本研究利用紅血球膜混合胰臟癌細胞膜的雜合膜包覆於中孔矽殼氧化鉍奈米粒子作為奈米載體，搭載化療藥物7-ethyl-10-hydroxycamptothecin (SN38) 及All-trans-retinoic acid (ATRA)，結合了化學/放射治療，用以改變胰臟癌微環境並提高胰臟癌的治療效果。研究中採取溶劑熱合成法製備氧化鉍奈米粒子，接著將中孔矽殼包覆其外層提供載藥空間，最後以超聲處理將雜合膜包覆於載體外。本研究利用氧化鉍本身為高原子序的原子，具有高X射線衰減係數及增強輻射作用，能應用於CT造影的顯影劑及化療的輻射增敏劑，加上雜合膜的修飾利於延長奈米載體於體內循環的時間且具同源靶向的特性，增加奈米載體於腫瘤處的累積，提高化學/放射治療的效果。我們於體外材料鑑定中，藉由TEM證明出本研究成功開發出具殼核結構的雜合膜包覆的奈米粒子，也證實含鉍的奈米載體具有CT顯影劑的潛力，在細胞實驗中證明雜合膜包覆的奈米載體細胞攝取優於只有紅血球膜包覆的奈米載體，且於同源的細胞株具同源靶向效果，此結果將利於精準醫學的客製化療程。接著藉由細胞毒性測試證明我們開發出搭載藥物的奈米載體能夠誘導胰臟癌細胞的死亡，最後利用維生素A的油滴生成與否證明載藥奈米藥物可以促進細胞中的維生素A油滴生成於胰臟星狀細胞中，逆轉胰臟星狀細胞的活化態以改變腫瘤的微環境，本研究期許藉由改變腫瘤微環境高度沉積的ECM，提高載藥奈米粒子於腫瘤處的累積，增加化學/放射治療的成功策略。

In this study we prepare a hybrid membrane by mixing red blood cell membrane and pancreatic cancer cell membrane, and use it to coat bismuth oxide nanoparticles loaded with SN38 and ATRA. The hybrid membrane provided excellent camouflage for immune escape and long-term body circulation, while the combination of chemo/radiotherapy and tumor microenvironment modification improved therapeutic effect. Bismuth oxide (Bi2O3) nanoparticles prepared by solvothermal method were coated with mesoporous silica shell to provide a space for drug loading. After the loading of SN38 and ATRA, bismuth oxide nanoparticles were camouflaged by hybrid membrane by sonication method. We utilized high Z element bismuth to efficiently absorb ionizing radiation to enhance therapeutic efficiency of X-ray radiation therapy and use Bi2O3 as a contrast agent for CT imaging. The modification of the hybrid cell membrane with the homologous targeting effect prolonged blood circulation by suppressing immune attack thereby allowing higher accumulation of nanoparticles at tumor. In the material identification, TEM image show that we developed hybrid cell membrane-coated nanoparticles with a core-shell structure. We further confirmed the use of our nanoparticles as CT imaging contrast agents. In vitro experiments proved the superior cellular uptake of nanoparticles coated with hybrid cell membrane as compared to nanoparticles coated with red blood cell membrane alone. This result will be beneficial to the customized therapy of precision medicine. The cytotoxicity test proved that the nanotherapeutics (S-MBO@A-RPCM) can induce the death of cancer cells and pancreatic stellate cells. Finally, the substantial accumulation of Vit. A lipid droplets in pancreatic stellate cells treated with nanotherapeutics can reverse the pancreatic stellate cells activation to change tumor microenvironment. This study expects to increase the accumulation of nanoparticles in tumor site by decreasing the extracellular matrix deposition and enhance chemo/radiotherapy strategy.

目錄 i
圖目錄 iv
表目錄 vi
摘要 vii
Abstract viii
致謝 x
一、研究動機 1
二、文獻探討 3
2.1 胰臟癌 3
2.1.1 胰臟癌的腫瘤微環境 4
2.1.2 化學治療 7
2.1.3 放射治療 8
2.1.4 醫學影像診斷系統 9
2.2 癌症治療策略與介紹 11
2.2.1 奈米藥物載體傳遞系統 11
2.2.2 Enhanced Permeation and Retention effects (EPR effects) 12
2.2.3 化療藥物7-ethyl-10-hydroxycamptothecin(SN38)介紹 13
2.2.4 All-trans-retinoic acid(ATRA)介紹 15
2.2.5 氧化鉍 16
2.2.6 中孔矽殼包覆奈米粒子之應用 19
2.2.7 細胞膜包覆奈米載體介紹 20
三、研究方法 26
3.1 材料合成與鑑定 26
3.1.1 氧化鉍奈米粒子 (Bi2O3) 製備 26
3.1.2 中孔矽殼包覆Bi2O3 (mesoporous silica coated Bi2O3, MBO) 合成 26
3.1.3 紅血球融合胰臟癌細胞膜之雜合膜包覆MBO (red blood cell membrane mixed pancreatic cancer cell membrane camouflaged MBO, MBO@RPCM) 製備 27
3.2 奈米載體製備與性質探討 29
3.2.1 搭載SN38及ATRA之奈米載體置備 29
3.2.2 奈米載體的粒徑分布以及表面電荷分析 30
3.2.3 奈米載體穩定度測試 31
3.2.4 奈米載體的CT顯影功能 32
3.2.5 膠體電泳分析奈米載體上保留之蛋白 32
3.2.6 奈米載體的藥物裝載量 33
3.3 體外細胞實驗 34
3.3.1 細胞來源及適合之培養環境 34
3.3.2 配置細胞培養液 35
3.3.3 細胞繼代 35
3.3.4 細胞計數 36
3.3.5 細胞對SN38及奈米載體吞噬情形分析 37
3.3.6 細胞毒性分析 39
3.3.7 誘導活化態的PSC轉變成靜止態 40
3.3.8 以Clonogenic survival assay探討放射線治療對細胞分裂之影響 41
四、結果與討論 43
4.1 奈米載體特性分析 43
4.1.1 奈米載體之性質鑑定 43
4.1.2 利用SDS-PAGE進行奈米載體之膜蛋白保留分析 48
4.1.3 奈米載體於CT顯影的材料分析 49
4.1.4 奈米載體於體外模擬生理環境下之穩定性 50
4.2 體外細胞實驗 51
4.2.1 細胞對奈米載體之吞噬情況 51
4.2.2 奈米載體對細胞毒性之分析 54
4.2.3 體外誘導活化態PSC轉變為靜止態 57
4.2.4 癌細胞之細胞分裂能力評估 58
五、結論 60
六、文獻參考 61

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