第一部分
至今，惡性腦瘤之治療策略仍極度匱乏。為此，本研究開發一可精準靶向至 腦腫瘤區的治療試劑，並結合光動力及光熱雙重療法進行如同手術般的精準治療。 此一治療手段乃建立於具 angiopep-2 修飾之升頻奈米粒子，藉由 angiopep-2 與內 皮細胞上大量表現之 low-density lipoprotein receptor-related protein-1 (LRP-1) 結 合後可經胞移作用 (transcytosis) 穿越內皮細胞構築而成的血腦障壁 (blood- brain barrier, BBB)，並得以進一步標靶至同樣具 LRP-1 過度表現之腦瘤細胞，此 舉大幅改善一般治療試劑於腦瘤區累積成效不彰的缺憾。光動力治療係利用對深 層組織具極佳穿透度之近紅外光 (980 nm) 照射升頻奈米粒子並透過升頻轉換 機制放射波長 660 nm 的可見光以活化搭載於載體的光動力治療藥物 mTHPC (此 舉有效克服光敏藥物於深層組織無法有效被光激活的困境) 產生活性氧化物 (reactive oxygen species, ROS)。光熱治療則係直接利用近紅外光 (808 nm) 直接 激活光熱治療藥物 IR-780 產生高溫，達到有效且精準的熱治療。細胞實驗表明 修飾angiopep-2之奈米粒子大幅提升腦瘤細胞 (ALTS1C1cancercells) 之吞噬效 率並達到有效毒殺癌細胞之效果，動物實驗亦闡明修飾 angiopep-2 之奈米載藥粒 子得以大幅地穿透血腦障壁累積於腦瘤。經此雙重光治療後之腦瘤亦透過免疫組 織化學切片確認光動力治療誘發之細胞凋亡 (apoptosis) 及光熱治療導致之細胞 壞死 (necrosis)。值得一提的是，經光動力/光熱雙重治療之小鼠組別其平均存活 天數相較於控制組延長了 1.7 倍。本研究紮實的數據與強而有力的結果論述在在 地表明其卓越的治療成效並充分地顯示其未來應用於臨床之可能。
第二部分
腦內類澱粉蛋白寡聚體 (amyloid-b oligomers, oAb42) 經神經元細胞吞噬後 造成毒殺及經腦內微膠細胞 (microglial cells) 攝取後誘發大量的促發炎因子釋出已證實為導致阿茲海默症 (Alzheimer's disease) 的主因 之一，且目前臨床上仍缺乏有效治療方案。為突破此困境，本研究開發之磁攪拌 棒平台得以透過物理性磁性攪拌進行極具毒性之類澱粉蛋白寡聚體捕捉，並將其 集結成較低毒性之磁性斑塊，亦協同活化微膠細胞對斑塊進行移除以達到有效之 阿茲海默症治療。免疫組織化學染色證實，經磁攪拌棒治療之神經元細胞仍保有 微管相關蛋白 (microtubule-associatedprotein2,MAP2) 之高度表達，相反地，僅 與 oAb42共培養之組別則大幅降低其表現。酵素免疫分析法 (enzyme-linked immunosorbent assay, ELISA) 則表明微膠細胞吞噬磁性斑塊後大幅降低其轉換 為 M1 表現型之可能，進一步遏止促發炎因子釋放。值得一提的是，類神經元細 胞 (N2a cells) 處於微膠細胞與磁性斑塊共培養後之培養基有較高之存活率，無 非係歸功於此治療策略大幅抑制微膠細胞釋放發炎因子。海馬迴組織切片分析 (H&E, SOSG, caspase-3 IHC staining) 則闡明經磁攪拌治療後之腦部組織無顯著 細胞凋亡，Prussian blue 結果則顯示磁攪拌棒能於腦部有效地被降解，血液生化 分析則進一步展現其優異之生物相容性。基於上述研究成果，此磁攪拌棒治療平 台無疑提供一有效並具前瞻性之阿茲海默症治療策略。

