V Contents Preface XVII List of Contributors XXI Part One Biosensing and Diagnosis 1 1 Nanomaterials-Based Magnetic Relaxation Switch Biosensors 3 Tom Lowery 1.1 Introduction 3 1.2 Superparamagnetic Nanoparticles 4 1.3 Agglomeration-Based Sensing 6 1.4 T Sensitivity of MRSW Particles 8 2 1.4.1 Fundamentals of T Relaxation 8 2 1.4.2 Detecting T Relaxation 11 2 1.4.3 Theoretical Model for T and Nanoparticle Size 14 2 1.5 Kinetics of Magnetic Relaxation Switch Biosensors 18 1.6 Demonstrations of Magnetic Relaxation Switch Biosensors 20 1.6.1 Detecting Nucleic Acids 21 1.6.2 Detecting Proteins 24 1.6.3 Detecting Enzymes 25 1.6.4 Detecting Viruses 29 1.6.5 Detecting Small Molecules 30 1.6.6 Detecting Ions 32 1.6.7 Detecting Cells 34 1.7 Methods Development 36 1.7.1 Reagent Synthesis, Preparation, and Characterization 36 1.7.2 Measurement and Sensitivity Enhancement Methods 38 1.8 Micro-NMR of Magnetic Relaxation Switch Biosensors 42 Acknowledgments 46 References 47 Nanomaterials for the Life Sciences Vol. 4: Magnetic Nanomaterials. Edited by Challa S. S. R. Kumar Copyright © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32154-4 VI Contents 2 Multiplexed Detection with Magnetic Nanoparticles 55 Robert Wilson 2.1 Introduction 55 2.2 Magnetism and Magnetic Particles 56 2.2.1 Separating and Mixing Magnetic Particles 58 2.3 Planar Arrays 58 2.4 Rotating Discs 63 2.5 Diagnostic Devices 64 2.6 Bio-Barcode Assays Based on Magnetic Microspheres 66 2.7 Spectrally Encoded Suspension Arrays of Magnetic Microspheres 66 2.7.1 Magnetically Encoded Suspension Arrays 70 2.8 Summary and Conclusions 72 References 72 3 Magnetophoretic Biosensing and Separation Using Magnetic Nanomaterials 77 Joo H. Kang, Young Ki Hahn, Kyu Sung Kim, and Je-Kyun Park 3.1 Introduction 77 3.2 Theory 79 3.2.1 Magnetic Properties of a Material 79 3.2.2 Magnetophoresis 80 3.2.3 High-Gradient Magnetic Separation 81 3.3 Magnetophoresis in Microfl uidic Devices 83 3.3.1 Design and Microfabrication Processes 83 3.3.2 Experimental Set-Up 85 3.3.3 Measurement and Analysis 88 3.4 Magnetophoretic Biosensing 88 3.4.1 Magnetophoretic Sandwich Immunoassay 89 3.4.2 Highly Sensitive Biosensors Using HGMS 92 3.4.3 Disease Diagnosis Using Magnetophoretic Assay Systems 93 3.4.4 Multiplexed Magnetophoretic Immunoassay 97 3.5 Magnetophoretic Separation 102 3.5.1 Cell Separation and Analysis 102 3.5.2 Separation of Nanomaterials 104 3.5.3 Isomagnetophoresis (IMP) 107 3.6 Concluding Remarks 111 Acknowledgments 112 References 112 4 Magnetic Nanomaterials as MRI Contrast Agents 119 Yurii K. Gun’ko and Dermot F. Brougham 4.1 Introduction 119 Contents VII 4.2 Classifi cation of Magnetic Nanomaterials Used for MRI Applications 121 4.2.1 Magnetic Oxide-Based Nanoparticles 122 4.2.2 Magnetic Metal- and Alloy-Based Nanoparticles as Contrast Agents 125 4.2.3 Rare Earth Metal-Loaded Nanoparticulate Contrast Agents 126 4.3 Coating and Surface Functionalization of Magnetic Nanoparticles 129 4.3.1 Surface Modifi cation with Monomeric Stabilizers 129 4.3.2 Modifi cation Using