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Surface functionalization of superparamagnetic iron oxide nanoparticles for potential cell targeting, imaging, and cancer therapy applications

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    SURFACE FUNCTIONALIZATION OF SUPERPARAMAGNETIC IRON OXIDE NANOPARTICLES FOR POTENTIAL CELL TARGETING, IMAGING, AND CANCER THERAPY APPLICATIONS           HUANG CHAO                     NATIONAL UNIVERSITY OF SINGAPORE 2012         SURFACE FUNCTIONALIZATION OF SUPERPARAMAGNETIC IRON OXIDE NANOPARTICLES FOR POTENTIAL CELL TARGETING, IMAGING, AND CANCER THERAPY APPLICATIONS HUANG CHAO (B.ENG., TIANJIN UNIVERSITY) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMICAL AND BIOMOLECULAR ENGINEERING NATIONAL UNIVERSITY OF SINGAPORE 2012               ACKNOWLEDGEMENTS My sincere and deep gratitude goes first and foremost to my supervisor, Professor Neoh Koon Gee, for her inspired guidance, valuable suggestions, insightful criticism, great patience, and constant encouragement and support throughout the entire period of my research study. Her enthusiasm, rigorous attitude and dedication to scientific research are strongly impressed on my memory. Her expert advices greatly help me improve the depth of my research. The profound and invaluable knowledge that I gained from her will benefit me in my future life and career. I am also very grateful to Professor Kang En-Tang for his kindly permission to access the equipments in his research lab. Further sincere thanks go to all my friends and colleagues for their assistance and support. In particular, big thanks go to Dr. Wang Liang for sharing with me his invaluable experience in the research field. I also owe a debt of gratitude to the lab officers and technical staff of Department of Chemical and Biomolecular Engineering, especially Dr. Yuan Zeliang, Mr. Chia Phai Ann, Dr. Yang Liming, Ms Xu Yanfang and Mr. Chan Chuin Mun for their kindly help during my research. The research scholarship for Ph.D study provided by National University of Singapore is also greatly appreciated. Finally, I would like to express my deepest gratitude to my beloved parents, my husband, and other relatives for their unconditional love and support.     I   TABLE OF CONTENTS ACKNOWLEDGEMENTS I TABLE OF CONTENTS . II SUMMARY VII LIST OF ABBREVIATIONS . VIII LIST OF FIGURES X LIST OF TABLES . XV CHAPTER INTRODUCTION 1.1 Background 1.2 Research Objectives and Scopes . CHAPTER LITERATURE REVIEW 2.1 SPIONs . 2.1.1 Basic Properties of SPIONs . 2.1.2 Synthesis of SPIONs 2.1.2.1 Co-precipitation . 2.1.2.2 Thermal Decomposition . 10 2.1.3 Challenges of SPIONs for Biomedical Applications . 11 2.2 Surface Functionalization of SPIONs 14 2.2.1 Materials for Surface Modification of SPIONs 15 2.2.1.1 Monomer Stabilizers 15 2.2.1.2 Polymer Stabilizers 17 2.2.1.3 Inorganic Stabilizers 18 2.2.2 Methods for Surface Modification of SPIONs . 20 2.2.2.1 Self-assembly . 20 2.2.2.2 Surface-initiated Controlled Polymerization . 22 II   2.3 Biomedical Applications of SPIONs 24 2.3.1 MRI 24 2.3.2 Drug/Gene Delivery . 28 2.3.3 Hyperthermia 31 CHAPTER SURFACE FUNCTIONALIZATION OF SUPERPARAMAGNETIC NANOPARTICLES FOR MODULATION OF MACROPHAGE UPTAKE 33 3.1 Introduction 34 3.2 Materials and Methods . 36 3.2.1 Materials . 36 3.2.2 Preparation of SPIONs . 