Facile Synthesis and X-ray Attenuation Properties of Hydrophilic Polymer-coated Ultrasmall PbO, CeO2, and Pt Nanoparticles as CT Contrast Agents : CT 조영제로 수용성 고분자가 코팅된 초소형 PbO, CeO2, Pt 나노입자의 간편한 합성과 X-선 감쇠특성

국문 초록 (Abstract)

CT는 임상에서 진단방법으로 널리 사용되고 있다. CT 민감도를 증가시키기 위해 분자성 요오드화합물이 주사용 조영제로 보통 사용되고 있다. 그러나, 요오드 조영제는 빨리 신장배출이 되어 혈관에서 회전하는 시간이 짧다. 빠른 신장배출로 인해 긴 혈관회전이 필수적인 사용에서는 요오드 조영제의 쓰임새는 제한적이다. 나아가서, 요오드의 낮은 X-선 감쇠력는 고에너지 X-선을 사용하는 임상용 CT에 최적은 아니어서, 많은 양이 투여되어 부작용을 일으킬수 있다. 이와 같은 단점들을 극복하기 위하여, 금속기반 금속 기반 나노입자 CT 조영제가 개발되고 있다. 금속기반 나노입자 조영제를 사용하면 혈관회전시간이 길고, 적은 투여량 때문에 부작용을 줄일 수 있어, 전반적으로 CT의 효율성과 안전성을 증가시킬 수 있다. X-선 감쇠는 원자번호에 비례하여 증가한다. 따라서, 금소기반 나노입자는 요오드 CT 조영제보다 큰 X-선 감쇠계수를 가진 고밀도의 중금속으로 되어 있어 CT 영상에서 높은 조영효과를 제공할 수 있다. 이 학위논문에서는 다양한 수용성 생체적합 고분자로 코팅된 초소형 나노입자 [즉, PbO, CeO2, Pt (Pb, Ce, Pt의 원자번호는 각각 82, 57, 78)]가 합성되었다. 3 종류의 고분자, 즉, PAA, PAAMA, PMVEMA가 코팅리간드로 사용되었다. 합성된 나노입자는 고분해투과현미경, X-선 회절, Fourier 변환 적외선흡수분광, 열분석, 동적 빛 산란, 세포활성분석, 형광분광, X-선 CT을 사용하여 분석되었다. 합성된 고분자가 코팅된 나노입자는 콜로이드 안정성이 뛰어났다 (즉, 합성 후 1.5년 이상 침전이 일어나지 않았음). 나노입자 직경은 거의 균일하였고, 평균직경은 거의 2 nm이었고, 세포독성은 매우 낮았다. 동일한 원자농도 및 수밀도에서, 나노입자의 X-선 감쇄는 상업용 Ultravist보다 높았다. X-선 조영제로써 PbO 및 CeO2 나노입자들의 잠재성은 샘플용액을 쥐 꼬리에 정맥주사 및 복막주사 후에 여러기관에서 조영증대를 관찰하여 생체내 입증하였다. 나아가, PbO 나노입자는 암부위에 직접 주사한 후 암부위에서 조영증대효과를 관찰하여, 암 이미징의 적용가능성도 알수있었다. 추가로, CeO2 나노입자는 과산화수소를 제거하는 항산화 효과도 보여주었는데, 이는 CeO2 나노입자가 방사선보호용 또는 진단/치료용 X-선 조영제로의 잠재성을 입증해 준다.

다국어 초록 (Multilingual Abstract)

Computed tomography (CT) is extensively employed as a diagnostic tool in clinical practice. To enhance the sensitivity of CT, molecular iodinated compounds are commonly used as injectable contrast agents. However, iodinated contrast agents are rapidly excreted through the kidneys, resulting in short circulation times. The swift renal clearance limits their use in applications that necessitate prolonged circulation. Furthermore, iodine's low X-ray attenuation is suboptimal for clinical CT, which utilizes high-energy X-rays, and thus high dosages are used, which could generate side-effects. To overcome these limitations, metal-based nanoparticle CT contrast agents have been developed. The metal-based nanoparticle agents offer increased circulation times and reduced adverse effects owing to low dosages, thus improving the overall efficacy and safety of CT. X-ray attenuation is proportional to atomic number. Therefore, metal-based nanoparticles can provide high contrast effects in CT images because they are made of a high density of heavy metal atoms with higher X-ray attenuation coefficients than iodinated CT contrast agents. In this thesis, various hydrophilic and biocompatible polymer-coated ultrasmall nanoparticles [i.e., PbO, CeO2, or Pt (atomic number = 82, 57, and 78 for Pb, Ce, and Pt, respectively)] were synthesized. Three kinds of polymers, namely poly(acrylic acid) (PAA), poly(acrylic acid-co-maleic acid) (PAAMA), and poly(methyl vinyl ether-alt-maleic acid) (PMVEMA), were used as surface-coating polymers. The synthesized nanoparticles were characterized using high-resolution transmission electron microscopy, X-ray diffraction, Fourier transform infrared absorption spectroscopy, thermogravimetric analysis, dynamic light scattering, cell viability assay, photoluminescence spectroscopy, and X-ray CT. The synthesized polymer-coated nanoparticles were colloidally stable (i.e., no precipitation after synthesis for > 1.5 years). They were nearly monodispersed in particle diameters, with average particle diameters of ̴ 2 nm, exhibiting very low cellular cytotoxicity. Based on the identical atomic concentration and number density, the X-ray attenuation of these nanoparticles was greater than that of the commercial contrast agent “Ultravist”. The potential of PbO and CeO2 nanoparticles as X-ray contrast agents was proved in vivo by observing contrast enhancements in organs after intravenous tail (IV) and intraperitoneal (IP) injections of sample solutions in mice. Furthermore, PbO nanoparticles demonstrated tumor-imaging ability through contrast enhancements at the tumor after intratumoral (IT) injection in tumor-model mice. In addition, CeO2 nanoparticles exhibited an antioxidant effect for the removal of hydrogen peroxide (H2O2), which demonstrated the potential as radioprotective or theragnostic X-ray contrast agents.

