根據世界衛生組織的數據，到2020年癌症相關死亡人數將增加到約1.5億。在90％的人類癌症相關死亡中，惡性轉移是主要原因。目前臨床上的主流療法，例如手術切除術，化學療法和放射療法，對於已經擴散和轉移的晚期癌症功效很有限，且對正常組織與細胞會造成附帶傷害，嚴重影響患者生活品質。許多研究顯示系統性激活免疫反應，在治療晚期或轉移性腫瘤方面有顯著效果。所以在本研究中我們將結合光熱消融(Photothermia ablation) 和免疫 (Immunotherapy) 的特性，合成出「高均一具尺寸優勢的三角Ag @ Au核/殼納米板」平台，並在外層裝飾巨噬細胞外泌體(Macrophage exosomes) ，以提高細胞的相容性和攝取量，並降低脫靶造成的毒性，及修飾「標靶性蛋白藥物爾必得舒 (Erbitux®)」，達到專一性標靶的目的。利用近紅外（NIR）照射以觸發由Ag @ Au納米板誘導的局部熱療，影響外泌體膜的滲透性，從而將包覆的治療性Ag @ Au納米板到標靶腫瘤區釋放，達到腫瘤穿透及治療效果。此外，等離子體貴金屬納米晶體的特徵，可以局部光熱療法（PTT）選擇性地消除腫瘤細胞，以產生腫瘤特異性抗原促進免疫。且治療性Ag @ Au納米板釋放的銀離子也可誘發免疫並協同免疫檢查點阻斷 (αPD-1)，建構了用於惡性和轉移性腫瘤的強效且可行的治療策略。
論文第一部分為巨噬細胞外泌體裝飾金/銀殼核三角納米板的合成與特性研究。以Ag納米片為犧牲模板的典型合成中，經由聚乙烯吡咯烷酮（PVP ) 作為用於調節晶體生長尺寸的封端劑、四氯合金酸(HAuCl4)作為Au源，可得到多孔Au-Ag合金納米板。但Au元素的比例僅為25.39％，使其結構穩定度不高並有過量的細胞毒性。因此，我們採用亞硫酸鹽絡合物( Na2Au（SO3）2 )作為Au源可以快速增加Au / Ag比，從而產生具化學穩定性的三角形Ag @ Au核/殼納米板，其周圍的金元素比率提升為56.67％。使用超聲處理外泌體，並且修飾爾必得舒最終合成Ag @ Au @ Exo-Er約為90-120 nm，可以減少其在血液的流動中被單核吞噬細胞系統清除的機會，同時增加腫瘤累積和癌症治療的效率。利用奈米粒子追蹤分析儀(Nanoparticle Tracking Analysis, NTA)分析外泌體的性質，得到平均大小約為88.5nm，透過不同時間點使用電子顯微鏡(TEM & EDS)、動態光散射(DLS)分析，觀察到外泌體逐漸凝結並裝飾Ag @ Au納米板的過程，且得知表面zeta電位為-18.3 mV，同時也確定金/銀三角納米板Ag的核心與分布周圍的Au元素輪廓。且使用凝膠電泳(SDS-PAGE)和西方墨點法專一性地檢測到Ag@Au@Exo上的外泌體蛋白質標記(CD63)。
第二部分以CT-26 (小鼠結腸癌成纖維細胞) 做為動物腫瘤模型。使用暗視野顯微鏡發現在不到2個小時Ag @ Au @ Exo-Er就有很明顯的細胞攝取，而12小時細胞累積的效果更大於Ag @ Au @ Exo組別。相較於單獨近紅外光生熱及單獨裝飾外泌體的組別，結合標靶性及光熱協同治療對於癌細胞的毒殺能力最佳。在流式細胞儀檢測CT-26腫瘤中T細胞浸潤比例，結果顯示給予光熱並結合αPD-1的組別可促使最佳免疫效果，數據分析cytotoxic T lymphocytes (CTLs) 達到6.52%，修飾標靶後更能提升至7.69%，而在單純Ag @ Au /αPD-1中，CTLs的百分比也增加到5.30％，顯然Ag @ Au釋放的銀離子可以誘導免疫應答，並進一步與αPD-1協同治療癌症，同時我們也發現在淋巴結中CTLs達到23.26%的顯著提升；在老鼠皮下腫瘤模式中，有修飾Erbitux的Ag @ Au@Exo納米板，尾靜脈注射後1天至3天腫瘤累積率可高達58-65%，接著施加NIR誘導外泌體包覆的治療性Ag @ Au納米板釋放與穿透至腫瘤深部，同時光熱轉換溫度達攝氏 53 度以上。腫瘤切片免疫螢光成像上，協同αPD-1免疫檢查點阻斷的激光治療組在CTLs細胞的浸潤顯著強於其他組別，而在Ag @ Au /αPD-1組別，還存在許多CTLs，表明腫瘤組織中仍存在抗腫瘤免疫，與流式細胞儀檢測結果相應。平均腫瘤生長方面有效的抑制，且在28天後皮下腫瘤已明顯消融。在治療組誘發記憶性免疫的成效，觀察到幾乎沒有肺轉移性腫瘤的產生，且沒有造成小鼠器官的傷害。故此光熱免疫協同αPD-1的標靶載體是一個有潛力的治療平台。

