Synthesis and biomedical applications of magnetic nanomaterials 9782759827152

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Current Natural Sciences

Yanglong HOU, Jing YU and Song GAO

Synthesis and Biomedical Applications of Magnetic Nanomaterials

This book was originally published by Science Press, © Science Press, 2019.

Printed in France

EDP Sciences – ISBN(print): 978-2-7598-2494-6 – ISBN(ebook): 978-2-7598-2715-2 All rights relative to translation, adaptation and reproduction by any means whatsoever are reserved, worldwide. In accordance with the terms of paragraphs 2 and 3 of Article 41 of the French Act dated March 11, 1957, “copies or reproductions reserved strictly for private use and not intended for collective use” and, on the other hand, analyses and short quotations for example or illustrative purposes, are allowed. Otherwise, “any representation or reproduction – whether in full or in part – without the consent of the author or of his successors or assigns, is unlawful” (Article 40, paragraph 1). Any representation or reproduction, by any means whatsoever, will therefore be deemed an infringement of copyright punishable under Articles 425 and following of the French Penal Code. The printed edition is not for sale in Chinese mainland. Customers in Chinese mainland please order the print book from Science Press. ISBN of the China edition: Science Press ISBN: 978-7-03-061281-6 ©

Science Press, EDP Sciences, 2022

Foreword I am honored to be invited to write the foreword for the book Synthesis and Biomedical Applications of Magnetic Nanomaterials. The three authors of this book are outstanding young scientists I am familiar with, who have accomplished a lot in their fields. Dr. Yanglong Hou has focused on the fabrication, modulation and applications of magnetic nanomaterials, Dr. Jing Yu has been using magnetic nanomaterials in diagnosis and therapy of cancer, while Dr. Song Gao is an expert in nano or molecular magnet. This book is valuable because it brings together the works of young scientists currently engaged in related research in the mainland of China. Magnetism is a unique property that is ubiquitous worldwide. Inspired by the phenomenon that some birds and insects can be navigated by using the Earth’s magnetic field, people begin to be interested in exploring the biological effects of magnetism. With the development of molecular biology, the relationship between magnetism and biosome, however, is tended to be studied in a cell or even molecular scale. Magnetic field applied in our daily life is relatively too big compared with organelle and atoms. Nanometer is a measure of length with the definition of 10−9 meter. It is in a similar scale to protein, nucleate and other biomolecules. As a result, magnetic materials in nanometer, which is termed as magnetic nanomaterials, are more likely to interact with biological molecules, and even can be applied for biological manipulation. In addition, these magnetic nanomaterials possess a biological favorable magnetic property, i.e., superparamagnetism, which reduced the aggregation during body circulation for much safer biological applications. Another feature of magnetic nanomaterials is their specific magnetization, and it brightened the improvement in magnetic-thermal conversion and enhanced the proton relaxation in ambient water molecule under magnetic field. These two advancements are beneficial to the adhibition of magnetic nanomaterials for magnetic-mediated hyperthermia and magnetic resonance imaging (MRI) in biomedicine. Since magnetism of magnetic nanomaterials is closely dependent on their phases, morphologies and sizes, controlled synthesis of these materials has been studied in depth. As the surface status of magnetic nanomaterials affected not only their magnetism, but also the body circulation and distribution, surface modification in

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magnetic nanomaterials has attracted much attention as well. In comparison to the researches in physics or chemistry, nano science and life science, particularly the interdisciplinary application by using magnetic nanomaterials in biomedicine is at its infancy. At the same time, I believe that the field of synthesis and biomedical applications of magnetic nanomaterials should afford many opportunities and challenges. As such, I hope that the publication of this book, ranging from synthesis and modification of magnetic nanomaterials to their biological applications in diagnosis and therapy, as well as the biocompatibility, will attract more young scientists to be engaged into this interdisciplinary field, which motivates me for this foreword.

