臺灣博碩士論文加值系統

奈米粒子(nanoparticles, NPs)包覆第二型拓撲異構酶之etoposide (ETO)誘導腫瘤細胞的DNA損傷，從而引起IAPs消耗且經由Smac模擬物的BV6和SM164增強與IAPs拮抗作用，同時於粒子表面修飾轉鐵蛋白(transferrin, Tf)透過其在血腦屏障與腫瘤細胞大量表現之受體達到專一靶向結合之特性，並接枝麥胚凝集素(wheat germ agglutinin, WGA)輔助粒子穿透血腦屏障之能力。粒子材料選用生物相容性之可可脂(cocoa butter, CB)和聚乙烯醇(polyvinyl alcohol, PVA)作為載體主體，添加界面活性劑分別穩定乳化液和整體結構之單硬脂酸甘油酯(glycerol monostearate, GMS)以及Pluronic F-127，益於降低材料間之聚合並提高結構穩定性有助於後續生物實驗之應用，經由標靶藥物Tf和WGA修飾NPs包覆治療藥物能夠增加對血腦屏障的穿透率，穩定釋放藥物治療in vitro腫瘤細胞於48小時後約有40%細胞毒殺性，藉由in vivo HE染色觀察經治療後之腫瘤細胞型態其細胞密度降低且非典型細胞核分裂減少，治療藥物降低了cIAP-1和XIAP表現並增強caspase-3表現量，造成癌細胞走向凋亡途徑，期望雙功能標靶之奈米粒子傳遞藥物有望應用於腦癌疾病相關治療。

Nanoparticles (NPs) encapsulating etoposide (ETO), inhibitors of type II topoisomerase, induce DNA damage in tumor cells, leading to the depletion of IAPs and enhanced antagonistic effects with IAPs through the use of Smac mimetics BV6 and SM164. Additionally, the particles are surface-modified with transferrin (Tf) to achieve specific targeting by binding to receptors that are abundantly expressed in the blood-brain barrier and tumor cells. Wheat germ agglutinin (WGA) is grafted onto the particle surface to assist in penetrating the blood-brain barrier. The particle material is composed of biocompatible cocoa butter (CB) and polyvinyl alcohol (PVA) as the main carrier, with the addition of surfactants including glycerol monostearate (GMS) and Pluronic F-127 to stabilize the emulsion and overall structure. This reduces aggregation between materials and improves structural stability, which is beneficial for subsequent biological experiments. By incorporating the targeted drugs Tf and WGA, the encapsulated therapeutic drug-loaded NPs can increase the permeability of the blood-brain barrier. The stable release of the drug results in a reduction of approximately 40% in cell viability of tumor cells after 48 hours of in vitro. Hematoxylin and eosin (HE) staining of in vivo experiment reveals a decrease in cell density and a reduction in atypical nuclear division in treated tumor cells, indicating the effectiveness of the therapeutic drug. The treatment reduces the expression of cIAP-1 and XIAP while enhancing caspase-3 expression, leading to apoptosis in cancer cells. It is expected that these dual-targeting nanoparticles delivering drugs hold promise for the treatment of brain cancer-related diseases.

