臺灣博碩士論文加值系統

我們的研究興趣與目標在於如何製備出新穎性的多功能奈米材料，並利用現有的儀器與技術來鑑定這些材料的特性，最後善加利用這些材料特性將其應用於生物醫學領域，並期許所設計之奈米材料在未來能被用來改善癌症治療之醫療技術，多功能複合型奈米材料較傳統單一組成之奈米材料最大的不同點在於，複合型材料往往具備有特殊的結構與多樣的材料性質(光學、磁性與催化活性等)，甚至可用來裝載難容於水或相對不穩定之藥物或試劑，並利用材料之特性來驅動藥物的控制釋放，因此這類型的材料在生物醫學領域有很大的應用潛力，我們的研究成功開發出三種多功能複合型奈米材料，每一種材料都有其特殊性與應用性，我們將分作三個主題進行詳細的探討與研究。
在第一個研究主題(Chapter2)，我們利用高溫誘導聚合物（苯乙烯-馬來酸）(PSMA) 進行酯化與交聯反應來製備偏心結構之無機-聚合物奈米粒子，因為Ag-PSMA Janus 奈米粒子具有偏心結構的特性，因此可以經由伽凡尼取代反應與金還原反應，成功將其轉換成小紅莓形貌之Au主體-PSMA Janus奈米粒子。
在第二個研究主題中(Chapter3)，我們設計出全新的多功能奈米粒子可經由遠程近紅外光的照射達到藥物釋放的目的，可被應用於生物醫學領域，不同於以往的球形結構之四氧化三鐵@金殼奈米粒子，我們首次使用斜截八面體四氧化三鐵奈米粒子作為核，並在其外覆蓋上二十四面體金殼層，合成過程中我們使用聚-L-賴氨酸做為氧化鐵與金殼之中間層，其可有效的補捉金的晶種，幫助緻密的金殼層生成，我們所得到的二十四面體四氧化三鐵@金殼奈米粒子具有高活性面{441}。為了結合光熱治療與化學治療，我們在二十四面體四氧化三鐵@金殼奈米粒子外再覆蓋上中孔洞二氧化矽殼層，並且在孔洞修飾上雙股寡核苷酸做為孔洞蓋子，可經由近紅外光雷射光的照射達到藥物控制釋放的目的，此外材料具備有磁性質可經由磁場的吸引達到磁標靶的功能，進而增加治療成效，而我們的實驗結果也證明本材料可以經由磁吸引與照射近紅外光的操作，對癌細胞與腫瘤有優異的結合治療(光熱+化療)成效，同時本材料也具有顯著的磁振造影負顯影效果，可作為全新的近紅外光驅動-磁標靶、結合治療與診斷的奈米生醫平台。
關於第三個研究主題(Chapter4)，芬頓反應(Fe2+ + H2O2 → Fe3+ + •OH + OH−)被發現於西元1894年，被廣泛的應用於廢水、汙染土壤與有機物的處理與淨化。關於活性氧物種可經由化學治療、放射線治療與光驅動治療所產生，這邊我們結合古老化學與新興奈米技術開發出不需要電磁波與氧氣即可產生活性氧物種的癌症治療平台，所設計的聚(乳酸-共-乙醇酸）奈米囊泡同時包埋四氧化三鐵奈米粒子與攜載雙氧水，可經由39度的低溫加熱產生足量的活性氧物種進行癌細胞的毒殺。

My research interest is that design the novelty multifunctional nanomaterials, and the unique properties materials were discovered by instrument. In the application, the nanomaterials had great potential to be used in the biomedical field. The multifunctional hybrid nanomaterials be provided with special structure and diversity properties (optical, magnetic and catalytic activity, etc.), and even can be used to load intolerable in water or relative instability drug or agent, and the use of characteristics of the material to drive the controlled release of drugs. My research has developed three multifunctional hybrid nanomaterials, each material has its own peculiarities and application, and it will be divided into three topics for discussed in detail.
In the first research topic (Chapter2), the thermally induced cross-linked esterification occurs for the formation of eccentric inorganic-polymeric nanoparticles. By taking advantage of eccentricity, Ag-PSMA eccentric structure is converted to raspberry-like Au-based Janus nanoparticles.
