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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 江建文(Kien Voon Kong) | |
dc.contributor.author | Yun-Chin Wu | en |
dc.contributor.author | 吳昀瑾 | zh_TW |
dc.date.accessioned | 2023-03-19T21:20:15Z | - |
dc.date.copyright | 2022-07-29 | |
dc.date.issued | 2022 | |
dc.date.submitted | 2022-07-25 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/83842 | - |
dc.description.abstract | 許多文獻證實高反應性的活性氧 (ROS),是促發神經突觸增長和抑制澱粉樣蛋白β?聚集和神經元纖維纏結的關鍵因子,神經細胞緩慢內化載體以及半衰期短的光敏劑藥物阻礙光動力治療的應用。本研究設計了一種由螺?喃 (spiropyran) 和金奈米粒子合成的水凝膠,有望成為有效的光敏劑並抑制Aβ?聚集。螺?喃和具有表面電漿共振之金奈米粒子作用後,穩定螺?喃異構化後的部花青(merocyanine) 結構(拉曼光譜顯示可穩定 1.7 倍)。由於部花青和表面電漿共振的金奈米粒子相互吸引作用,而增加了平面共振結構的穩定性,增加光敏劑的半衰期時間(~24小時),由於水凝膠生物相容性高,螺?喃@Au 奈米凝膠表現出顯著神經元細胞快速內化(比螺?喃奈米凝膠快約 3 倍)和應用於抑制32% Aβ?聚集和神經元纖維纏結。這種高效能光動力治療和快速神經元內化的實驗結果,提高了光致變色分子和等表面電漿共振水凝膠材料應用的機會。 | zh_TW |
dc.description.abstract | Reactive oxygen species (ROS) has been identified as the key mechanism leading to neurite outgrowth and inhibition of β-amyloid (Aβ) accumulation and neurofibrillary tangles (NFTs). Slow neuronal internalization and short half-life of photosensitizing effects still impede the application of photosensitizers for photodynamic therapy (PDT). Here we demonstrate that the nanogels made of spiropyran and gold nanoparticles can be an effective and long-acting photosensitizer for anti-Aβ accumulation. Spiropyran and plasmonic nanoparticles are rationally integrated to stabilize the isomerization process of spiropyran to merocyanine (a 1.7-fold decrease in Raman intensity). The perfect match configuration of spiropyran and nanoparticles increases the stability of the planar merocyanine structure, resulting in generation of long-lived phototherapy response (an increase stability ~ 24 h). Owing to the compositional benefits, the spiropyran@Au shows remarkable rapid neuronal internalization (~ 3 times faster than the spiropyran) and anti-β-amyloid plaques activity (a 32% reduction of Aβ and NFTs aggregation). This combination of high photodynamic therapy efficiency and quick neuronal translocation reveals intriguing opportunities for applications of photochromic and plasmonic materials | en |
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dc.description.tableofcontents | Contents Acknowledgement i 摘要 ii Abstract iii Contents iv List of Figures viii List of Tables xvi Chapter 1 Introduction 1 1.1 Alzheimer's disease (AD) 4 1.2 Therapeutic approaches 5 1.3 New therapeutic approaches 6 1.4 Reactive oxygen species for neurodegenerative therapy 7 1.5 Properties of Spiropyran 9 1.6 Biological Applications of Spiropyran 12 1.7 Spiropyran - generation of singlet oxygen in cells 14 1.8 Limitation of spiropyran 15 1.9 Research motivation 18 Chapter 2 Spiropyran nanogel for anti-tau aggregation 20 2.1 Preparation of spiropyran 20 2.2 Characterization of spiropyran hydrogel 23 2.3 Analysis of fluorescence and Raman properties 30 2.4 Internalization of spiropyran@Au nanogels in cells 38 2.5 Cell viability and inhibitory effect of β-amyloid (Aβ) aggregation and neurofibrillary tangles (NFTs) with nanogels in cells 43 2.6 ROS and singlet oxygen generation with nanogel in cells 48 2.7 Conclusion 54 Chapter 3 Soft nano-photosensitizers for promotion of neurite outgrowth 55 3.1 Overview 55 3.2 Preparation of Spiro-H, Spiro-CH3 and Spiro-NO2 57 3.3 Cell viability with Spiro-H, Spiro-CH3 and Spiro-NO2 60 3.4 Characterization of hydrogel 62 3.5 Cell viability with nanogels in cells 67 3.6 Internalization of spiropyran@Au nanogels in cells 68 3.7 ROS generation with nanogel in cells 70 3.8 Singlet oxygen generation with nanogel in cells 72 3.9 Neurite outgrowth with nanogels in cells 74 3.10 Conclusion 78 Chapter 4 Experimental section 79 4.1 Chemicals and solvents 79 4.2 Methods 81 4.2.1 Synthesis of spiropyran 81 4.2.2 Preparation of hydrogel 83 4.2.3 