致謝 I
摘要 II
Abstract III
Abbreviation IV
目錄 V
表目錄 XI
圖目錄 XIII
第一章 研究動機與目的 1
第二章 文獻回顧 2
2.1 腦瘤(brain tumors) 2
2.2 血腦屏障(blood-brain barrier, BBB) 3
2.3 藥物載體 5
2.4 奈米粒子(nanoparticles, NPs) 5
2.5 轉鐵蛋白(transferrin, Tf) 6
2.6 麥胚凝集素(wheat germ agglutinin, WGA) 7
2.7 細胞凋亡抑制劑(inhibitor of apoptosis) 8
2.8 BV6 9
2.9 etoposide (ETO) 10
2.10 SM164 10
第三章 實驗材料、儀器、方法及步驟 12
3.1 實驗材料 12
3.1.1 奈米載體製備材料 12
3.1.2 奈米載體修飾 12
3.1.3 蛋白質定量分析 13
3.1.4 BV6、etoposide和SM164包覆和釋放 13
3.1.5 HBMECs、HAs和HBVPs繼代培養 13
3.1.6 U87MG cells繼代培養 15
3.1.7 HBCSCs繼代培養 15
3.1.8 細胞冷凍處理 15
3.1.9 細胞計數計算 15
3.1.10 細胞毒性測試 16
3.1.11 HBMECs/HAs/HBVPs共培養 16
3.1.12 免疫螢光染色 16
3.1.13 西方墨點法(western blot) 17
3.1.14 體內模型建立 19
3.1.15 HE stain 19
3.1.16 免疫組織染色 19
3.1.17 in vivo Western blot 20
3.2 其他實驗器材 21
3.3 實驗儀器 23
3.4 實驗方法與步驟 26
3.4.1 奈米載體製備 26
3.4.2 奈米載體修飾 26
3.4.2.1 Transferrin (Tf)定量分析 27
3.4.2.2 Wheat germ agglutinin (WGA)定量分析 28
3.4.3 粒徑及電位量測 28
3.4.4 場發射掃描式電子顯微鏡(Field emission scanning electron microscopes, FE-SEM) 29
3.4.5 穿透式電子顯微鏡(Transmission electron microscopes, TEM) 29
3.4.6 Fourier transform infrared spectroscopy (FTIR)分析 29
3.4.7 Differential scanning calorimetry (DSC)分析 30
3.4.8 X-ray photoelectron spectroscopy (XPS)分析 30
3.4.9 H-Nuclear magnetic resonance spectroscopy (H-NMR)分析 30
3.4.10 BV6-SM164-ETO-NPs製備 30
3.4.11 BV6、ETO和SM164包覆率分析 31
3.4.12 BV6、ETO和SM164藥物釋放率分析 32
3.4.13 最適化分析 34
3.4.14 U87MG cells培養液配置 35
3.4.15 Human brain cancer stem cells (HBCSCs)培養液配置 35
3.4.16 細胞培養預處理 35
3.4.17 U87MG cells繼代培養 36
3.4.18 HBCSCs繼代培養 37
3.4.19 HBMECs、HAs和HBVPs繼代培養 37
3.4.20 U87MG cells保存 38
3.4.21 HBCSCs保存 38
3.4.22 HBMECs、HAs和HBVPs保存 39
3.4.23 Transwell培養皿上PET模的表面預處理 40
3.4.24 星形細胞條件化培養基(astrocyte-condition medium, ACM)及周細胞條件化培養基(pericyte-condition medium, PCM) 40
3.4.25 HBMECs/HAs/HBVPs共培養 40
3.4.26 細胞的電阻測定(transendothelial electrical resistance, TEER) 41
3.4.27 Propidium iodide檢量線 42
3.4.28 Propidium iodide穿透實驗 42
3.4.29 體外血腦屏障模型實驗 43
3.4.30 Cell viability 44
3.4.31 螢光染色 44
3.4.31.1 Live/Dead 44
3.4.31.2 螢光奈米粒子製備 45
3.4.31.3 U87MG cells、HBCSCs免疫螢光染色 46
3.4.32 西方墨點法(western blot) 47
3.4.33 體內模型建立 51
3.4.34 藥物治療 52
3.4.35 H&E stain 52
3.4.36 免疫組織染色 52
3.4.37 大腦組織蛋白western blot分析 53
第四章 結果與討論 55
4.1 NPs之特性分析 55
4.1.1 Dynamic light scattering / zeta potential analyzer分析 55
4.1.2 Field emission scanning electron microscope (SEM) & Transmission electron microscope (TEM)分析 56
4.1.3 Differential scanning calorimetry (DSC)分析 57
4.1.4 Furier transform infrared (FTIR)分析 57
4.1.5 X-ray photoelectron spectra分析 58
4.1.6 H-Nuclear magnetic resonance spectroscopy (H-NMR)分析 58
4.2 NPs對藥物之包覆與釋放 60
4.2.1 藥物包覆率 60
4.2.2 藥物釋放率 61
4.3 NPs之最適化分析 62
4.4 NPs之表面接枝 63
4.5 體外血腦屏障模型穿透實驗 64
4.5.1 TEER和propidium iodide穿透率影響 64
4.5.2 藥物穿透率 65
4.6 細胞毒性分析與Live and dead 66
4.7 cIAP-1、XIAP、caspase-3 對於 U87MG cells 和 HBCSCs之螢光染色與蛋白表現量分析 68
4.8 in vivo GBM model 72
4.8.1 HE staining of brain tissue 72
4.8.2 cIAP-1、XIAP、caspase-3於GBM mice之免疫組織化學染色與蛋白表現量分析 73
第五章 結論與建議 76
參考文獻 77
附錄 162

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