In the second research topic (Chapter3), a new multifunctional nanoparticle to perform a near-infrared (NIR)-responsive remote control drug release behavior was designed for applications in the biomedical field. Different from the previous studies in formation of Fe3O4-Au core-shell nanoparticles resulting in a spherical morphology, the heterostructure with polyhedral core and shell was presented with the truncated octahedral Fe3O4 nanoparticle as the core over a layer of trisoctahedral Au shell. The strategy of Fe3O4@polymer@Au was adopted using poly-L-lysine as the mediate layer, followed by the subsequent seeded growth of Au nanoparticles to form a Au trisoctahedral shell. Fe3O4@Au trisoctahedra possess high-index facets of {441}. To combine photothermal and chemotherapy in a remote-control manner, the trisoctahedral core-shell Fe3O4@Au nanoparticles were further covered with a mesoporous silica shell, yielding Fe3O4@Au@mSiO2. The bondable oligonucleotides (referred as dsDNA) were used as pore blockers of the silica shell that allowed the controlled release, resulting in a NIR-responsive DNA-gated Fe3O4@Au@mSiO2 nanocarrier. Taking advantage of the magnetism, remotely triggered drug release was facilitated by magnetic attraction accompanied by the introduction of NIR radiation. DNA-gated Fe3O4@Au@mSiO2 serves as a drug control and release carrier that features functions of magnetic target, MRI diagnosis, and combination therapy. The results verified the significant therapeutic effects on tumors with the assistance of combination therapy consisting of magnetic guidance and remote NIR control.
In the third research topic (Chapter4), Since its discovery in 1894, the Fenton reaction, Fe2+ + H2O2 → Fe3+ + •OH + OH−, has been used to treat wastewater and contaminated soil and oxidize organic pollutants. Apart from the reactive oxygen species (ROS) manipulation strategies known as chemotherapy, radiotherapy, and phototherapy, the merge of nanotechnology with old chemistry without electromagnetic waves and O2 creates an appealing exogenous and controllable ROS-generating platform to produce ROS that acts against cancer cells. Hydrogen peroxide-encapsulated Fe3O4-embedded poly(lactic-co-glycolic acid) polymersomes produce ROS at a temperature as low as 39 °C, the temperature a human body can withstand for killing cancer cells.

Contents
Abstract in Chinese I
Abstract in English III
Acknowledgement VI
Contents VIII
Table Contents XV
Figure Contents XVI
Abbreviation list XXIV
Chapter 1 Introduction 1
1.1. Nanotechnology 1
1.1.1. Nanoscale 1
1.1.2. Properties of nanomaterials 2
1.1.3. Preparation methods 3
1.2. Janus nanoparticles 4
1.2.1. Synthesis of Janus nanoparticles 4
1.2.2. Application of Janus nanoparticles 5
1.3. Metal and metal oxide nanoparticles 6
1.3.1. Surface plasmon resonance 6
1.3.2. Types of nanostructures 7
1.3.3. Polyhedron nanocrystals 8
1.3.4. Magnetic Properties 9
1.4. Vesicles 10
1.4.1. Emulsion 10
1.4.2. Liposomes ＆ Polymersomes 12
1.5. Biomedical applications 14

1.5.1. Drug delivery system 14
1.5.2. Photo-induced therapy 15
1.5.3. Magnetic resonance imaging 16
1.5.4. Magnetic targeting 17
Chapter 2
Eccentric inorganic-polymeric nanoparticles formation by thermal induced cross-linked esterification and conversion of eccentricity to raspberry-like Janus 18
2.1. Background and motivation 18
2.2. Materials and instruments 19
2.2.1. Materials 19
2.2.2. Transmission electron microscopes 19
2.2.3. Field-emission scanning electron microscope 19
2.2.4. X-ray diffractometer 20