Raman measurements 83 4.2.4 Cell culture 84 4.2.5 Cell viability 84 4.2.6 Mitochondria ROS assays 85 4.2.7 Singlet oxygen assays 85 4.2.8 Tau protein aggregation and amyloid-beta (Aβ) plaque assays 86 4.2.9 Filamentous actin (F-actin) detection 86 4.2.10 Flow Cytometry Measurements 87 4.2.11 DFT Calulations 88 4.3 Analytical instruments 89 4.3.1 Nuclear Magnetic Resonance Spectroscopy, NMR 89 4.3.2 Attenuated tatal reflectance FTIR 89 4.3.3 Ultraviolet/Visible Spectrophotometer 89 4.3.4 Raman spectrometer 90 4.3.5 ESI-MS 90 4.3.6 Transmission Electron Microscopy (TEM) 90 4.3.7 Scanning electron microscope (SEM) 91 4.3.8 Cell Imaging Multi-Mode Reader 91 Chapter 5 Manuscripts under review/accepted 92 Chapter 6 References 94 Chapter 7 Appendix 117 ? List of Figures Figure 1 1 Illustration of Alzheimer's disease.36 4 Figure 1 2 Agents currently in clinical trials for AD.38 5 Figure 1 3 Biomaterials in treatment of Alzheimer's disease.39 6 Figure 1 4 Schematic the dissociation of pre-formed Aβ42 aggregates by photo-excited methylene blue.43 8 Figure 1 5 Mechanism of photochemical and thermal isomerization of spiropyran.46 10 Figure 1 6 Photochromism and acidochromism of spiropyran. 11 Figure 1 7 The application of spiropyran in Biosensing.50 12 Figure 1 8 Schematic representation of the spiropyran’s drug delivery system.51 13 Figure 1 9 Spiropyran-containing nanoparticles controls generation of singlet oxygen.52 14 Figure 1 10 Mechanism of isomerization and photodegradation of spiropyran. 15 Figure 1 11 Absorbance measured for cyclical switching between SP and MC.53 16 Figure 1 12 A reversibly switchable spiropyrans within the polymeric nanoparticles. 17 Figure 1 13 The binding features of photochromic spiropyran molecule with metal.56 18 Figure 1 14 The design of spiropyran@Au nanogels. 19 Figure 2 1 (a) Illustration of the synthesis process of spiropyran. (b) Synthesis process of changes in color. (c) Exact mass spectrum showing the high purity spiropyran. 20 Figure 2 2 NMR spectrum of alkenylation spiropyran as monomer to prepare hydrogel. 21 Figure 2 3 (a) Infrared spectrum indicating the successful incorporation of alkene into spiropyran. (b) UV result of spiropyran showing strong π-π* band. 22 Figure 2 4 (a) Illustration of the isomerization process of spiropyran to merocyanine. (b) UV results showing bands associated with the nπ* electron transfer of trans and cis structures of merocyanine upon irradiation of 370 nm. (c) Images of spiropyran of the color changes. 24 Figure 2 5 Illustration of the π-π stacking modes of merocyanine, including H-aggregation and J-aggregation. 25 Figure 2 6 (a) UV light (370 nm) irradiation to the spiropyran solution in methanol (b) Reversible and repeatable transition of spiropyran solution shutter between the spiropyran and merocyanine states. 26 Figure 2 7 (a) UV results showing bands associated with the nπ* electron transfer of merocyanine@Au upon irradiation of 370 nm. (b) Images of spiropyran@Au of the color changes. (c) Reversible and repeatable transition of spiropyran@Au solution shutter between the spiropyran and merocyanine states. (d) Absorption spectra of different concentration spiropyran@Au. (e) UV light and Vis light irradiation repeated spectra correspond to constructive cycles. 