36 3.2.3 Synthesis of PLMA Copolymers 37 3.2.4 Synthesis of PLMA-PEG Copolymers . 37 3.2.5 Preparation of PLMA-SPIONs and PLMA-PEG-SPIONs 38 3.2.6 In Vitro Quantification of Nanoparticles Uptake by Macrophages 38 3.2.7 Cytotoxicity Assay of Nanoparticles 40 3.2.8 MRI Experiments . 40 3.2.9 Characterization . 42 3.3 Results and Discussion . 45 3.3.1 Characterization of PLMA . 45 3.3.2 Characterization of PLMA-PEG 46 3.3.3 Characterization of PLMA-SPIONs . 48 3.3.4 Characterization of PLMA-PEG-SPIONs 52 3.3.5 Uptake of PLMA-SPIONs by Macrophages 55 3.3.6 Uptake of PLMA-PEG-SPIONs by Macrophages . 59 3.3.7 Cytotoxicity of Nanoparticles 61 3.3.8 Magnetic Properties of Nanoparticles and MR Relaxometry 62 III   3.4 Conclusion 70 CHAPTER SURFACE MODIFIED SUPERPARAMAGNETIC IRON OXIDE NANOPARTICLES FOR HIGH EFFICIENCY FOLATE-RECEPTOR TARGETING WITH LOW UPTAKE BY MACROPHAGES . 71 4.1 Introduction 72 4.2 Materials and Methods . 74 4.2.1 Materials . 74 4.2.2 Preparation of SPIONs . 74 4.2.3 Synthesis of Initiator 75 4.2.4 Synthesis of Initiator Coated SPIONs 76 4.2.5 Surface Initiated ATRP on SPIONs . 76 4.2.6 Chemical Modification of Epoxy Groups with EDA . 77 4.2.7 Folic Acid Conjugation 77 4.2.8 Cell Culture 78 4.2.9 In Vitro Evaluation of Uptake of Nanoparticles . 78 4.2.10 Cytotoxicity Assay . 79 4.2.11 MRI Experiments . 79 4.2.12 Characterization . 79 4.2.13 Statistical Analysis . 80 4.3 Results and Discussion . 81 4.3.1 Synthesis of SPIONs-PGMA-FA . 81 4.3.2 Size and Zeta Potential of Nanoparticles . 85 4.3.3 Magnetic Properties 87 4.3.4 Cellular Uptake of Nanoparticles . 90 4.3.5 Cytotoxicity Assay . 94 4.4 Conclusion 96 IV   CHAPTER COMBINED ATRP AND ‘CLICK’ CHEMISTRY FOR DESIGNING LONG-CIRCULATING TUMOR-TARGETING SUPERPARAMAGNETIC IRON OXIDE NANOPARTICLES 97 5.1 Introduction 98 5.2 Materials and Methods . 100 5.2.1 Materials . 100 5.2.2 Preparation of SPIONs . 100 5.2.3 Preparation of Initiator-coated SPIONs. 100 5.2.4 Preparation of SPIONs-P(GMA-co-PEGMA) via ATRP 100 5.2.5 Preparation of SPIONs-P(GMA-co-PEGMA)-N3 . 102 5.2.6 Preparation of Alkyne-functionalized FA 102 5.2.7 Preparation of SPIONs-P(GMA-co-PEGMA)-FA . 103 5.2.8 Cell Culture 104 5.2.9 Cytotoxicity Assay . 104 5.2.10 In Vitro Evaluation of Folate Receptor Targeting 104 5.2.11 Characterization . 105 5.2.12 Statistical Analysis . 106 5.3 Results and Discussion . 107 5.3.1 Surface Characterization of SPIONs-P(GMA-co-PEGMA)-FA . 107 5.3.2 Nanoparticle Size and Stability 113 5.3.3 Magnetic Property 116 5.3.4 Cytotoxicity Assay . 117 5.3.5 In Vitro Cellular Uptake . 118 5.4 Conclusion 122 CHAPTER CISPLATIN-CONJUGATED MAGNETIC NANOPARTICLES FOR POTENTIAL BLADDER CANCER THERAPY . 123 6.1 Introduction 124 6.2 Materials and Methods . 127 V   6.2.1 Materials . 127 6.2.2 Preparation of SPIONs . 127 6.2.3 Synthesis of PCL 127 6.2.4 Synthesis of PCL-b-P(PMA-co-PEGMA) . 128 6.2.5 Synthesis of PCL-b-P(PMA-click-MSA-co-PEGMA) 128 6.2.6 Preparation of SPIONs-loaded PNs . 129 6.2.7 Preparation of Cisplatin-conjugated PNs (Pt-Fe-PNs) . 129 6.2.8 In Vitro Cisplatin Release 130 6.2.9 Cell Culture 131 6.2.10 Cytotoxicity Evaluation 131 6.2.11 Cellular Uptake 132 6.2.12 Characterization . 133 6.3 Results and Discussion . 134 6.3.1 Synthesis of PCL-b-P(PMA-click-MSA-co-PEGMA) 135 6.3.2 Preparation of Fe-PNs and Pt-Fe-PNs 139 6.3.3 In Vitro Drug Release . 