Design and Evaluation of Plasmonic/Magnetic Au-MFe2O4 (M-Fe/Co/Mn) Core-Shell Nanoparticles Functionalized with Doxorubicin for Cancer Therapeutics (eBook)

Ravichandran Manisekaran received his degrees from Thiruvalluvar Univeersity, B.Sc in Biochemistry (2008) and M.Sc. in Medical Bionanotechnology from Chettinad University (2010). Recently, he received his PhD in the field of Nanoscience and Nanotechnology (March 2017), from the Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV-IPN), Zacatenco, Mexico City. He will be joining as a research associate in the Nanobio-optics laboratory, Center for Applied Physics and Advanced Technology (CFATA), UNAM campus, Juriquilla. His current research interests are focused on the use of surface functionalized multifunctional nanoparticles for various biomedical applications such as targeted drug delivery, hyperthermia, contrast agents, thermal ablation, electrospinning and biosensing. He was awarded a CONACYT fellowship for carrying out his doctoral research in CINVESTAV-IPN from 2013-2017.

Dedication 7
Supervisor’s Foreword 9
Preface 11
Compilation Thesis 13
Acknowledgements 14
Contents 17
List of Figures 20
List of Tables 27
Abbreviations 28
List of Symbols 32
Chapter 1: Introduction to Nanomedicine and Cancer Therapy 34
1.1 Introduction 35
1.1.1 Nanomedicine 35
1.1.2 Cancer Therapy 38
1.1.3 Essential Properties of Nanoparticles for Therapeutic Purpose and Their Applications in Cancer 40
1.1.3.1 Essential Properties of Nanoparticles for Therapeutic Purpose 40
1.1.3.1.1 Nanoparticle as Scaffolds 41
1.1.3.1.2 Surface Area of Nanoparticles 41
1.1.3.1.3 Size Matters! 42
1.1.3.1.4 Shape of a Nanoparticle 43
1.1.3.1.5 Optical Properties 45
1.1.3.1.6 Magnetic Properties 46
1.1.3.1.7 Nanoparticles Platform 47
1.1.3.2 Applications of Nanomaterials in Cancer 47
1.1.3.2.1 Cancer Detection 48
1.1.3.2.1.1 MR Imaging 48
Working Principle of MRI 50
MR Imaging Parameters 51
Relaxations 51
1.1.3.2.1.2 Computed Tomography (CT) 52
1.1.3.2.1.3 Optical Imaging 53
1.1.3.2.2 Nanopharmacotherapy 53
1.1.3.2.2.1 Targeted Therapy 53
1.1.3.2.2.2 Controlled Release 54
1.1.3.2.3 Nanotherapies 55
1.1.3.2.3.1 Drug Delivery 55
1.1.3.2.3.2 Photothermal Therapy (PTT) 56
1.1.3.2.3.3 Hyperthermia/Magnetocytolytic Therapy 56
1.1.3.2.3.4 Thermal Ablation Therapy* 59
Microwave Ablation (MwA) 59
1.1.4 Motivation and Outline of the Thesis 61
1.1.4.1 Motivation 61
1.1.4.2 Outline of the Thesis 62
References 63
Chapter 2: Literature Survey on Magnetic, Gold, and Core-Shell Nanoparticles 70
2.1 Synthesis, Properties, Surface Functionalization, and Applications of Nanoparticles 71
2.1.1 Magnetic Nanoparticles (MNPs) 71
2.1.1.1 Synthesis and Properties 71
2.1.1.2 Surface Functionalization 72
2.1.1.3 Applications 73
2.1.1.3.1 Delivery of siRNA/DNA 73
2.1.1.3.2 Delivery of Drugs 73
2.1.1.3.3 MR Imaging 74
2.1.1.3.4 Hyperthermia 75
2.1.2 Gold Nanoparticles (GNPs) 76
2.1.2.1 Synthesis and Properties 76
2.1.2.2 Surface Functionalization 76
2.1.2.3 Applications 77
2.1.2.3.1 Delivery of siRNA/DNA 77
2.1.2.3.2 Delivery of Drugs 78
2.1.2.3.3 Plasmonic Photothermal Therapy (PPTT) 79
2.1.2.3.4 Photodynamic Therapy (PDT) 80
2.1.3 Core-Shell Nanoparticles (CSNPs) 81