27 Figure 2 8 (a) Illustration of the preparation of spiropyran@Au hydrogel. (b) SEM images of spiropyran@Au with Au species mapping. (c) EDX spectrum of spiropyran@Au hydrogel. (d) DLS of nanogels size distribution (average size = 189 nm) 29 Figure 2 9 (a) Fluorescence images of spiropyran@Au nanogels suspension in PBS solution. (b) and (c) Single nanogel fluorescence image and intensity. (d) Fluorescence images of spiropyran@Au nanogels immersed in PBS solution for different time. (e) Nanogels suspension into PBS solution average size for different time. 30 Figure 2 10 (a) Half-life of merocyanine and merocyanine@Au determined by UV spectrum measurement. (b) Half-life of merocyanine@Au nanogel determined by fluorescence measurement. (c) zeta potential of Au nanoparticles and merocyaine@Au. 32 Figure 2 11 (a) Illustration of Raman scanning for spiropyran@Au nanogel (b) Fluorescence spectrum of spiropyran@Au (c) Raman spectra were collected during irradiating spiropyran@Au with UV light for 10 minutes. (d) DFT calculation for the Raman spectrum. (e) DFT of geometry optimization structure (f) Raman 2D spectra scanned localize signals of 951 cm-1. 33 Figure 2 12 2D Raman spectrum showing peak at 951 cm-1 changes over UV irradiation. (a) Spiropyran nanogel (b) Spiropyran@Au nanogel (c) Extracted Raman counts from in situ Raman scans. (d) A schematic representation of molecular orientation on the surface of Au. 35 Figure 2 13 Three-dimensional minimum-energy configuration of (a) spiropyran and (b) merocyanine molecular dimers.64 36 Figure 2 14 (a) UV results showing spiropyran and spiropyran@Au λmax shift upon irradiation of 370 nm (b) UV results showing spiropyran@Au and Au nanoparticles red shift. (c) DFT calculation for energy gap. 37 Figure 2 15 (a) Schematic showing of intracellular trafficking of spiropyran@Au (red). (b) Deep imaging of live cell showing spiropyran@Au was internalized into neuronal cells. 38 Figure 2 16 (a) and (b) Bright field images and fluorescence images for time evolution of spiropyran@Au (red) incubated with neuronal cells. Scale bar = 20 nm. (c) Internalization profile of spiropyran@Au and other particles. 40 Figure 2 17 (a) Flow cytometry scatter plots: side scattering (SSC-A) versus forward scattering (FSC-A) of N2a cells exposed to nanogels for 24 h (b) SSC-A versus forward scattering PE-A (emission at 575 nm) (c) Flow cytometry histograms of PE-A fluorescence intensity for calculation about per cell uptaking of 200 nm nanogels. 41 Figure 2 18 (a) Relative viability of Neuro-2a cells after incubation with spiropyran@Au for 24?h. (b) Plot of cell viability with spiropyran@Au nanogels for 24?h. (c) Photostability profile of spiropyran@Au and other photosensitizers. 44 Figure 2 19 Live cells were stained with pFTAA before incubation of OA (6 h) or spiropyran@Au (24 h) + OA (6 h). Observing the aggregation of tau in the presence of OA and spiropyran@Au (a) with UV light. (b) without UV light. The apparent average aggregated tau protein relative fluorescence analyzed and plotted (c) with UV light. (d) without UV light. (p value was calculated using two-tailed student t-test, *p < 0.05, **p < 0.01.) 45 Figure 2 20 (a) Aβ42 (30 ?M) aggregation monitored by Thioflavin T fluorescence (b) Aβ42 incubated with different concentratoin of nanogel was added to N2a cells for 24 h. The cell viability was measured by MTS assays. 46 Figure 2 21 (a) Mitochondria ROS production. Scale bar = 30??m. (b) The generated singlet oxygen concentration in cells. Scale bar = 30?μm. (c) In vitro PDT effects of spiropyran@Au resulted in mitochondria ROS generation in neuronal cells. (d) Intracellular singlet oxygen concentration for various concentration of spiropyran@Au. 49 Figure 2 22 The generated ROS concentration (relative fluorescence) with irradiation time in cells. 49 Figure 2 23 A schematic representation of merocyanine absorb on the surface of Au, that generated singlet oxygen. 50 Figure 2 24 Molecular orbitals of (a) merocyanine and (c) merocyanine@Au, relative energies and transitions of (c) merocyanine and (d) merocyanine@Au 51 Figure 2 25 Illustration of producing singlet oxygen to inhibit Aβ aggregation 53 Figure 3 1 (a) Illustration of the synthesis process of spiropyran. (b) Exact mass spectrum showing the high purity Spiro-H, Spiro-CH3 and Spiro-NO2 57 Figure 3 2 NMR spectrum of alkenylation spiropyran as monomer to prepare hydrogel. 