142 6.3.4 In Vitro Cytotoxicity Evaluation 144 6.4 Conclusion 148 CHAPTER CONCLUSIONS AND RECOMMENDATIONS FOR FUTURE WORK 149 7.1 Conclusions 150 7.2 Recommendations for Future Work . 153 REFERENCES . 155 LIST OF PUBLICATIONS ARISING FROM PHD WORK . 173     VI   SUMMARY Superparamagnetic iron oxide nanoparticles (SPIONs) are very useful for biomedical applications, such as magnetic resonance imaging (MRI), hyperthermia for cancer therapy, cell targeting, drugs or gene delivery. However, once introduced into blood, SPIONs will be captured by the macrophages and then rapidly cleared out from circulation which can drastically reduce the efficiency of SPIONs-based diagnosis and therapy. Therefore, the bio-interfaces of SPIONs are crucial for their biomedical applications. The overall aim of this thesis is to modify SPIONs with different polymers for potential cell targeting, MRI and cancer therapy applications. In the first project, SPIONs were coated with either poly(DL-lactic acid-co-malic acid) (PLMA) or poly(ethylene glycol)-conjugated PLMA (PLMA-PEG) to modulate uptake by macrophages. PLMA-SPIONs are readily taken up by macrophages but the extent of uptake can be reduced by increasing the PEG content of the PLMA-PEG coating. 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Surface modified superparamagnetic iron oxide nanoparticles (SPIONs) for high efficiency folatereceptor targeting with low uptake by macrophages. J. Mater. Chem., 21, pp.16094-16102. 2011. (4) Huang C., K. G. Neoh, and E. T. Kang. Combined ATRP and ‘Click’ chemistry for designing stable tumor-targeting superparamagnetic iron oxide nanoparticles. Langmuir, 28, pp.563-571. 2012. (5) Huang C., K. G. Neoh, L. Q. Xu, E. T. Kang and E. Chiong. Polymeric nanoparticles with encapsulated superparamagnetic iron oxide and conjugated cisplatin for potential bladder cancer therapy. Biomacromolecules, 13, pp.2513-2520. 2012. 173 [...]... technologies of the 21st century, and it has greatly enabled the design of advanced functional nanomaterials of dimensions of 11000 nm in the biomedical field (Gupta and Gupta 2005) Among the different types of nanomaterials, magnetic iron oxide nanoparticles are of intense current interest and have been successfully used for clinical applications, for example, molecular imaging Magnetic iron oxide nanoparticles. .. organs is crucial for SPIONs-based biomedical applications 1.2 Research Objectives and Scopes The overall aim of this thesis is to develop various functional polymers as surface coatings of SPIONs for potential cell targeting, MRI, and cancer therapy applications This thesis consists of seven chapters In Chapter 1, a general introduction of the current problems for SPIONs-based biomedical applications, ... (s-1) and 1/T2 (s-1) in water as a function of the iron concentration of (a) PLMA-2-SPIONs and (b) PLMA-1PEG-3-SPIONs (for all plots, correlation coefficient R2 > 0.97) Relaxometric measurements were performed by MRI.      Figure 3-14  MR images of phantoms containing (a) macrophages without nanoparticles at a cell density of 200×103 cells/mL, and PLMA-2SPIONs-labeled macrophages at a cell density of. .. enhancing the selectivity in targeting of cancer cells ATRP of GMA and poly(ethylene glycol) methyl ether methacrylate (PEGMA) from the surface of SPIONs was first carried out, followed by ‘click’ chemistry to conjugate FA with controlled surface densities In Chapter 6, the preparation of nanoparticles incorporating SPIONs and drug for potential bladder cancer therapy is described Amphiphilic poly(ε-caprolactone)-b-poly(propargyl... (blue), and (c) combined with FITC and DAPI channels Scale bar=100 μm.  