奈米鑽石已被開發成為生物應用中的有力工具和具有前景的材料,奈米鑽石的 化學惰性,表面化學可修改性,以及生物相容性等,這些內在獨特的特性賦予奈米鑽石 不僅在生物體外或生物體內的研究應用上都具有吸引力。然而,目前仍然有一些必須解 決的奈米鑽石應用上的問題,例如溶液中的穩定分散性以及表面修飾的簡易性,以推進 其在生命科學研究中實際應用的潛力。其中一個主要問題是所有納米粒子都易於在生理 介質中聚集和沈澱,例如磷酸鹽緩衝鹽水(PBS),從而削減其基本優勢並限制其應用能 力。我們的研究提供了一種熟練且簡易的方法,使用生物相容材料:牛血清白蛋白(BSA) 蛋白,作為奈米鑽石的優良穩定劑,使其能夠長時間抵抗生物介質中的絮凝。這個方法 易於加工並能適用於各種表面修改的鍵結。通過這個方法以及奈米鑽石的特性,這篇論 文將引入不同的奈米鑽石複合物,以有利於各種研究。
螢光奈米鑽石 (FND) 複合物可以簡易吸附的方式包覆糖蛋白(或新糖蛋白),這 些醣蛋白表面修飾著多個糖基,可作為配體 - 受體標靶的生物成像劑。我們還通過聚乙 二醇化和 BSA 的助劑證實了鏈黴抗生物素蛋白接枝的 FND 可用於抗體 - 抗原的標記。 (透過同時應用生物素鍵結的目標抗體。) 這些方法能廣泛適用於細胞特異性靶把和標記 的各種情況。FNDs 複合物的另一個新平台是同時結合磁性與光學特性,用於小鼠人類膠 質母細胞瘤的雙系統成像。結合超小順磁性氧化鐵-FND 納米複合物透過磁共振圖像 (MRI)提供改善的小鼠腫瘤成像的靈敏度,以及隨後在組織學研究中詳述。該方法將 癌症成像的空間分辨率從厘米級的體內MRI擴展到微米級甚至納米級的體外熒光顯影。 另外,全世界存在越來越多的實質性臨床問題,即病原體經常隨著時間的推移而產生抗 生素抗性,導致治療嚴重失敗。然而,如果過度使用,目前成功替代抗生素的銀奈米粒 子(AgNP)是具有有毒性的。為了克服過量的 AgNP 暴露對人體健康產生負面影響,我們提出了一種具有殺菌功能的奈米鑽石複合物, Ag-ND @ BSA,一種具有抗菌活性和增 強生物相容性的新方法。它還提供了解決細菌對銀奈米粒子抗性的解決方案,其解除了 常規抗微生物劑所遇到的限制。任何與銀奈米粒子的尺寸,形狀,聚集和毒性相關的問 題在很大程度上都將被消除。Ag-ND @ BSA 塗層或嵌入的裝置,可為醫療用品和設備相 關的感染問題提供了可能的解決方案,可以實際應用於醫院的臨床應用,並將徹底改變 臨床醫學。
利用前述的方法和奈米鑽石的特性,我們引入螢光奈米鑽石和奈米鑽石 (1) 作為生物成像劑,用於基於配體的靶把和基於抗體的標記的體外研究, (2) 雙功能成像劑, 用於磁共振成像(MRI)和組織學研究的染色分析,以及 (3) 作為臨床與公共衛生上的殺菌劑

