同診斷生物標記。
英文摘要 Nanomaterials have been widely applied in the biomedical field including the development of biosensors, tissue engineering scaffolds, immunomodulation, and carriers for targeted drug delivery. Some nanomaterials such as Fullerene-C60 and nanodiamond were identified to harbor endogenous anti-cancer potency without carrying any chemotherapy drugs. While more and more bare nanomaterials have drawn increasing attention, cancer drug resistance is becoming a critical issues in nanomedicine field. Nanomedicine resistance is critical for its ultimate clinical success and for further advancing therapeutic designs in cancer therapy despite such issue is rarely discussed in the literatures. Our previous studies showed that iron core-gold shell (Fe@Au) nanoparticles have selective anti-cancer activity which can lead to mitochondria dysfunction. The cytotoxicity is mainly caused by the non-oxidized zero valent iron (ZVI) core. However, some resistant cell lines have been identified in colon and oral cancers. In this study, we applied different types of ZVI NPs to systematically screen out sensitive versus resistant head and neck cancer cell lines. OEC-M1, OC3 and SCC9 were identified as ZVI-sensitive cell lines, while HSC-3, SAS, KOSC-3 and OC2 showed high tolerance to these ZVI NPs challenges. We discovered that free Fe2+ ion release is a major mechanism that triggered Fenton reaction followed ZVI NPs treatment. In contrast, ZVI-refractory cell lines can limit surge of reactive oxygen species (ROS). Such anti-cancer potency of ZVI NPs is derived by a ROS-dependent cell death without accompanying apoptosis. We further confirmed that ferroptosis is the central mechanism governing therapeutic efficacy and resistance of ZVI NPs treatment. In ZVI-sensitive cells, ZVI NPs-induced ferroptosis was characterized by mitochondrial lipid peroxidation and reduced glutathione peroxidases (GPx) in subcellular organelles. However, the resistant cells can attenuate ZVI-induced oxidative stress and GPx reduction. The resistant lines also presented stronger mitochondrial respiration activity to resist ZVI NPs-induced mitochondrial membrane potential loss. Pairwise transcriptome comparison and quantitative polymerase chain reaction (qPCR) of cell lines resistant versus sensitive to ZVI nanoparticle treatment revealed that ZVI-resistant clone expressed a gene set conferred enhanced NADPH supply, higher detoxification capacity of reactive oxygen species, and reduced sensitivity to ferroptosis inducers (FINs). Finally, we discovered that certain FINs were able to sensitize ZVI-resistant cancer cells to become treatable without compromising healthy non-malignant cells. These findings suggest that ferroptosis can serve as a druggable target for anti-cancer nanomedicine and resensitization strategy using ZVI NPs. We anticipate this study will inspire optimization of companion biomarkers diagnostics based precision nanomedicine.
論文目次 摘要………………………………………………………………………………………................................................................................................................. II
Abstract………………………………………………………………………………................…................................................................................................IV
Acknowledgement……………………………………………………………………..............................................................................................................VI
Table of Content……………………………………………………………………...........................................................................................................VIII
List of Figures……………………………………………………………………………...........................................................................................................XI
List of Tables…………………………………………………………………………...........................................................................................................XIII
Abbreviations……………………………………………………………………...............................................................................................................XIV
Chapter 1. Introduction……………………………………………………………….........................................................................................................1
1.1 Nanotechnology……………………………………………………………...................................................................................................2
1.1.1 Nanomedicine in cancer therapy…………………...................................................................................................3
1.1.2 Application of bare nanomaterials in cancer therapeutics………………..................................................................................5
1.2 Nanoparticle-triggered programmed cell death……….…...............................................................................................7
1.2.1 Ferroptosis and tumor suppression…………………………………………...............................................................................................8
1.2.2 Emerging strategies for ferroptosis induction in cancer cells………...............................................................................10
1.3 Zero-valent ion nanoparticles…………………………………………..............................................................................................……….12
1.3.1 Development of zero-valent-iron-based nanoparticles as the cancer-selective ferroptosis agent…………………………….......................................13
1.3.2 Cancer drug resistance issue in ZVI-based nanomedicine………………...................................................................................14
Chapter 2. Materials and methods……………..................................................................................................................17
2.1 Preparation of ZVI-based NPs…………………………………………………................................................................................................18
2.2 Characterization of ZVI@CMC NPs…………………………………………................................................................................................18
2.3 Cell culture and cell survival assays…………………………..............................................................................................……19
2.4 Intracellular and mitochondrial ROS analysis…………...............................................................................................20
2.5 Determination of cell apoptosis…………………………......................................................................................................21
2.6 Measurement of mitochondrial membrane potential…...............................................................................................21
2.7 Assessment of mitochondrial respiration function...............................................................................................22
2.8 Assessment of mitochondrial LPO and morphological changes…………….................................................................................22
2.9 Western blot analysis of GPx-1 and GPx-4 levels in subcellular fractions…......................................................................23
2.10 RNA extraction, microarray, and qPCR measurement…..............................................................................................24
2.11 Xenograft model……………………………………………...............................................................................................................25
2.12 Statistical analysis………………………………………………………………...................................................................................................25
Chapter 3. Results ………………………………………………………………………....................................................................................................26
3.1 Characterization of ZVI@CMC NPs and the stability assessment…………...............................................................................27
3.2 Head and neck cancer cell lines displayed heterogeneous susceptibility to ZVI-based NPs……………………………………………………………………….............................28
3.3 Excessive Fenton reaction-derived oxidative stress was induced in ZVI-sensitive cells by ZVI@CMC NPs....................................................................................................................................................28
3.4 ZVI@CMC NPs-treated sensitive cells underwent oxidative non-apoptotic cell death……………………………………………………………………………..................................29
3.5 Mitochondrial hyperoxidation and dysfunction are the hallmarks in ZVI@CMC NPs-induced ferroptosis…………………………………...……............................30
3.6 Transcriptome analysis links the ferroptosis pathway to ZVI-resistance...................….....................................................32
3.7 FINs enhanced the anti-cancer potency of ZVI@CMC NPs in ZVI-refractory cancer……………………………………………………………………….....................................……36
Chapter 4. Discussion……………………………………………………………………........................................................................................................37
Chapter 5. Conclusion………………………………………………………………….........................................................................................................41
REFERENCES………………………………………………………………………….................................................................................................................44
FIGURES and LEGENDS………………………………………………………………............................................................................................................60
TABLES …………………………………………………………………………………................................................................................................................91
ACHIEVEMENTS………………………………………………………………………................................................................................................................93
CURRICULUM VITAE (CV)………………………………………………………............…............................................................................................... 94
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