목차 (Table of Contents)

• CHAPTER 1 1
• Introduction 2
• 1.1. Background 2
• 1.2. Computed Tomography (CT) 4
• 1.3. X-ray CT contrast agents 7
• 1.3.1. Iodine-based CT contrast agents 8
• 1.3.2. Metal nanoparticle-based CT contrast agents 10
• 1.4. Principles of X-ray attenuation properties at Hounsfield Unit . 11
• 1.5. Principles of ionizing X-ray radiation during CT scan 17
• 1.6. Research Objective . 19
• 1.7. References 21
• CHAPTER 2 24
• Experimental Sections 25
• 2.1. Chemicals 25
• 2.2. One-pot polyol synthesis of polymer-coated ultrasmall nanoparticles 26
• 2.2.1. Polymer-coated ultrasmall PbO nanoparticles . 26
• 2.2.2. Polymer-coated ultrasmall CeO2 nanoparticles 28
• 2.2.3. Polymer-coated ultrasmall Pt nanoparticles 29
• 2.3. General characterizations 32
• 2.3.1. High-resolution transmission electron microscope 32
• 2.3.2. Particle size analyzer . 32
• 2.3.3. X-ray diffraction 33
• 2.3.4. Fourier transform-infrared . 33
• 2.3.5. Inductively coupled plasma-atomic emission spectrometer . 33
• 2.3.6. Thermo-gravimetric analysis 34
• 2.3.7. Photoluminescence spectroscopy 34
• 2.4. In vitro cell viability assay . 35
• 2.5. X-ray phantom image measurements 36
• 2.6. In vivo experiments 36
• 2.6.1. In vivo CT image measurements . 37
• 2.6.2. Tumor-model mice preparation 37
• CHAPTER 3 38
• Ultrasmall Lead Oxide Nanoparticles 39
• 3.1. Introduction 39
• 3.2. Results and Discussion . 41
• 3.2.1. Physicochemical Properties: Particle Diameters, Hydrodynamic
• Diameters, Zeta Potentials, Colloidal Stability, and Crystal Structures 41
• 3.2.2. Polymer-Grafting Structure and Amount in wt % . 51
• 3.2.3. In Vitro Cytotoxicity Results 56
• 3.2.4. X-ray Attenuation Properties 58
• 3.2.5. In Vivo CT Images in Normal Mice . 62
• 3.2.6. In Vivo CT Images in Tumor-Model Mice 67
• 3.3. Conclusions 69
• 3.4. References 70
• CHAPTER 4 77
• Ultrasmall Cerium oxide nanoparticles with antioxidant effect 78
• 4.1. Introduction 78
• 4.2. Results and discussion 81
• 4.2.1. Colloidal stability, particle diameter, hydrodynamic diameter, zeta potential, and crystallinity 81
• 4.2.2. Fourier transform-infrared (FT-IR) absorption spectra and TGA curves . 89
• 4.2.3. In vitro cytotoxicity results 93
• 4.2.4. Antioxidant effect 95
• 4.2.5. X-ray attenuation: phantom images 100
• 4.2.6. In vivo CT images 104
• 4.3. Conclusions . 106
• 4.4. References 107
• CHAPTER 5 . 115
• Ultrasmall Platinum Nanoparticles 116
• 5.1. Introduction . 116
• 5.2. Results 119
• 5.2.1. Physical Characteristics of Polymer-Coated Pt-NPs . 119
• 5.2.2. Polymer-Coating Amount and Structure . 127
• 5.2.3. In Vitro Cellular Cytotoxicity Results 133
• 5.2.4. X-ray Phantom Images and X-ray Attenuation Power . 135
• 5.3. Discussion 140
• 5.4. Conclusion 143
• 5.5. References 144
• CHAPTER 6 . 151
• Summary of Thesis 152
• List of publications 155
• Abstract in (English) . 159
• Abstract in (Korean) . 161

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