Nanodiamonds (NDs) have captured tremendous attention in biomedical field because of their unique properties such as distinct fluorescence and excellent biocompatibility that render them attractive for in vitro and in vivo applications. The lack of proper surface structure modification and functionalization however, has limited their practical applications. Other complications including agglomeration and precipitation in biological medium are also major issues that needs to be solved. Surface coating and/or conjugation of NDs with biomolecules, proteins, polymer or other materials are therefore essential to overcome these problems. The formation of such hybrids not only enable integrations of NDs with more functionality but also expand their use in advanced biomedical applications.
In this thesis, three ND hybrids are introduced. First, a protein-functionalized ND hybrid was developed. In order to maximize NDs potential for practical use in life science research, it is vital to develop stable dispersion NDs and their ease of bio-conjugation. Bovine serum albumin (BSA) protein serves as an excellent stabilizer to resist flocculation in biological medium. To endow them with specific targeting ability, NDs were coated with carbohydrate- modified BSA or streptavidin for bioimaging. The method is straightforward and achieved by simple physical adsorption or PEGylation. The second hybrid, ultra-small paramagnetic iron oxide-fluorescent nanodiamond (FND) nanohybrid was introduced for dual-modality imaging. Iron oxide nanoparticle provides magnetic resonance image (MRI) contrast enhancement; however, it emits no fluorescence for straightforward histological examination. The hybrids integrate magnetic and optical properties, extending the spatial resolution from in-vivo MRI at the centimeter scale to in-vitro fluorescence microscopy at nanometer scale. Furthermore, a ND-supported AgNP (Ag-ND@BSA) hybrids was developed to overcome problem associated with antibiotic resistance pathogens. Antibiotic resistance pathogens leading to serious failure of treatment are becoming an increasing clinical problem worldwide. Although silver nanoparticles (AgNP) was a successful alternative of antibiotic, it can cause negative impact on patient’s health if it is overused. This thesis successfully presented a Ag-ND@BSA hybrids, where NDs provide a new and proficient method with antibacterial activity and strengthened biocompatibility by eliminating aggregation and significantly reducing toxicity of AgNPs. Moreover, ND-supported silver nanoparticle-incorporated devices, providing a possible solution to medical supplies and devices-related infection issues, are readily applicable for practical clinical use in hospitals and will revolutionize clinical medicine.
In summary, this research successfully developed three novel FNDs and nanodiamond hybrids for (1) a bio-imaging agent for protein targeting and labeling, (2) a dual-modality agent for MRI and histological studies, and (3) a bactericidal agent for clinical and public health.

中文摘要 ii
ABSTRACT iv
CONTENTS vi
LIST OF FIGURES ix
LIST OF TABLE xix
LIST OF ABBREVIATIONS xx
Chapter 1 Nanodiamonds 1
1.1 Introduction 1
1.2 Classification of diamonds 1
1.3 Production of diamonds 3
1.3.1 HPHT diamonds 4
1.3.2 Detonation diamonds 4
1.3.3 CVD diamond 6
1.4 Properties of Nanodiamonds 6
1.4.1 Biocompatibility 7
1.4.2 Photoluminiscence 9
1.5 Bio-application of NDs 13
1.5.1 Particle tracking in vitro and in vivo 13
1.5.2 Surface modified NDs for practical applications 14
1.6 Summary 18
Chapter 2 Multi-functionalized nanodiamond hybrids 36
2.1 Protein-functionalized nanodiamonds 36
2.2 Magnetic– optical nanodiamond hybrids 42
2.3 Nanodiamond enhanced bactericidal hybrids 47
Chapter 3 Methods and Materials 54
3.1 Materials 54
3.2 FND production 54
3.3 Synthesis of nanocomposites 55
3.3.1 Noncovalent conjugation of FND with (neo)glycoproteins 55
3.3.2 Covalent conjugation of FND with streptavidin 55
3.3.3 Conjugation of USPIO-FND 56
3.3.4 Conjugation of Ag-ND@BSA 57
3.4 Cell culture and targeting 59
3.4.1 Cell culture and preparation 59
3.4.2 Cell labeling with nanocomposites 60
3.4.3 Bacteria culture and antimicrobial activity examination 63
3.5 Fluorescence spectroscopy and quantification 65
3.6 Confocal fluorescence imaging 66
3.7 Flow cytometry and FACS 66
3.8 In Vivo experiment and Histological analysis 67
3.9 Cell viability and safety assessment 68
3.10 Practical applications hydrogels 69
3.10.1 Fabrication of Contact Lens 69
3.10.2 Fabrication of Wound dressing 70
Chapter 4 Result and Discussion 71
4.1 Highly fluorescent nanodiamonds protein-funtionalized for cell labeling and targeting 71
4.1.1 FND characterization 71
4.1.2 Noncovalent hybridization of FND with (neo)glycoproteins 72
4.1.3 Covalent hybridization of FND with streptavidin 73
4.1.4 Ligand-based targeting 73
4.1.5 Antibody-based labeling 74
4.1.6 summary 77
4.2 Multiscale cancer imaging and detection of glioblastoma by magnetic nanoparticles – optical nanodiamond hybrids 89
4.2.1 Synthesis and characterization of USPIO-FND nanohybrids 89
4.2.2 Cell-labeling and quantification of USPIO-FND nanohybrids 91
4.2.3 Tumor-Scale in vivo MRI imaging 93
4.2.4 Cellular-Scale histological fluorescent imaging 94
4.2.5 Summary 96
4.3 Three-in-One: Nanodiamond-supported silver nanoparticles in hydrogels with enhanced antibacterial activities and safety 108
4.3.1 Synthesis of silver nanoparticles and silver nanoparticles carried ND. 108
4.3.2 Antibacterial Examinations 110
4.3.3 Practical applications: 3-in-1 Hydrogel 115
4.3.4 Summary 120
Chapter 5 Conclusions 134
REFERENCE 136

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