Academician, CAS Early summer of 2019

Preface Magnetism is an old but still promising field that encountered in everyday life. In recent years, the integration of state-of-the-art magnetic materials with advanced nanotechnology has driven magnetic materials into the “nano” era, and forms a new term “magnetic nanomaterials”. These magnetic nanomaterials possess extraordinary unique magnetic properties such as single domain, superparamagnetism, and specific magnetism due to their unique characteristics induced by nanosized effects, and caused great attentions in either research or industry. As a result, they have blossomed into one of the most important branches in magnetic materials, which used alone or accompanied with other materials, show great potentials in biomedicine ranging from magnetic resonance imaging to magnetic-mediated hyperthermia, molecular imaging, diagnostics and cancer therapy. This book aims to address cutting-edge progress in the area of synthesis and biomedical applications of magnetic nanomaterials. It compiles a broad spectrum from fundamental principles to technological advances, from synthesis and modification to biomedical applications along with biocompatibility. The main topics include principles in nanomagnetism, technologies for magnetic nanomaterials fabrication, developments in their biomedical applications, and the challenges in the toxicity in clinical translation. The book is contributed by leading researchers in chemistry, magnetism, nanomaterial and biology worldwide. The first part introduces the principles of nanomagnetism and specific properties in magnetic nanomaterials. Then, some typical fabrication strategies in magnetic nanomaterials for controlled composition, morphologies and sizes are reviewed; and surface modification methods with better hydrophilcity and biocompatibility are presented. Next, magnetic nanomaterials-based applications in biomedical field are highlighted in detail, mainly including magnetic resonance image, magnetic hyperthermia, cancer therapy, multi-mode imaging, imaging-guided therapy and manipulation of biological objects. Finally, biocompatibility issues caused by magnetic nanomaterials are also overviewed. Currently, researches in magnetic nanomaterials are moving rapidly with their synthesis ways and applications fast changing. As the applications of magnetic nanomaterials have broadened into various fields, strategies introduced in this book for synthesizing and modifying magnetic nanomaterials are also suitable for the applica-

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tions in new energy, communication, and environmental fields. The main audiences of this book are graduate students and professional researchers in magnetism, materials science and engineering, nanoscience, biomaterials and life science. It is believed that, with the cooperation of magnetists, nanomaterials scientists and biologists, magnetic nanomaterials will definitely get more breakthroughs and be transferred to clinical use in more fantastic ways in near future.

Contents Foreword Preface

Introduction Chapter 1

Nanomagnetism: Principles, Nanostructures, and Biomedical Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1.2 Nanomagnetic effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 1.2.1 Single domain and superparamagnetism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 1.2.2 Exchange-coupling effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 1.2.3 Exchange bias effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 1.3 Magnetism of nanomaterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 1.3.1 Magnetism of NPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 1.3.2 Magnetism of nanoplates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 1.3.3 Magnetism of nanorings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 1.4 Biomedical applications of nanomagnetism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 1.4.1 T 2 MRI contrast agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 1.4.2 Magnetic hyperthermia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 1.4.3 Biosensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 1.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Controlled Synthesis and Modification Chapter 2

Chemical Synthesis of Magnetic Nanocrystals: Recent Progress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 2.2 Chemical synthesis of single-component magnetic NCs . . . . . . . . . . . . . . . . . 25 2.2.1 Metal oxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 2.2.2 Metals and alloys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2.2.3 Metal carbides, phosphides, and chalcogenides . . . . . . . . . . . . . . . . . . . . . . . 33

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2.3 Chemical synthesis of multi-component magnetic NCs . . . . . . . . . . . . . . . . . . 38 2.3.1 Core/shell heterostructure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 2.3.2 Oligomer-like heterostructure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 2.3.3 Anisotropically shaped material-based heterostructure . . . . . . . . . . . . . . . . 49 2.4 Chemical synthesis of hollow/porous magnetic NCs . . . . . . . . . . . . . . . . . . . . 53 2.4.1 Fe-based hollow/porous NCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 2.4.2 Mn-based hollow/porous NCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 2.5 Summary and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Chapter 3 3.1 3.2 3.3 3.4

Magnetic Iron Oxide Nanoparticles: Synthesis and Surface Coating Techniques for Biomedical Applications . . . . . . . . . . . 68 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Fe3 O4 and γ-Fe2 O3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Size-induced magnetism evolution and application mechanisms . . . . . . . . . 72 Synthesis approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 3.4.1 Physical vapor deposition (PVD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 3.4.2 Chemical vapor deposition (CVD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 3.4.3 Electrodeposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 3.4.4 Hydrothermal synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 3.4.5 Co-precipitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 3.4.6

High-temperature (thermal) decomposition of organometallic precursors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

3.5 Surface coating for biomedical application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 3.5.1 Au coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 3.5.2 SiO2 coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 3.5.3 TaOx coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 3.5.4 Polymer coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 3.5.5 Small molecular coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 3.5.6 Carbon coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 3.6 Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 Chapter 4

Surface Modification of Magnetic Nanoparticles in Biomedicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 4.2 Surface modification with organic molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 4.3 Coating modification with macromolecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 4.3.1 Polymer coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

Contents 4.3.2

vii Liposome and micelle encapsulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

4.4 Coating modification with inorganic materials . . . . . . . . . . . . . . . . . . . . . . . . 120 4.4.1 Silica coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 4.4.2 Metal element coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 4.5 Conclusions and outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

