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研究生： 陳家怡
Chen, Chia-Yi
論文名稱： 負載順鉑的奈米藥物透過損傷溶酶體誘導鐵死亡與自噬失調增強三陰性乳癌的放射敏感性
Cisplatin-Loaded Nanomedicine Enhances Radiosensitivity by Inducing Ferroptosis and Autophagy Dysfunction via Impairment of Lysosomes in Triple-Negative Breast Cancer
指導教授： 王應然
Wang, Ying-Jan
學位類別： 碩士
Master
系所名稱： 醫學院 - 環境醫學研究所
Department of Environmental and Occupational Health
論文出版年： 2023
畢業學年度： 111
語文別： 中文
論文頁數： 71
中文關鍵詞： 三陰性乳癌 、放射療法 、順鉑 、奈米金 、溶酶體失調 、鐵死亡 、細胞自噬
外文關鍵詞： Triple-negative breast cancer, Radiotherapy, Cisplatin, Gold nanoparticle, Lysosomal dysfunction, Ferroptosis, Autophagy
相關次數： 點閱：96  下載：0 
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    • 據世界衛生組織於2020年的統計，乳癌是全球最常被診斷出的癌症，且其死亡率高，而其中大約有15至20%的患者屬於三陰性乳癌，其雌激素受體、黃體素受體與第二型人類上皮生長因子受體表達均呈陰性，因而無法使用賀爾蒙療法與標靶療法，而大多只能使用放射療法與化學療法進行治療。順鉑是一種有效的化療藥物，廣泛用於治療實體瘤，如乳腺癌、睾丸癌、卵巢癌、肺癌與頭頸癌等。在臨床上，順鉑經常被用作放射增敏劑，它可以與DNA結合形成鉑與DNA的鍵結物，使癌細胞DNA更容易受到游離輻射的傷害，進而引起更多的DNA損傷，對癌症的治療達到加成的效果。然而，傳統的化療藥物在臨床上依舊面臨著許多問題，如因缺乏標靶能力而導致嚴重的副作用等。因此，近年來，奈米技術在生物醫學領域上蓬勃發展。與傳統的抗癌藥物相比，奈米技術具有許多優勢。奈米藥物能夠透過靶向遞送，來減輕全身毒性，同時提高目標部位的治療效果。因此，本研究想設計一種奈米藥物來改善順鉑在治療上的嚴重問題。我們使用具有腫瘤靶向能力的褐藻醣膠進行載體修飾，使用pH敏感的苯乙烯馬來酸酐共聚物負載順鉑。我們將探討奈米藥物是否可以透過溶酶體損傷，誘導鐵死亡和自噬失調來增強三陰性乳癌對放射線的敏感性。
    奈米藥物由實驗室自行合成，並分析其物化特性。細胞實驗使用人類三陰性乳癌細胞MDA-MB-231-Luc細胞，並分成三個方面進行探討，分別是細胞對奈米藥物的攝取、有效性與機制探討，以細胞存活率、螢光顯微鏡、流式細胞儀、西方墨點法與免疫螢光染色等方法，觀察細胞存活狀況、溶酶體功能、細胞凋亡、鐵死亡與細胞自噬等相關分子機制。動物實驗使用NOD scid小鼠的原位異種移植模式，探討聯合療法的抗腫瘤功效，並以血清生化值與器官切片染色評估奈米藥物的生物安全性。
    由奈米藥物的X射線能量散布分析儀、紫外光光譜與傅立葉轉換紅外線光譜之結果證實成功合成出目標奈米藥物，且其平均水合粒徑為137.0奈米，界面電位為-67.3毫伏，表示奈米藥物的分散性穩定。細胞實驗結果顯示，與人類正常乳腺上皮細胞MCF-10A相比，P選滯蛋白在乳癌細胞中表達較多，並且在人類三陰性乳癌MDA-MB-231-Luc中的表現量是最高的，因此後續會選用MDA-MB-231-Luc細胞來進行實驗。接著在細胞存活率試驗中，看到隨著奈米藥物與放射線的劑量上升，MDA-MB-231-Luc細胞的存活率隨之下降，並且經計算後奈米藥物結合放射線是具有協同作用的，後續則選擇Au@PSMA-cis-fu 25 μg/mL合併放射線6 Gy來進行細胞實驗。在機制探討的研究結果中，看到奈米藥物可以在溶酶體內積累，並透過誘導溶酶體鹼化和膨脹，進一步導致MDA-MB-231-Luc細胞的溶酶體膜透化。此外，合併療法誘導MDA-MB-231-Luc細胞的凋亡、鐵死亡和自噬失調。動物實驗的結果顯示，合併療法相比單獨療法，能夠更好地抑制原位乳腺腫瘤的生長。
    目前奈米藥物之合成步驟已經確定，並且已透過紫外光光譜、傅立葉轉換紅外線光譜與動態光散射儀等儀器確認奈米藥物的確實合成以及其物化特性。而在細胞實驗中也透過檢測P選滯蛋白之表達來選定細胞株，並且以藥物合併指數選擇後續實驗將使用的奈米藥物與放射線劑量。此外，也觀察到合併療法可以透過損傷溶酶體，誘導細胞凋亡、鐵死亡與自噬失調。在體內研究中，合併療法具有良好的抗腫瘤功效。綜上所述，我們的實驗結果證實奈米藥物Au@PSMA-cis-fu與放射線的合併療法在三陰性乳癌的治療中是具有潛力的。