According to the World Health Organization, the number of cancer-related deaths will increase to about 150 million by 2020. Malignant metastasis is the leading cause of 90% of human cancer-related deaths. Many studies have shown that activation of the immune system has a significant effect in the treatment of advanced or metastatic tumors. In this study, we will combine the characteristics of photothermal ablation and immunity to synthesize a "highly uniform triangular Ag @ Au core/shell nanoplate" platform, and decorate macrophage exosomes in the outer layer to reduce the toxicity caused by off-target. In addition, the characteristics of metal nanoparticles can be used to selectively eliminate tumor cells by local photothermotherapy to produce tumor-specific antigens to promote immunity. Silver ions released from therapeutic Ag @ Au nanoplates can also induce immunity and synergistic immunological checkpoint blockade (αPD-1), constructing a powerful and feasible therapeutic strategy for malignant and metastatic tumors.
The first part of the article is the synthesis and characterization of Ag@Au@Exo-Er. The use of a sulfite complex (Na2Au(SO3)2) as the Au source can rapidly increase the Au / Ag ratio, resulting in a chemically stable triangular Ag @ Au core/shell nanoplate with an increase in the ratio of gold elements around it to 56.67%. The nature of the exosomes was analyzed using a nanoparticle tracking analyzer to obtain an average size of about 88.5 nm. Analysis of Ag @ Au @ Exo-Er is approximately 90-120 nm using an transmission electron microscope. The exosomal protein marker (CD63) on Ag@Au@Exo was specifically detected by gel electrophoresis (SDS-PAGE) and Western blotting.
The second part of the essay is in the cell experiment, and CT-26 (mouse colon cancer fibroblast) is used as an animal tumor model. In less than 2 hours, Ag @ Au @ Exo-Er has obvious cellular uptake, and the combination of target and photothermal therapy has the best ability to kill cancer cells. The cytotoxic T lymphocytes (CTL) reached 7.69%, while in Ag @ Au /αPD-1, the percentage of CTL increased to 5.30%. It is clear that the silver ions released by Ag @ Au can induce an immune response and further with αPD-1 synergistic treatment of cancer. In the subcutaneous tumor model of mice, the tumor accumulation rate can be as high as 58-65% from 1 day to 3 days after the tail vein injection. Effective inhibition in terms of mean tumor growth, and subcutaneous tumors had a significant ablation after 28 days. Then, the effect of the memory immunity induced by the treatment group was studied. It was observed that almost no lung metastatic tumor was produced, and no damage was caused to the organs in the mouse. This sophisticated Ag@Au@Exo-Er is an excellent delivery platform .

中文摘要 I
Abstract III
致謝 V
List of Figures X
List of Schemes XVII
Chapter 1 Literature Review and Theory 1
1.1 Progress of metastatic tumors 1
1.2 Nanoparticles as drug delivery systems 4
1.2.1 The particle size effect 7
1.2.2 The particle shape effect- Nanodisk vs Nanosphere 9
1.2.3 The surface chemistry effect 14
1.3 Nanocomposites targeted tumor delivery systems. 16
1.4 Characteristics of Gold-silver alloy nanoparticles 17
1.4.1 Gold-silver alloy nanoparticles reduce the toxicity of silver 21
1.4.2 Application of gold-silver alloy nanoparticle in anticancer and photothermal therapy 24
1.5 Cancer Immunotherapy 31
1.6 Immunomodulatory properties of silver nanoparticles 37
1.7 Application of metal nanoparticles in photothermal immunotherapy 39
1.8 Synergistic treatment of Anti-PD1 checkpoint blockers 43
1.9 Exosome summary and exosomes secreted by macrophages 48
1.9.1 Exosome for drug delivery systems 53
Chapter 2 Experimental Section 56
2.1 Materials 56
2.2 Apparatus 60
2.3 Method 62
2.3.1 Synthesis of Ag Nanoplates (Seeds) 62
2.3.2 Preparation of Growth Solution of Au 62
2.3.3 Synthesis of Triangular Ag@Au Core/Shell Nanoplates 64
2.3.4 Synthesis of Ag@Au@Exo-Er 65
2.3.5 Characterizations 67
2.3.6 Photothermal Ablation Effect of Ag@Au 68
2.3.7 Ag@Au Loading Efficiency and Encapsulation Efficiency 68
2.3.8 Synthesis of the triangular Ag@Au core/shell nanoplates analysis 69
2.3.9 Cell culture 69
2.3.10 Cellular Uptake 71
2.3.11 Cell viability assay 72
2.3.12 Targeting ability of the Ag@Au@Exo-Er was quantified by flow cytometry 73
2.3.13 SDS PAGE experiments 74
2.3.14 Western Blot 74
2.3.15 Ex vivo analysis of different groups of T cells 75
2.3.16 Long-term immune effect of Ag@Au@Exo-Er (L) + AP on post-therapy rechallenged tumor 78
2.3.17 CT-26 Cells were stained to visualize live and dead cells 79
2.3.18 Histology Analysis. 80
2.3.19 Cell loading for spheroid formation 80
2.3.20 Penetration of the nanoparticles in CT-26 spheroids 82
2.3.21 Tissue section immunostaining 83
2.3.22 In vivo experiments 84
Chapter 3 Results and Discussions 86
3.1 Synthesis and morphology of Ag nanoplates, Exosome, Holey Au@Ag alloy nanoplates, Triangular Ag@Au Nanoplates and Ag@Au@Exo-Er 88
3.2 Characterization of Ag@Au, Ag@Au@Exo, Exosome and Ag@Au@Exo-Er 103
3.3 Triangular Ag @ Au core / shell nanoplates by NIR-laser photothermal conversion 109
3.4 Cytotoxicity and cell uptake of Ag@Au@Exo-Er 111
3.8 In vivo animal experiment 127
Chapter 4 Conclusions 143
Reference 144

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