2.2.5. UV-vis spectrophotometer 20
2.2.6. Inductively coupled plasma atomic emission spectrometer 20
2.2.7. Fourier transformation infrared spectrometer 20
2.3. Experiment methods 20
2.3.1. Preparation of Au icosahedral nanoparticles 20
2.3.2. Preparation of 24 nm-sized Au spherical nanoparticles 21
2.3.3. Preparation of eccentric Au-PSMA nanoparticles 22
2.3.4. Preparation of Ag nanoparticles and eccentric Ag-PSMA 22
2.3.5. Formation of raspberry-like Au-based Janus nanoparticles 23
2.4. Results and discussion 23
2.4.1. Preparation and characterization of Janus nanoparticles 23
2.4.2. Mechanism of cross-linked esterification reaction 27
2.4.3. The generation of eccentric structure by hydrophobic interaction 35
2.4.4. Preparation of other type Janus nanoparticles 36
2.4.5. The raspberry-like Janus nanoparticles were generated via galvanic replacement and reduction reaction 38
2.5. Conclusion 46
Chapter 3
Formation of oligonucleotide-gated silica shell-coated Fe3O4-Au core-shell nanotrisoctahedra for magnetically targeted and near-infrared light-responsive theranostic platform 47
3.1. Background and motivation 47
3.2. Materials and instruments 49
3.2.1. Materials 49
3.2.2. Transmission electron microscopy 50
3.2.3. High- resolution scanning electron microscope 50
3.2.4. UV-vis absorption spectrometer 50
3.2.5. X-ray diffractometer 51
3.2.6. Laser scanning confocal microscope 51
3.2.7. Inductive coupled plasma atomic emission spectrometer 51
3.2.8. Superconducting quantum interference device vibrating sample magnetometer 51
3.2.9. Fourier transform infrared spectrometer 51
3.2.10. Fluorescence spectrophotometer 52
3.2.11. Surface area and pore size analyzer 52
3.2.12. Enzyme-linked immune-sorbent assay reader 52
3.2.13. Minispec contrast agent analyzer 52
3.2.14. Dynamic light scattering spectrometer 52
3.3. Experiment methods 52
3.3.1. Preparation of truncated octahedral Fe3O4 NPs 52
3.3.2. Ligand exchange of truncated octahedral Fe3O4 NPs 53
3.3.3. Preparation of trisoctahedral Fe3O4@Au NPs 53
3.3.4. Preparation of Fe3O4@Au@mSiO2 and its subsequent modification 54
3.3.5. Hybridization of double-stranded oligonucleotides (dsDNA) 55
3.3.6. Preparation of DOX-loaded Fe3O4@Au@mSiO2-dsDNA 55
3.3.7. Preparation of FAM-labeled double-stranded DNA-modified Fe3O4 @Au@mSiO2 56
3.3.8. Preparation of Au nanospheres 57
3.3.9. Preparation of Au nanotrisoctahedra 58
3.3.10. Stability test for Fe3O4@Au@mSiO2-dsDNA/DOX without laser illumination 58
3.3.11. Temperature elevation profile by photothermal conversion 59
3.3.12. In Vitro release of DOX upon laser irradiation 59
3.3.13. Cell Culture 59
3.3.14. In Vitro cellar uptake with or without magnetic attraction 60
3.3.15. In Vitro cytotoxicity studies of Fe3O4@Au@mSiO2-dsDNA/DOX nanoparticles without laser illumination 60
3.3.16. In Vitro cytotoxicity studies of Fe3O4@Au@mSiO2-dsDNA/DOX and Fe3O4@Au@mSiO2-dsDNA with laser illumination 61
3.3.17. Fluorescence examination by the laser confocal microscope 61
3.3.18. In Vivo antitumor efficacy of Fe3O4@Au@mSiO2-dsDNA/DOX 62
3.3.19. Biodistribution studies 63
3.3.20. Evaluation of magnetic resonance imaging 63
3.3.21. Blood analysis of Fe3O4@Au@mSiO2-dsDNA/DOX 65
3.4. Results and discussion 65
3.4.1. Strategy of material preparation and tumor therapy 65
3.4.2. Preparation and structure analysis of trisoctahedral Fe3O4@Au NPs 67
3.4.3. The gold shell was generated by seed-mediated growth method 72
3.4.4. The property analysis of Fe3O4 and Fe3O4@Au NPs 76
3.4.5. Building up mesoporous silica shell 79