58 Figure 3 3 Infrared spectrum indicating the incorporation of alkene into Spiro-H, Spiro-CH3 and Spiro-NO2 59 Figure 3 4 Relative viability of Neuro-2a cell after incubation with Spiro-H, Spiro-CH3 and Spiro-NO2 (a) without UV light (b) with UV light Plot of cell viability with Spiro-H, Spiro-CH3 and Spiro-NO2 for 24?h. (c) without UV light (d) with UV light. 61 Figure 3 5 (a) Illustration of the synthesis of spiropyran@Au hydrogel. (b) and (c) Fluorescence image and intensity of spiropyran@Au nanogels suspension in liquid. (d) Amplify of single nanogel fluorescence image. (e) and (f) SEM images of spiropyran@Au with Au species mapping, the distribution of gold nanoparticles through the hydrogel. (g) TEM image of spiropyran@Au nanogels, the size is about 200 nm. 63 Figure 3 6 Raman spectra were collected during irradiating spiropyran@Au with UV light for 10 minutes. 64 Figure 3 7 Raman spectra of NIPPA, MBAA, TEMED and APS, spiropyran in powder and spiropyran nanogels. 65 Figure 3 8 Raman spectra of spiropyran and merocyaine (a) experimental result (b) DFT calculation 66 Figure 3 9 (a) Relative viability of Neuro-2a cell after incubation with spiropyran@Au nanogels (b) Plot of cell viability with spiropyran@Au nanogels for 24?h. 67 Figure 3 10 (a) Schematic showing of intracellular trafficking of spiropyran@Au (red). (b) Bright field images and fluorescence images for time evolution of spiropyran@Au (red) incubated with neuronal cells. Scale bar = 20 nm. 68 Figure 3 11 Deep imaging of live cell showing spiropyran@Au was internalized into neuronal cells. 69 Figure 3 12 Mitochondria ROS production. Scale bar = 30??m. (a) with UV and (b) without UV (c) In vitro PDT effects of spiropyran@Au resulted in mitochondria ROS generation in neuronal cells. 71 Figure 3 13 The generated singlet oxygen concentration in cells. Scale bar = 30?μm. (a) Without UV (b) with UV (c) Intracellular singlet oxygen concentration for various concentration of spiropyran@Au. 72 Figure 3 14 (a) 4x images (b) 40x images of neurite outgrowth in Neuro-2a cells cultured for 48 hours. 74 Figure 3 15 (a) Schematic showing of neurite outgrowth treated with spiropyran@Au nanogels (b) Nanogels promoted neurite outgrowth. Fluorescent staining of F-actin is used to outline neurites for measurement and analysis of outgrowth. (c) Analysis of average of neurite length. Statistical significance of the difference was determined using ANOVA. (***p<0.001) 76 Figure 7 1 NMR spectrum of Indolum salt 117 Figure 7 2 NMR spectrum of spiro-H precursor 118 Figure 7 3 NMR spectrum of spiro-Cl precursor 119 Figure 7 4 NMR spectrum of spiro-CH3 precursor 120 Figure 7 5 NMR spectrum of spiro-NO2 precursor 121 Figure 7 6 13C NMR spectrum of spiro-H 122 Figure 7 7 13C NMR spectrum of spiro-Cl 123 Figure 7 8 13C NMR spectrum of spiro-CH3 124 Figure 7 9 13C NMR spectrum of spiro-CH3 125 ? List of Tables Table 2 1 Selected transitions and excitation energies calculated for merocyanine and merocyanine@Au 52 Table 4 1 Chemicals and solvent 79 | |
dc.language.iso | en | |
dc.title | 表面電漿共振奈米凝膠光敏劑促使神經細胞快速內化應用於抗 Tau 蛋白聚集 | zh_TW |
dc.title | Photosensitizers Loaded Plasmonic Nanogels with Rapid Neuronal Internalization for Anti-Tau Aggregation | en |
dc.type | Thesis | |
dc.date.schoolyear | 110-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳振中(CHUN-CHUNG CHAN),廖尉斯(WEI-SSU LIAO) | |
dc.subject.keyword | 神經退化行性疾病,光敏劑,表面電漿納米粒子,水凝膠,細胞測試,拉曼光譜學, | zh_TW |
dc.subject.keyword | Neurodegenerative Diseases,Photosensitizer,Plasmonic nanoparticles,hydrogel,Bio-testing,Raman spectroscopy, | en |
dc.relation.page | 125 | |
dc.identifier.doi | 10.6342/NTU202201639 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2022-07-26 | |
dc.contributor.author-college | 理學院 | zh_TW |
dc.contributor.author-dept | 化學研究所 | zh_TW |
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