現今治療腦瘤的方法大致分為以下幾種，包括手術切除、放射治療與化學療法等方式，但往往會受到許多限制，而治療後的效果也不如其他癌症類型顯著。隨著藥物遞送系統的發展，許多研究均合成奈米藥物載體，透過標靶及控制釋放的特性，提高藥物在腫瘤的累積及治療效果。在腦瘤的治療上，由於血腦障壁的阻隔，大多數的藥物都無法完全穿透至腦腫瘤區，因此開發出一種同時兼具治療與穿透能類的藥物載體是必須的。
本研究中，我們合成出外泌體(Exosomes)修飾的多孔性奈米氧化鐵奈米粒子，利用其多孔洞的結構，載負含有免疫調節功能的免疫佐劑 Resiquimod (R-848) 的次級載體-樹狀聚合物。根據TEM與SEM的分析，成功製備出粒徑約150奈米，表面含有膜狀結構的多孔性材料，經過蛋白質分析鑑定確認此膜狀結構來自外泌體。在細胞試驗中，經過表面修飾後的載體與為修飾前相比，載體在濃度300 μg/ 時的細胞毒性降低約40%，表現出良好的生物相容性，在與細胞一同培養4 小時後，載體可完全進入細胞內。然而，隨著高週波磁場照射的時間增長，細胞的存活率隨之下降至60% 左右，即表現出磁熱治療的可行性。為了減少動物試驗的誤差與實驗動物數量，我們透過3D細胞微球實驗來模擬載體在腫瘤微環境的穿透度與治療效果，經長時間觀察可以發現到載體本身對癌細胞有良好的攝取能力，且在照射磁場後，展現出良好的癌細胞殺傷能力。
另外，我們透過對流增強遞送系統 ( Convection-enhanced delivery, CED) 的方式輸送藥物至腦腫瘤區域，直接穿越血腦障壁的阻擋，提高藥物於腫瘤位置的濃度以達到更佳的治療效果。在動物試驗上，透過CED的輔助，奈米粒子在腦腫瘤區具有良好的分布，且並未發生明顯的逆流現象。小鼠在施加外部高週波磁場後，獲得良好的熱治療效果並誘發免疫反應發生，治療組別在腫瘤區域的T細胞明顯增加，在搭配免疫調節劑後以增強免疫治療的效果，腫瘤生長明顯受到抑制，並成功延長小鼠的中位存活期，由原本的31天增加至43 天。
因此，外泌體修飾的多孔性複合型奈米粒子可視為具有潛力的多功能藥物輸送平台，除載體本身具有磁性性質可達到熱治療的效果，搭載R-848免疫佐劑增強腫瘤區域的免疫應答，達到有效的癌症抑制，對於腦癌治療來說，此種療法可作為一良好的選擇。

Despite the advancement of medical technology in recent years, brain cancer is still considered difficult to treat. In this study, we developed a mesoporous iron oxide nanoparticle functionalize the exosomes membrane. To enhance the penetration and drug loading capacity, we use the dendrimer as a secondary drug carrier to deliver the immune modulator (R848). Through convection-enhanced delivery (CED), we could across the BBB directly and make sure that the drug was maintained at the therapeutic dose. Moreover, we applied the high-frequency magnetic field (HFMF) to trigger magneto-thermal therapy and also stimulate the immune response. The immune modulator (R848) may enhance the immune system to achieve the more effective immunotherapy. The results indicated that Fe3O4-Den-Exo present low toxicity and high cellular uptake efficiency. The cell viability increased 40% after the iron oxide nanoparticles modified with exosomes, and decreased to 60 % when applied with HFMF. This method inhibited the tumor growth and extended the mice median survival from 31 to 43 days. It was successful to combined the hyperthermia and immune therapy for brain cancer treatment in this study.

中文摘要 ------I
Abstract ------III
List of scheme ------VII
List of table ------VIII
List of figure ------IX
Chapter 1 Introduction ------ 1
Chapter 2 Literature review and theory ------3
2.1. Nowadays brain cancer ------3
2.2. The magnetic nanoparticles property and cancer applications ---4
2.3. Exosomes ------7
2.3.1. Introduction of exosomes ------7
2.3.2. Exosomes in cancer treatment ------9
2.4. Convection-enhanced delivery system ------12
2.4.1. Introduction of Convection-enhanced delivery ------13
2.4.2. Convection-enhanced delivery for the treatment of brain cancer ------15
2.4.3. Catheter design ------18
2.5. Immunotherapy of brain cancer ------21
2.5.1. Interaction between the immune system and brain cancer ----21
2.5.2. Immunotherapy of brain cancer ------23
Chapter 3 Experimental section ------28
3.1 Materials ------28
3.2 Apparatus ------31
3.3 Method ------33
3.1.1 Synthesis of mesoporous iron oxide nanoparticles ------33
3.3.2 Synthesis of G2-PBA dendrimers and Fe3O4-Den ------33
3.3.3 Modification of transferrin ------34
3.3.4 Modification of Exosome ------34
3.3.5 Cell culture ------35
3.3.6 Cellular uptake ------35
3.3.7 Flow Cytometry ------36
3.3.8 Cell viability assay ------37
3.3.9 Penetration of the nanoparticles in ALTS1C1 spheroids ------37
3.3.10 In vivo experiments ------39
3.3.11 SDS-PAGE experiments ------40
3.3.12 Western Blot ------42
Chapter 4 Results and Discussions ------43
4.1 Synthesis and characterization of Fe3O4-Den-Exos ------43
4.2 Cell uptake and cytotoxicity of Fe3O4-Den-Exos ------50
4.3 Flow cytometry of Fe3O4-Den-Exos ------54
4.4 Penetration of Fe3O4-Den-Exos into tumor spheroids ------55
4.5 In vivo animal experiment ------61
4.5.1 In vivo animal experiment for biodistribution ------61
4.5.2 The effect of the immune system by hyperthermia treatment ---64
4.5.3 In vivo therapy ------66
Chapter 5 Conclusions ------70
Reference ------71

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