臺灣博碩士論文加值系統

奈米科技在醫學領域上已由實驗室走入真實的臨床應用，轉譯奈米醫學已成為本世紀重要發展脈絡，快速疾病診斷與治療而避免傷害正常細胞等副作用是現代醫療的新興趨勢。而奈米材料由於可以提供特殊的材料性質而有機會打破傳統醫學診治上的瓶頸，為醫學領域帶來重要的改變以及龐大的生物醫學產業經濟利益。在這篇論文中，我們將分為兩個主要章節，第一部份探討β-FeOOH和α-Fe2O3 所組成具有孔洞的奈米柱體之合成，並在其表面修飾上四層具有相反電性的高分子聚合物(PAA/PEI/PAA/PEI)形成多層的奈米膠囊。藉由綠色螢光分子(FITC)模擬藥物，裝載在此具有多層高分子膜的奈米膠囊內，我們發現奈米膠囊具有微環境控制藥物釋放的功能，並在子宮頸癌細胞(Hela)具有細胞核專一投遞功能。FITC呈現為環境控制釋放或持續釋放的行為決定在奈米棒表面高分子的包覆緊實程度。用雷射共軛聚焦顯微鏡可以觀察到FITC被緩慢釋放進入Hela細胞的細胞質到細胞核需要24小時。
第二部份在探討模組式設計之標靶奈米粒子的可行性及其特性。藉由Fe3O4奈米粒子上的特殊辨識分子(Ni-NTA)能與在RGD4C上的六個組氨酸標記進行自組裝結合，而達成組合標靶胜肽精準導向所需之的結合位置方向性控制的目的。原子吸光光譜儀證實，自組裝的Fe3O4-NTA-Ni-RGD4C奈米粒子比起常見的化學連接方式，對於口腔癌細胞具有更好的辨識力。倉鼠的口腔癌動物模型證實自組裝奈米粒子與體內的癌細胞能形成專一性鍵結，並在核磁共振攝影展現其分子造影的能力。原子吸光光譜儀和核磁共振分子造影都顯示了自組裝的奈米粒子，比起常見的化學連接方式改善了標靶辨識能力，並減少了肝臟的非特異性攝入。
透過自組裝的方式可以重新組裝客製化標靶物件和不同功能性的奈米粒子的整合高分子的釋放控制。這個新的模組化設計平台可以提供增強標靶診斷的效能和治療效率，使得磁性氧化鐵奈米材料得以在奈米醫學上的應用提供更寬廣的選擇。

Nanotechnology has become part of our lives, especially with regard to medical applications, in the 21st century. Rapid diagnosis and treatment of diseases while devoid of collateral damage to healthy cells and potential side effects has been a new trend in biomedicine. Nanomaterials provide unique characteristics that can be used to provide tools for breaking through innovations beyond the limitations of current traditional medicine and bring about a powerful revolution in health care and biomedical industrial profits. In this thesis, porous nanorods with integrated β-FeOOH and α-Fe2O3 were synthesized. The derived porous nanorods were engineered to assemble with four layers of polyelectrolytes on their surfaces. FITC molecules were loaded into the polyelectrolyte multilayer coated nanocapsules to study the drug release kinetics and the intracellular delivery in Hela cells. The FITC release behavior exhibited either controlled- or sustained-release trends, depending on the compactness of the polyelectrolyte shells on the nanorod surfaces. The laser confocal microscopy data indicates that the nanocapsules show the release of the FITC from the initial perimembrane space into the cytoplasm followed by targeting into the nucleus after 24 h.
In addition, specific molecular recognition of nickel nitrilotriacetate on Fe3O4 nanoparticles with a hexahistidine tag on RGD4C peptides resulted in precisely controlled orientation of the targeting peptides. AAS demonstrated better selectivity of the self-assembled Fe3O4-NTA-Ni-RGD4C nanoparticles targeting oral cancer cells than that achievable through a conventional chemical cross-link strategy. An oral cancer hamster model was applied to reveal specific in vivo targeting and MR molecular imaging. Both AAS and MRI revealed that the self-assembled nanoparticles improved the targeting efficiency and reduced the hepatic uptake as compared to the conventional chemical cross-link particles. The nanoparticles were significantly cleared from the liver and kidneys after one week.
By recombining the desired targeting moiety and various functional nanoparticles through self-assembly and the property of polymer control release, this new modularly designed platform has the capability of enhancing the efficiency of targeted diagnosis and therapies for a wide spectrum of nanomedicine applications.