2.1.3.1 Design of Core-Shell Nanomaterials 82
2.1.3.2 Fabrication Techniques of Core-Shell Nanomaterials 83
2.1.3.2.1 Core Materials 83
2.1.3.2.2 Shell Fabrication 84
2.1.3.2.2.1 Metal-Oxide Shell 84
2.1.3.2.2.2 Noble Metal Shells 84
2.1.3.2.2.3 Dense Shells 85
2.1.3.2.2.4 Mesoporous Shells 85
2.1.3.3 Characterization Techniques for Core-Shell Nanoparticles [141] 85
2.1.3.4 Applications of Core-Shell Nanoparticles 86
2.1.3.4.1 Biomedical Applications 86
2.1.3.4.1.1 Drug Targeting and Delivery 87
2.1.3.4.1.2 Bioimaging 87
2.1.3.4.1.3 Sensors 87
2.1.3.4.2 Catalytic Applications 88
2.1.4 Gold Coated Magnetic Nanoparticles (MNPs@Au) 88
2.1.4.1 Synthesis of MNPs@Au 89
2.1.4.2 Challenges in Au Shell Formation 89
2.1.4.3 Formation Mechanism of MNP@Au 89
2.1.4.4 Direct Au Coating 90
2.1.4.5 Indirect Au Coating 90
2.1.4.6 Surface Functionalization of MNPs@Au 91
2.1.4.7 Applications of MNPs@Au 91
2.1.4.8 Imaging 91
2.1.4.9 Hyperthermia 92
2.1.4.10 Magnetic-Induced Hyperthermia 92
2.1.4.11 Photo-Induced Hyperthermia 92
2.1.4.12 Drug Delivery 93
2.1.4.13 Gene Delivery 93
2.1.4.14 DNA-Based Biosensors 93
2.1.4.15 Enzyme-Based Biosensors 94
2.1.4.16 Cell Sorting and Separation 94
2.1.4.17 Catalysis 94
References 95
Chapter 3: Characterization Techniques, Experimental Setup, and Cell Cultivation 106
3.1 Characterization Techniques 106
3.1.1 Structural Characterization (Table 3.1) 106
3.1.1.1 X-ray Diffraction (XRD) 106
3.1.1.2 Transmission Electron Microscopy (TEM) 107
3.1.1.3 Cryo Electron Microscopy (CryoEM) 108
3.1.1.4 Fourier Transform Infrared Spectroscopy (FTIR) 108
3.1.1.5 Zeta (?) Potential Analysis 109
3.1.1.6 X-ray Photoelectron Spectroscopy (XPS) 109
3.1.1.7 Thermogravimetric Analysis (TGA) 110
3.1.2 Magnetic Characterization 110
3.1.2.1 Superconducting Quantum Interference Device (SQUID) 110
3.1.3 Optical Characterization 110
3.1.3.1 UV-Visible Spectroscopy 110
3.1.4 Experimental Setup for Applications Studies 111
3.1.4.1 In Vitro Drug Release Studies 111
3.1.4.2 Drug Kinetics Models 111
3.1.4.2.1 Zero Order 112
3.1.4.2.2 First Order 112
3.1.4.2.3 Higuchi Model 112
3.1.4.2.4 Hixson-Crowell Model 112
3.1.4.3 Magnetic Resonance (MR) Imaging Experiments 113
3.1.4.3.1 Phantom Preparation for MR Imaging 114
3.1.4.4 Hyperthermia Experiment Setup 114
3.1.4.4.1 Temperature Measurements 115
3.1.4.4.2 Hyperthermia Measurements 115
3.1.5 Materials 115
3.1.6 Synthesis Methods 116
3.1.6.1 Synthesis of Core Nanoparticles 116
3.1.6.2 Core Seed Preparation 116
3.1.6.3 Synthesis of Gold Nanoshell 117
3.1.6.4 Synthesis of Core-Shell Nanoparticles (CSNPs) 117
3.1.6.4.1 Au Iterations 117
3.1.6.5 Folic Acid Activation and Attachment onto CSNPs 118
3.1.6.6 Surface Functionalization of Doxorubicin 119
3.1.7 Doxorubicin Loading and Loading Efficiency 119
3.1.8 Cell Studies 120
3.1.8.1 Cell Culture Preparation 120
3.1.8.2 Cytotoxicity Assay 120
3.1.8.3 Cell Labeling 120
3.1.8.4 Confocal Imaging 121
3.1.9 Software for Data Processing 121
References 121
Chapter 4: Designing a Nanocargo with Fe3O4@Au: A Tri-pronged Mechanism for MR Imaging, Synaphic Drug-Delivery, and Apoptosis Induction in Cancer Cells 124
4.1 Introduction 124
4.2 Results and Discussion 126