Polymeric Stabilizers 130 4.3.3 Modifi cation Using Inorganic Coatings 133 4.3.4 Vectorization of Magnetic Nanomaterials for Targeted Imaging 137 4.4 Properties and Characterization of Magnetic Nanoparticle Suspensions 138 4.4.1 Characterizing the Suspensions 139 4.4.1.1 Nanoparticle Size: Transmission Electron Microscopy 139 4.4.1.2 Magnetic Properties: Magnetometry 139 4.4.1.3 Hydrodynamic Size: Photon Correlation Spectroscopy 140 4.4.1.4 Magnetic Resonance Properties: Nuclear Magnetic Resonance Dispersion 141 4.4.2 NMR Relaxation in the Presence of Superparamagnetic Nanoparticles 141 4.4.3 SPM Theory Applied to Suspensions of Nanoparticle Clusters 143 4.4.4 General Application of Relaxation Time Measurements 144 4.5 Application of Magnetic Nanomaterials in MRI 145 4.5.1 Current Clinical Applications 145 4.5.1.1 Gastrointestinal Tract and Bowel Imaging 145 4.5.1.2 Liver and Spleen Imaging 146 4.5.1.3 Lymph Node Imaging 147 4.5.1.4 Bone Marrow Imaging 148 4.5.1.5 Brain Imaging 149 4.5.1.6 Blood Pool Imaging and MR Angiography 151 4.5.1.7 Atherosclerosis Imaging 152 4.5.2 Potential Clinical Applications 152 4.5.2.1 Cellular Labeling and Tracking 152 4.5.2.2 Molecular Imaging 154 4.6 Summary and Future Outlook 159 4.6.1 Improved Imaging Methods 160 4.6.2 Improved Imaging Hardware 161 4.6.3 Improved Contrast Agents 161 References 164 VIII Contents Part Two Diagnosis and Therapy 187 5 Magnetic Nanomaterials for In Vivo and In Vitro Cancer Diagnostics 189 Kelly Y. Kim 5.1 Introduction 189 5.2 Physico-Chemical Properties of Magnetic Nanoparticles 190 5.3 Surface Coating for Improved Biocompatibility and Bioavailability 191 5.4 MRI for In Vivo Diagnostics 194 5.4.1 Principles of MRI 194 5.4.2 SPIOs as MRI Contrast Agents 195 5.4.3 Specifi c Targeting of Tumors for Imaging 195 5.5 MRI for the Monitoring of Treatment 196 5.6 Application of Magnetic Nanoparticles in In Vitro Diagnostics 197 5.6.1 Magnetic Nanoparticle-Based Improvements on Immunoassays 198 5.6.1.1 Electrochemical Immunoassays 198 5.6.1.2 Immunoassays Using Magnetic Luminescent Nanoparticles (MLNPs) 199 5.6.2 Magnetic Relaxation Switch (MRSw) Biosensors for Multi-Sample Analysis 199 5.6.3 DNA Sequence Detection by Brownian Relaxation Frequency Measurement 201 5.7 Detection of Circulating Tumor Cells 202 5.8 Aptamers as an Alternative to Antibodies 203 5.9 Conclusions 204 References 205 6 Magnetic Nanoparticles for Cancer Imaging and Therapy 209 Arutselvan Natarajan, Rajeswari Sundrarajan, and Sally J. DeNardo 6.1 Introduction 209 6.2 Synthesis and Surface Modifi cations of MNPs for Biological Applications 211 6.2.1 Fabrication of the Magnetic Nanoparticle Core 211 6.2.2 Surface Coatings and Chemistry 211 6.2.3 Physico-Chemical Characterization of MNPs 212 6.2.4 Plasma Stability and Pharmacokinetic Profi le of the MNPs 212 6.3 Development of MNPs as Cancer Diagnosis and Imaging Agents 214 6.3.1 MNPs Used in MR Imaging for Cancer Diagnosis 214 6.3.2 MNPs Used in Optical Imaging for Cancer Diagnosis 219 6.3.3 Ligand-Directed MNPs for Cancer Imaging 225 