Figure 6-11 In vitro cytotoxicity profile of (a) free cisplatin, (b) Fe-PNs, and PtFe-PNs against UMUC3 bladder cancer cells Cells were exposed to the drug or nanoparticles for 2 h and further cultured with fresh medium for 72 h                                             XIV   LIST OF TABLES Table 3-1 Molecular weight and PEG... PLMA-2SPIONs, and (b) with PLMA-2-SPIONs at an iron concentration of 0.5 mM, after staining with Prussian Blue.      Figure 3-9  Uptake of PLMA-2-SPIONs by macrophages (a) as a function of incubation time at incubated iron concentration of 0.5 mM and (b) as a function of incubated iron concentration for an incubation period of 4 h Inset is the image of macrophages incubated with PLMA-2-SPIONs at an iron concentration... growth of nanotechnology over the past decade provides exciting possibilities for synthesis, characterization, and functionalization of nanoscale materials for biomedical applications and diagnostics (Schladt et al 2011) Among the variety of promising nanoscale materials, SPIONs have gained significant attention due to their great potential for various biomedical applications, including MRI for cell. .. nanoparticles by the addition of a base to an aqueous mixture of Fe3+ and Fe2+ salts under an inert atmosphere The size, shape, and composition of the iron oxide nanoparticles depends on the type of salts (e.g nitrates, chlorides, sulphates, etc.), the ratio of Fe3+ /Fe2+, the reaction temperature, the pH value and ionic strength of the medium 8  Chapter 2 The formation of magnetite (Fe3O4) is expected... kidney, and thyroid (Moghimi et al 2001) Figure 2-3 In vivo behavior of nanoparticles in blood vessels The EPR effect of nanoparticles is greatest at tumors (Jun et al 2008) 2.2 Surface Functionalization of SPIONs Although superparamagnetic iron oxide nanoparticles synthesized by hightemperature decomposition method are monodisperse, they are typically coated with hydrophobic ligands, such as oleic acid and. .. acidstabilized SPIONs and (b) Pt-Fe-PNs Figure 6-8 Release profiles of cisplatin from Pt-Fe-PNs in DI water, PBS, and artificial urine at 37 oC Inset shows the release profile in the first 10 h Figure 6-9 Size increase of a mixture of Pt-Fe-PNs and mucin after incubation at 37oC for 2 h Pure mucin and nanoparticle suspensions were used as controls Figure 6-10 Fluorescence images of UMUC3 bladder cancer cells after .           NATIONAL UNIVERSITY OF SINGAPORE 2012     SURFACE FUNCTIONALIZATION OF SUPERPARAMAGNETIC IRON OXIDE NANOPARTICLES FOR POTENTIAL CELL TARGETING, IMAGING, AND CANCER THERAPY APPLICATIONS .     SURFACE FUNCTIONALIZATION OF SUPERPARAMAGNETIC IRON OXIDE NANOPARTICLES FOR POTENTIAL CELL TARGETING, IMAGING, AND CANCER THERAPY APPLICATIONS      HUANG. Superparamagnetic iron oxide nanoparticles (SPIONs) are very useful for biomedical applications, such as magnetic resonance imaging (MRI), hyperthermia for cancer therapy, cell targeting, drugs

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