Part I
To enhance the therapeutic efficacy of photo-based treatments on brain tumor, a versatile upconversion nanoparticle (UCNP) therapy delivery system capable of converting deep tissue-penetrating near-infrared (NIR) light into visible wavelength for activating photochemical reaction was developed in this work. The functionalized nanoparticle-based therapy system was attained from the assembly of oleic acid-coated UCNPs along with angiopep-2/cholesterol- conjugated poly(ethylene glycol) and hydrophobic photosensitizers, IR-780 for photothermal therapy (PTT) and 5,10,15,20-tetrakis(3-hydroxyphenyl)chlorin (mTHPC) for photodynamic therapy (PDT), respectively. The PDT was triggered upon the reactive oxygen species (ROS) generation by irradiation at 980 nm with the upconversion reaction of UCNPs for resonance energy transfer to mTHPC at 660 nm. Angiopep-2 was employed as a targeting ligand on nanoparticle (NP) surfaces by its binding ability with the low-density lipoprotein receptor-related protein-1 (LRP-1) of endothelial and astrocytoma cells to enhance blood-brain barrier (BBB) penetration and tumour accumulation. The in vitro data demonstrate the enhanced uptake of the drug-loaded NPs by murine astrocytoma cells (ALTS1C1) and pronounced cytotoxicity by combined photoactivated PDT and PTT. The immunohistochemical (IHC) examination of tumor sections confirmed the prominent apoptotic and necrotic effects on tumour cells from mice receiving the targeted dual photo-based therapies, which also led to the promoted median survival (24 days) as compared to the NP treatment without angiopep-2 (14 days).
Part II
Soluble amyloid-b oligomers (oAb42)-induced neuronal death and inflammation response has been recognized as one of the major causes of Alzheimer’s disease (AD). In this work, a novel strategy adopting silica-coated iron oxide stir bar (MSB)-based AD therapy system via magnetic stirring- induced capture of oAb42 into magnetic plaques (mpAb42) and activation of microglia on cellular plaque clearance was developed. With oAb42 being effectively converted into mpAb42, the neurotoxicity toward neuronal cells was thus greatly reduced. In addition to the well preservation of neurite outgrowth through the diminished uptake of oAb42, neurons treated with oAb42 under magnetic stirring also exhibited comparable neuron-specific protein expression to those in the absence of oAb42. The phagocytic uptake of mpAb42 by microglia was enhanced significantly as compared to the counterpart of oAb42, and the M1 polarization of microglia often occurring after the uptake of oAb42 restricted to an appreciable extent. As a result, the inflammation induced by pro- inflammatory cytokines was greatly alleviated.Furthermore, the brain tissue histologic study showed no obvious tissue damage with the mice receiving the MSB stirring treatment in the hippocampus area. Neither cell apoptosis nor ROS generation in the brain tissues were found significantly increased. The MSBs were extensively degraded over 15 days after the intracranial injection. These results strongly suggest that the magnetic stirring treatment with MSBs be a promising strategy for improving the AD treatment.

Part I
Abbreviation list............................................................................................5
Table list.......................................................................................................9
Figure list.....................................................................................................10
1. Abstract....................................................................................................11
2. 摘要 .........................................................................................................12
3. Literature review and theory....................................................................13
3.1 Glioblastoma multiforme........................................................................13
3.2 Blood-brain barrier.................................................................................14
3.3 BBB permeation mechanisms................................................................15
3.4 Targeting delivery...................................................................................16
3.5 Phototherapy..........................................................................................18
3.6 Upconversion nanoparticles...................................................................20
4. Materials and methods.............................................................................22
4.1 Reagents and materials..........................................................................22
4.2 Synthesis of UNCPs...............................................................................24
4.3 Preparation and characterization of functionalized therapeutic NPs....24
4.4 Cellular uptake.......................................................................................26
4.5 In vitro photothermal and photodynamic effects of ANG-IMNPs..........27
4.6 In vitro BBB penetration of NPs.............................................................28
4.7 Orthotopic glioblastoma model and biodistribution..............................28
4.8 Anti-GBM effect....................................................................................29
4.9 Immunohistological examination of tumor tissues................................29
4.10. Stastical analysis................................................................................30
5. Results and discussion............................................................................30
5.1 Synthesis and characterization of ANG-IMNPs.....................................30
5.2 In vitro photo-induced therapy..............................................................35
5.3 In vivo imaging and biodistribution........................................................38
5.4 Photo-mediated destructuion of orthotopic glioblastoma....................39
6. Conclusions.............................................................................................41
7. References...............................................................................................58
Part II
Abbreviation list...........................................................................................74
Table list.......................................................................................................77
Figure list.....................................................................................................78
1. Abstract....................................................................................................80
2. 摘要..........................................................................................................81
3. Literature review and theory....................................................................82
3.1 Alzheimer’s disease................................................................................82
3.2 Amyloid beta generation........................................................................85
3.3 Microglial cell polarization......................................................................87
4. Materials and methods.............................................................................91
4.1 Reagents and materials...........................................................................91
4.2 Preparation and characterization of MSBs.............................................92
4.3 Preparation and characterization of oAb42 and natural Ab42 plaques.93
4.4 In vitro stirring-induced oAb42 capture.................................................94
4.5 Cell membrane damage and neurite outgrowth impairment...................95
4.6 Cell functions..........................................................................................97
4.7 Phagocytic acitvity of microglial cells.....................................................98
4.8 Cytokine production................................................................................98
4.9 Brain tissue toxicity and damage with MSB stirring................................98
4.10 Statistical analysis.................................................................................99
5. Results and discussion............................................................................100
5.1 Preparation and characterization of MSBs............................................100
5.2 Capture efficiency of Ab42 by magnetic stirring of MSBs and in vitro
therapeutic efficiency..................................................................................102
5.3 Functionality of N2a cells and phagocytic action of BV-2 cells............106
6. Conclusions.............................................................................................109
7. References...............................................................................................134

Part I
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