Contents
摘要 I
Abstract III
誌謝 V
Contents VII
Table Contents XII
Figure Contents XIII
Abbreviation List XV
Chapter 1 Introduction 1
1-1. Nanotechnology in our lives 2
1-2. "Nano" definition and the development history 3
1-3. Novel materials-Nanomaterials 4
1-4. The fundamental characteristics of metallic nanoparticles 5
1-4-1. Surface effect 6
1-4-2. Size effect 7
1-4-3. Quantum effect 7
1-5. The stability of metal nanoparticles 8
1-6. Metal nanoparticle surface modification 10
1-7. Magnetic nanoparticles 11
1-7-1 Magnetic properties of magnetic nanoparticles 12
1-7-2. Ferromagnetic and Paramagnetic properties 13
1-7-3. Paramagnetic and superparamagnetic properties 16
1-8. The stability of magnetic nanoparticles 16
1-9. Magnetic iron oxide nanoparticles 18
1-10. The preparation method for magnetic iron oxide nanomaterials 19
1-10-1. The thermal decomposition method 20
1-10-2. The hydrothermal method 20
1-10-3. The microemulsion method 21
1-10-4. The chemical co-precipitation method 22
1-11. The nanomedical applications of magnetic nanoparticles 25
1-11-1. What is nanomedicine 25
1-11-2. Using limited conditions 26
1-11-3. Drug delivery applications 28
1-11-4. Thermotherapy Applications 30
1-11-5. Purification Applications 31
1-11-6. Magnetic transgenics 36
1-11-7. Magnetic resonance imaging 37
1-1-12. Specific aim and rationale of thesis 42
Chapter 2 Experimental Section 44
2-1. Preparation of porous iron oxide based nanorods 45
2-2. Characterization of porous iron oxide 45
2-3. Sequential deposition of polyelectrolytes onto porous nanorod surfaces with loading of FITC 46
2-4. Release studies on the polyelectrolyte multilayer nanocapsules 47
2-5. The effect of NaCl concentration on FITC release from the polyelectrolyte multilayer nanocapsules 47
2-6. Cell culture and maintenance 48
2-6-1. Prepared for porous nanorods 48
2-6-2. Preparation for Fe3O4 nanoparticles 48
2-7. Biocompatibility evaluation 50
2-7-1. WST-1 assay 50
2-7-2. MTT assay 50
2-7-3. The systemic toxicity assay 51
2-8. Laser confocal microscopy of the FITC-loaded nanocapsules 51
2-9. Preparation of dispersed, water-Soluble Fe3O4 nanoparticles 52
2-10. Fe3O4 nanoparticle modification, peptide synthesis, and conjugation to nanoparticles. 53
2-11. Ligand competition assay 54
2-12. Animals and tumor model 55
2-13. Atomic absorption spectrometry analysis 55
2-14. Magnetic resonance imaging 56
2-15. Histological examination 57
2-16. Statistical analysis 57
Chapter 3 Porous Iron Oxide Based Nanorods Developed as Delivery Nanocapsules 58
Introduction 59
Results and Discussion 64
3-1. Synthesis and characterization of porous iron oxide based nanorods 64
3-2. Polyelectrolytes multi-layered onto porous nanorod surfaces with FITC loading 67
3-3. FITC Release evaluated on the polyelectrolyte multilayer nanocapsules 67
3-4. The effect of ion concentration on FITC release 70
3-5. Biocompatibility of the nanorods 71
3-6. FITC-loaded nanocapsules exposed to Hela Cells 71
Chapter 4 Modularly Assembled Magnetite Nanoparticles Enhance in Vivo Targeting for Magnetic Resonance Cancer Imaging 74
Introduction 75
Results and Discussion 78
4-1. The strategy of in vivo cancer image 78
4-2. Cytotoxicity of Fe3O4-NTA-Ni-RGD4C nanoparticles 78
4-3. Dose-dependent affinity targeting of Fe3O4-NTA-Ni-RGD4C nanoparticles 79
4-4. Selective targeting of Fe3O4-NTA-Ni-RGD4C nanoparticles 79
4-5. Biocompatibility of Fe3O4-NTA-Ni-RGD4C nanoparticles in Vivo 81
4-6. Molecular MR imaging of oral cancer using Fe3O4-NTA-Ni-RGD4C nanoparticles 81
4-7. Histological analysis 82
4-8. In Vivo targeting efficiency in the tumor lesions quantified using AAS 83
4-9. Biodistribution and excretion of iron oxide nanoparticles 84
4-10. The new concept of a modular nanoparticle platform 86
Chapter 5 Overall Discussion & Conclusion 88
References 126
Publications 135

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