4.2.1 Mechanism Involved in the Synthesis of Core/Shell Nanoparticles (CSNPs) 126
4.2.2 Structural Characterizations of CSNPs 127
4.2.3 Magnetic Characterizations 130
4.2.4 Surface Composition of Fe@A 130
4.2.5 Surface Modification Using Fa and Dox onto the Fe@A Surface 132
4.2.6 Stability and Zeta Potential Studies of NPs 134
4.2.7 Fa-Fe@A NPs Internalization in Cells 135
4.2.8 Evaluating Cytocompatibility in L6 and Hep2 Cells 136
4.2.8.1 L6 Cells 136
4.2.8.2 Hep2 Cells 137
4.3 Applications of Fe@A 138
4.3.1 Drug Release and Kinetics Studies at Different pH 139
4.3.2 MR Imaging Using Fe@A in L6 and Hep2 Cells 139
4.3.3 Hyperthermal Studies of Fe@A at 2.45 GHz 140
4.4 Conclusion 142
References 143
Chapter 5: Multiple Iterative Seeding of Surface Plasmon Enhanced Cobalt-Iron Oxide Nanokernels for Cancer Theranostics 147
5.1 Introduction 147
5.2 Results and Discussion 149
5.2.1 Characterization of Plasmonic/Magnetic NPs 149
5.2.1.1 XRD Measurement 149
5.2.1.2 Morphological Analysis by TEM 149
5.2.1.3 Magnetic Measurements by SQUID 151
5.2.1.4 Elemental Analysis by XPS 152
5.2.2 Tethering Folic Acid Linker and Doxorubicin Molecules on Nk@A 154
5.2.2.1 UV–Vis Spectroscopy to Confirm Nk@A Formation, FA Attachment and Dox Binding 154
5.2.2.2 FTIR Spectroscopy for CTAB Removal, FA Attachment and Dox Binding onto Nk@A 155
5.2.2.3 TGA Analysis to Confirm the Stability of NPs 156
5.2.3 Internalization and Stability Studies 157
5.2.3.1 CryoEM and Zeta Potential Analysis 157
5.2.3.2 Intracellular Localization of Dox and Dox-FA-Nk@A by Confocal Microscopy 158
5.2.3.3 Cell Viability by MTT Assay 159
5.2.3.4 Cell Viability Visualized by Confocal Morphology 159
5.3 Applications of Nk@A 160
5.3.1 In vitro Dox Release Kinetics 160
5.3.2 Magnetic Resonance Imaging in Normal and Cancerous Cells 163
5.3.3 Microwave-Based Hyperthermia Therapy 164
5.3.3.1 In Vitro Hyperthermia and Chemo-Hyperthermia Therapy 165
5.4 Summary 166
References 167
Chapter 6: Nano-Flotillas MnFe2O4@Au Core-Shell Nanoparticles: An Efficient MRI Contrast Agent, Magneto-hyperthermal and Drug-Delivery Armada for Cancer 171
6.1 Introduction 171
6.2 Results and Discussions of Optimization and Characterization of CTAB Stabilized MnFe2O4@Au Core/Shell Nanoparticles: Formation Mechanism of Core/Shell Nanoparticles 173
6.2.1 Structural and Magnetic Characterization of Mf@A NPs 174
6.2.2 Elemental Composition of Mf@A NPs 176
6.2.3 Bioconjugation of Folic Acid Linker and Doxorubicin Molecules on Mf@A 178
6.2.3.1 Optical Analysis 178
6.2.3.2 Spectroscopy Analysis 178
6.2.4 Zeta Potential, Cytotoxicity Studies of Nanoparticle Complexes 179
6.2.5 Nanoparticles Internalization Studies 182
6.2.6 Dox Intracellular Distribution 183
6.2.7 Cellular and Nuclear Morphology Studies 183
6.3 Applications of MF@A 183
6.3.1 In Vitro Dox Release and Its Kinetics 183
6.3.2 Microwave Ablation Therapy 186
6.4 Summary 188
References 189
Chapter 7: Concluding Remarks and Future Prospects 192
7.1 Concluding Remarks 192
7.2 Future Prospects 193
Appendix: Publications 196
Book Chapter 196
Publications in Peer-Reviewed Journals 196
Article Under Preparation 197
Conferences 197
Oral and Poster Presentation 197