Contents IX 6.3.3.1 Antibody-Directed MNPs 225 6.3.3.2 Antibody Fragment-Directed MNPs 226 6.3.4 Radioimmunonanoparticles 228 6.3.5 Annexin 5-Directed MNPs 230 6.3.6 Chemotherapeutic Drugs Loaded with MNPs for Cancer Therapy 230 6.3.7 Lymph Node-Targeting MNPs 231 6.3.8 Other Novel MNPs for Cancer Targeting 231 6.4 MNPs Applied to Cancer Therapy 232 6.4.1 MNPs Utilized in Targeted Therapy for Cancer 232 6.4.1.1 Brain Tumor Therapy 232 6.4.1.2 Breast Cancer Therapy 234 6.4.1.3 MNPs in Hyperthermia and Thermal Ablation 237 6.4.1.4 MNPs-Directed Toxicity 240 6.5 Summary 242 References 244 7 Core–Shell Magnetic Nanomaterials in Medical Diagnosis and Therapy 259 Marites P. Melancon and Chun Li 7.1 Introduction 259 7.2 Synthesis 260 7.2.1 Formation of the Magnetic Core 260 7.2.1.1 Coprecipitation from Solution 260 7.2.1.2 Thermal Decomposition 261 7.2.1.3 Microemulsions 262 7.2.1.4 Pyrolysis 262 7.2.2 Formation of the Core–Shell Structure 263 7.2.2.1 Inorganic Core with Organic Shell 263 7.2.2.2 Inorganic Core with Inorganic Shell 264 7.3 Applications: Magnetic Resonance Imaging 270 7.4 Applications: Hyperthermia and Thermal Ablation 273 7.4.1 Passive Targeting 275 7.4.1.1 Dextran-Coated Magnetite 275 7.4.1.2 Aminosilan-Coated Magnetic Particles 275 7.4.1.3 Magnetic Cationic Liposomes 276 7.4.2 Active Targeting 277 7.4.2.1 Antibodies 277 7.4.2.2 Peptides 277 7.4.2.3 Folic Acid 278 7.4.3 Laser-Induced Hyperthermia/Thermal Ablation Therapy 278 7.5 Application: Drug Delivery 279 7.6 Summary and Perspectives 281 Acknowledgments 282 References 282 X Contents Part Three Tissue Engineering 291 8 The Use of Magnetic Particles in Tissue Engineering 293 Sarah H. Cartmell and Jon Dobson 8.1 Introduction 293 8.1.1 Mechanotransduction 293 8.1.2 Cell Seeding: Scaffolds and 3-D Structures 296 8.2 Magnetic Particle Technology Used in Various Tissue Types 297 8.2.1 Bone and Cartilage 297 8.2.2 Blood Vessels and Cardiac Structure 299 8.2.3 Skin 300 8.2.4 Lung 301 8.2.5 Eye 301 8.2.6 Liver 302 8.2.7 Nervous Tissue 302 8.2.8 Stem Cell Targeting 303 8.2.9 Use of Magnetic Particles to Create Acellular Scaffolds 303 8.3 Summary and Concluding Remarks 303 References 304 Part Four Environmental Applications 309 9 Magnetic Nanomaterials for Environmental Applications 311 Marvin G. Warner, Cynthia L. Warner, R. Shane Addleman, and Wassana Yantasee 9.1 Introduction 311 9.1.1 The Aim of the Chapter 311 9.1.2 The Role of Nanomaterials in Environmental Detection 311 9.2 Synthesis and Functionalization of Magnetic Nanoparticles 313 9.2.1 Synthetic Strategies for Magnetic Metal Oxide Nanoparticles 313 9.2.1.1 Coprecipitation 314 9.2.1.2 Thermal Decomposition 315 9.2.1.3 Other Synthetic Methods 317 9.2.2 Functionalization of Magnetic Nanoparticles 317 9.2.2.1 Organic Ligand Modifi cation 318 9.2.2.2 Stabilization with Polymers 319 9.2.2.3 Inorganic Stabilization with Silica or Carbon 319 9.2.2.4 Less Common Methods of Passivation 324 9.3 Magnetic Nanoparticles for the Separation and Detection of Analytes 324 9.3.1 Chemical Separations with