    In this study, human triple-negative breast cancer cells MDA-MB-231-Luc were used to investigate the effect and molecular mechanism of cisplatin-loaded nanomedicine, Au@PSMA-cis-fu, combined with radiation on cancer treatment. The results of in vitro test showed that Au@PSMA-cis-fu accumulated in the lysosome following cellular uptake. Then, gold nanoparticles in Au@PSMA-cis-fu induced lysosomal alkalinization and enlargement, which further caused lysosomal membrane permeabilization. After the combination treatment with radiation, the lysosome damage induced by Au@PSMA-cis-fu further caused the cancer cells death through apoptosis and ferroptosis. Additionally, lysosomal dysfunction also leaded to the blockage of autophagic flux, preventing the radioresistane of cancer cells via autophagy. In order to achieve the effect of radiosensitivity, in the in vivo study, we can verify that the combination treatment of Au@PSMA-cis-fu and radiation had great tumor suppression activity in MDA-MB-231-Luc tumor-bearing mice. However, the toxicity and side effects of nanomedicines on healthy tissues could still be observed in vivo. Therefore, we should be careful of the selection of doses.

    第一章、序論 1 第二章、背景介紹 2 一、三陰性乳癌(Triple-negative breast cancer, TNBC)及其治療方式 2 二、鐵死亡(Ferroptosis) 3 三、放射療法(Radiotherapy) 5 1. 抗癌原理 5 2. 放射抗性(Radioresistance)與放射敏感性(Radiosensitivity) 6 四、順鉑(Cisplatin) 9 1. 抗癌原理 9 2. 放射增敏機制 10 五、癌症領域的奈米技術(Nanotechnology) 10 1. 腫瘤標靶策略─以褐藻醣膠(Fucoidan)標靶三陰性乳癌中的P-selectin 11 2. 藥物釋放策略─PSMA於酸性環境中調控藥物釋放 11 六、奈米金(Gold nanoparticle, GNP/AuNP)的抗癌機制 12 第三章、研究目的 14 第四章、研究架構 15 一、奈米藥物的合成與物化特性分析 15 二、細胞實驗(In vitro study) 16 三、動物實驗(In vivo study) 17 1. 體內生物分布研究(In vivo biodistribution study) 17 2. 腫瘤抑制研究(Tumor suppression study) 18 第五章、研究材料與方法 19 一、研究材料 19 1. 細胞株 19 2. 試劑與溶液 19 3. 儀器 20 4. 耗材 21 二、研究方法與實驗步驟 23 1. 奈米藥物合成步驟與物化特性分析 23 2. 細胞實驗(In vitro study) 25 3. 動物實驗(In vivo study) 30 4. 統計分析 32 第六章、研究結果 33 一、奈米藥物合成步驟與物化特性分析 33 二、P-selectin蛋白表現量之評估 34 三、MDA-MB-231-Luc細胞對奈米藥物Au@PSMA-cis-fu的攝取情形觀察 35 四、Au@PSMA-cis-fu與放射線對MDA-MB-231-Luc的細胞毒性與協同效應 35 五、Au@PSMA-cis-fu累積在MDA-MB-231-Luc細胞的溶酶體內並造成溶酶體失調 36 六、Au@PSMA-cis-fu與放射線的合併處理誘導MDA-MB-231-Luc細胞凋亡 38 七、Au@PSMA-cis-fu與放射線的合併處理誘導MDA-MB-231-Luc細胞鐵死亡 39 八、Au@PSMA-cis-fu與放射線的合併處理誘導MDA-MB-231-Luc細胞自噬失調 39 九、褐藻醣膠能夠提高奈米藥物對MDA-MB-231-Luc腫瘤的標靶能力 40 十、Au@PSMA-cis-fu與放射線的合併處理抑制MDA-MB-231-Luc腫瘤生長 41 十一、Au@PSMA-cis-fu的正常組織的影響與副作用評估 41 第七章、討論 43 第八章、結論及建議 50 第九章、文獻參考 51 圖表 58

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