3.4.6. Near-infrared optical properties 83
3.4.7. Surface modification 85
3.4.8. Stability test 88
3.4.9. Photothermal conversion efficiency and control release 91
3.4.10. In vitro experiments 93
3.4.11. In vivo experiments 99
3.4.12. Analysis of bio-security 101
3.4.13. The contract efficiency of magnetic resonance imaging 105
3.5. Conclusion 109
Chapter 4
Chemical reaction-induced ROS cancer therapy: Fenton reaction-activable polymersomes generating ROS against cancer cells 110
4.1. Background and motivation 110
4.2. Materials and instruments 113
4.2.1. Materials 113
4.2.2. Transmission electron microscopy 114
4.2.3. High-resolution transmission electron microscopy 114
4.2.4. High-resolution scanning electron microscope 114
4.2.5. UV-Vis absorption spectrometer 115
4.2.6. X-ray diffractometer 115
4.2.7. Laser scanning confocal microscope 115
4.2.8. Atomic spectrometer 115
4.2.9. Superconducting quantum interference device vibrating sample magnetometer 115
4.2.10. Fourier transform infrared spectrometer 115
4.2.11. Fluorescence spectrophotometer 116
4.2.12. Enzyme-linked immune-sorbent assay reader 116
4.2.13. Dynamic light scattering spectrometer 116
4.2.14. Thermogravimetric analysis 116
4.2.15. X-ray photoelectron spectroscopy 116
4.3. Experiment methods 117
4.3.1. Preparation of 10 nm and 22 nm Fe3O4 nanoparticles 117
4.3.2. Preparation of Fe3O4@PLGA nanoparticles 117
4.3.3. Preparation of Fe3O4-PLGA polymersomes 117
4.3.4. Preparation of H2O2 (200, 400, or 600 μL)/Fe3O4-PLGA polymersomes 119
4.3.5. Quantitation of BSA on polymersomes from the protein kit 119
4.3.6. Preparation of H2O2(600μL)/Fe3O4(Dio)-PLGA polymersomes 120
4.3.7. Ultrasection of Polymersomes 121
4.3.8. Analysis of Fenton reaction for Fe3O4@PLGA NPs 121
4.3.9. Quantitation of H2O2 loaded in polymersomes 122
4.3.10. Fluorescence intensity derived from the process of Fenton reaction for the polymersomes containing different H2O2 concentration 122
4.3.11. Analysis of Fenton reaction from Fe3O4 NPs with H2O2 under intracellular concentration (100 μM) 123
4.3.12. The morphology of the polymersomes and fluorescence intensity derived from the process of Fenton reaction at different heating temperature 123
4.3.13. Fluorescence intensity derived from the process of Fenton reaction for H2O2(600μL)/Fe3O4-PLGA polymersomes at 38 ºC as a function of heating period 123
4.3.14. The degradation of xylenol orange dye by the Fenton reaction 124
4.3.15. Stability performance of H2O2(600 μL)/Fe3O4-PLGA polymersomes 124
4.3.16. In vitro DOX resistant studies of HeLa cells and MES-SA/Dx5 cells 125
4.3.17. Biocompatibility studies evaluated by MTT assay for polymersomes 125
4.3.18. In vitro cellular uptake of the polymersomes 125
4.3.19. Cell images for cellular uptake of the polymersomes: the lysosome-mediated pathway 126
4.3.20. In Vitro cytotoxicity studies of polymersomes under a heating condition 126
4.3.21. Cell images for the intracellular ROS staining 128
4.3.22. Cell images for intracellular acidic organelles staining 129
4.4. Results and discussion 129
4.4.1. Preparation and characterization of polymersomes 129
4.4.2. Verification of Fenton reaction derived from H2O2/Fe3O4-PLGA polymersomes 142
4.4.3. Deformation of polymersomes by Fenton reaction under a heating circumstance 149
4.4.4. Cytotoxicity evaluation in malignant cells 157
4.5 Conclusion 168
Chapter 5 Research experience and future research directions 170
References 172
Appendix 181
Curriculum Vitae 182

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