Functionalized Magnetic Nanoparticles 324 9.3.2 High Magnetic Field Gradient Separation and Preconcentration 327 Contents XI 9.3.3 Electrochemical Detection Enhanced by Magnetic Nanomaterials for Preconcentration 330 9.3.4 Analyte Detection Using Magnetic Nanoparticles through Nonelectrochemical Methods 334 9.4 Summary and Future Perspective 336 Acknowledgments 337 References 337 Part Five Biofunctionalization and Characterization 345 10 Magnetic Core–Polymer Shell Nanoparticles: Synthesis and Biomedical Applications 347 Koon Gee Neoh, Lihan Tan, and En-Tang Kang 10.1 Introduction 347 10.2 Synthesis of Magnetic Nanoparticles 348 10.2.1 Primary Synthesis Methods 348 10.2.2 Effect of Synthesis Conditions on Particle Size and Surface Properties 349 10.3 Magnetic Nanoparticles with Polymeric Shell 350 10.3.1 Coating with Polymer During MNP Synthesis 350 10.3.1.1 Dextran-Coated MNPs via the Coprecipitation Method 350 10.3.1.2 Starch-Coated MNPs via the Coprecipitation Method 352 10.3.1.3 PEG-Coated MNPs via the Coprecipitation Method 353 10.3.1.4 MPEG-COOH-Coated MNPs via the High-Temperature Decomposition Method 354 10.3.1.5 Triethylene Glycol-Coated MNPs via the High-Temperature Decomposition Method 356 10.3.1.6 4-Methylcatechol-Coated MNPs via High Temperature Decomposition Method 356 10.3.2 Modifi cation of Preformed MNPs 357 10.3.2.1 Physical Adsorption of Polymer onto Preformed MNPs 357 10.3.2.2 Grafting of Polymer on Preformed MNPs 359 10.4 Encapsulation of Magnetic Nanoparticles in a Polymeric Matrix 371 10.4.1 Nanospheres for Imaging 372 10.4.1.1 PLGA and PLLA Coating 372 10.4.1.2 PEG-PEI, Crosslinked Poly(Maleic Anhydride-alt-1-Tetradecene) and Lipid Micelles Coating 373 10.4.1.3 Iodinated Polymer Coating 374 10.1.4.4 Poly(Styrene-co-Acrylic Acid) Coating 375 10.4.2 Nanospheres with Targeting and Recognition Capability 375 10.4.2.1 Polypyrrole Coating with FA as the Targeting Ligand 376 10.4.2.2 PPY Coating with Herceptin as the Targeting Ligand 377 10.4.2.3 PLGA Coating with Arginine Peptide as the Targeting Ligand 379 10.4.2.4 Phospholipid Coating with Antibodies as the Targeting Ligand 379 XII Contents 10.4.2.5 Poly(MMA-co-EGDMA) Coating with BSA Surface-Imprintation 380 10.4.3 Nanospheres as Drug/Gene Delivery System 380 10.4.3.1 PLGA Loaded with Taxol 381 10.4.3.2 PLLA and PCL Loaded with Tamoxifen 381 10.4.3.3 Chitosan Loaded with Cefradine 382 10.4.3.4 PECA or PCL Loaded with Cisplatin or Gemcitabine 382 10.4.3.5 Poly(Alkylcyanoacrylate) Loaded with Tegafur or 5-Fluorouracil 384 10.4.3.6 PHDCA-PEI Loaded with Doxorubicin 386 10.4.3.7 PLGA Loaded with QDs, DOX, and Functionalized with FA 386 10.4.3.8 PEI and Transferrin-Mediated Gene Delivery 388 10.4.3.9 Polyamidoamine (PAMAM) Dendrimer-Mediated Gene Delivery 389 10.5 Future Perspectives 389 References 392 11 Magnetosomes: Bacterial Biosynthesis of Magnetic Nanoparticles and Potential Biomedical Applications 399 Sarah S. Staniland 11.1 Introduction 399 11.2 Magnetic Nanoparticles for Medical Applications 400 11.2.1 Introduction 400 11.2.2 Requirements and Specifi cations for Biomedical Applications 401 11.2.2.1 Safety Aspects 401 11.2.2.2 Magnetic Properties 402 11.2.2.3 Particle Size and Shape 402 11.2.2.4 Particle Coatings 402 11.2.3 General Synthetic Methods 403 11.2.3.1 Precipitation 403 11.2.3.2 Thermal Decomposition 405 11.3 What Is Biomineralization? Biogenic Inorganic Materials 405 11.4 Magnetosomes: Biomineralization in Magnetic Bacteria 407 11.4.1 Bacteria Characterization 409 11.4.2 Magnetosome Characterization 412 11.4.3 Magnetosome Formation 415 11.4.3.1 Proteomics 416 11.4.3.2 Genetics 417 11.4.3.3 Mechanism 418 11.5 Progress and Applications of Novel Biomedical Magnetosome Materials 419 11.6 The Future for Biomedical Magnetosomes 422 References 424 12 Approaches to Synthesis and Characterization of Spherical and Anisometric Metal Oxide Magnetic Nanomaterials 431 Lorenza Suber and Davide Peddis 12.1 Introduction 431 Contents XIII 12.2 Magnetism in Nanostructured Metal Oxides 433 12.2.1 Magnetism in Condensed Matter 433 12.2.2 Magnetic Anisotropy Energy 435 12.2.3 Magnetism in Small Particles: An Experimental Approach 436 12.2.3.1 Zero Field-Cooled and Field-Cooled Magnetization 438 12.2.3.2 Thermoremanent Magnetization 439 12.2.4 Magnetic Metal Oxides 440 12.3 Synthesis Methods for Spherical and Anisometric Iron Oxide Nanomaterials 442 12.3.1 Synthesis of Spherical and Anisometric Nanoparticles 443 12.3.1.1 Metal Salt Precipitation in Water 443 12.3.1.2 Sol–Gel 445 12.3.1.3 Microemulsions 447 12.3.1.4 Autocombustion Method 448 12.3.1.5 Surfactant-Assisted Hydrothermal Treatment 448 12.3.1.6 Surfactant-Assisted Ultrasound Irradiation 449 12.3.2 Ferrofl uids 449 12.3.2.1 Surfactant-Assisted Dehydration 450 12.3.2.2 Hydrophobic–Hydrophilic Phase Transfer 450 12.3.3 Core–Shell Spherical and Anisometric Particles 451 12.3.3.1 Core–Shell Fluorescent Magnetic Iron Oxide–Silica Particles 452 12.3.3.2 Synthesis of Anisometric Iron Oxide Nanocapsules 453 12.3.4 Maghemite and Magnetite Nanotubes 455 12.3.4.1 Solid Nanotube Template 455 12.3.4.2 Soluble Nanotube Template 456 12.4 Correlations between Synthesis and Magnetic Behavior in Iron Oxide Nanomaterials 457 12.4.1 Spherical and Anisometric Iron Oxide Particles 457 12.4.1.1 Spherical Magnetite (FeO) Nanoparticles 457 3 4 12.4.1.2 Stable Iron Oxide Spherical Nanoparticle Dispersions (Ferrofl uids) 459 12.4.1.3 Surfactant Effect 461 12.4.1.4 Anisometric Maghemite (γ-FeO) Particles 462 2 3 12.4.2 Core–Shell Nanoparticles 463 12.4.2.1 γ-FeO/Silica Core Coated with Gold Nanoshell 464 2 3 12.4.2.2 Effect of Particle Size and Particle Size Distribution on the Magnetic Properties of Magnetite/PDMS Nanoparticles 466 12.4.3 Nanocomposites 468 12.4.3.1 Magnetic Properties of Cobalt Ferrite–Silica Nanocomposites Prepared by a Sol–Gel Autocombustion Technique 468 12.4.3.2 Ordered Mesoporous γ-FeO/SiO Nanocomposites 472 2 3 2 12.4.3.3 FeO/Polymethylmethacrylate 473 3 4 12.4.4 Iron Oxide Nanowires and Nanotubes 474 12.4.4.1 FeO Nanowires 475 3 4 12.4.4.2 FeO Nanowires and γ-FeO Nanotubes 475 3 4 2 3