Diagnosis and Therapy Chapter 5 Magnetic Nanoparticle-Based Cancer Nanodiagnostics . . 133 5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 5.2 Magnetic resonance imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 5.3 Diagnostic magnetic resonance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 5.4 Multifunctional MNPs for multimodal probing . . . . . . . . . . . . . . . . . . . . . . . 166 5.5 Conclusion and future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 Chapter 6 Magnetic Microbubble: A Biomedical Platform Co-constructed from Magnetics and Acoustics . . . . . . . . . . . . 183 6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 6.2 Magnetic nanoparticles and magnetic characteristics . . . . . . . . . . . . . . . . . . 185 6.2.1

Preparation, surface modification, assembly of magnetic nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

6.2.2

Special features of magnetic nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . 186

6.2.3

Biomedical applications of magnetic nanoparticles . . . . . . . . . . . . . . . . . . 190

6.2.4

Ultrasonic characteristics of magnetic nanoparticles liquid . . . . . . . . . . . 192

6.3 Microbubble formalism and acoustic characteristics . . . . . . . . . . . . . . . . . . . 193 6.3.1 Design and preparation of microbubbles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 6.3.2 Actions of MBs with ultrasound waves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 6.4 Magnetic and acoustic character of magnetic microbubbles (MMBs) . . . 197 6.4.1 Fabrication of magnetic microbubbles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 6.4.2 Acoustic response of magnetic microbubbles . . . . . . . . . . . . . . . . . . . . . . . . 198 6.4.3 Magnetic response of magnetic microbubbles . . . . . . . . . . . . . . . . . . . . . . . 200 6.5 Applications of magnetic microbubbles in biomedicine . . . . . . . . . . . . . . . . 203 6.5.1 Multimodal imaging of MMBs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203 6.5.2 Ultrasound assisted drug delivery of MMBs . . . . . . . . . . . . . . . . . . . . . . . . 204 6.5.3 Magnetic field-controlled drug delivery and release of MMBs . . . . . . . . . 204 6.6 Summary and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

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MMBs as physical triggering smart drug delivery system . . . . . . . . . . . . 206

6.6.2

MMBs for gene delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206

MMBs for treating diseases of the central nervous system . . . . . . . . . . . . 207 . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 6.6.3

Chapter 7

Multifunctional Magnetic Nanoparticles for Magnetic Resonance Image-guided Photothermal Therapy for Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 7.2 ICG-loaded MNPs for MR/fluorescence bimodal image-guided PTT . . . 215 7.2.1 Fabrication of ICG-loaded SPIO NPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 7.2.2 In vivo MR/fluorescence bimodal imaging of ICG-loaded SPIO NPs . . 216 7.2.3 In vivo photothermal therapy with ICG-loaded SPIO NPs . . . . . . . . . . . 218 7.3 Gold-nanoshelled magnetic cerasomes for MRI-guided photothermal therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 7.3.1

Cerasomes combine the advantages of both liposomes and silica nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

7.3.2

Contrast-enhanced MRI imaging using GNMCs . . . . . . . . . . . . . . . . . . . . . 220

7.3.3

Synergistic effect in killing cancer cells using GNMCs . . . . . . . . . . . . . . . 220

7.4 Gold-nanoshelled magnetic nanocapsules for MR/ultrasound bimodal image-guided photothermal therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 221 7.4.1

SPIOs-embedded PFOB nanocapsules with PEGylated gold shells (PGS-SP NCs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

7.4.2

Bimodal US/MRI contrast imaging capability of PGS-SP NCs . . . . . . . 222

7.5 Conclusion and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 Chapter 8 Magnetic-mediated Hyperthermia for Cancer Treatment: Research Progress and Clinical Trials . . . . . . . . . . . . . . . . . . . . . . 228 8.1 Cancer hyperthermia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 8.2 Overview of magnetic-mediated hyperthermia (MMH) . . . . . . . . . . . . . . . . 230 8.2.1 Working mechanism and brief introduction to MMH . . . . . . . . . . . . . . . . 230 8.2.2 Categories of MMH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 8.3 Research progress of MMH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 8.3.1 IIH by thermoseeds and magnetic stent hyperthermia . . . . . . . . . . . . . . . 234 8.3.2 AEH for liver cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 8.3.3 Magnetic hyperthermia by MNPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 8.4 Clinical applications of MMH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 8.4.1 Clinical trials of MMH by thermoseeds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

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8.4.2

Clinical trials of MSH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242

8.4.3

Clinical Trials of MNH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243

8.4.4

Clinical trials of AEH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244

8.5 Multifunctional magnetic devices for cancer multimodality treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 8.5.1 Multifunctional magnetic device for thermoradiotherapy . . . . . . . . . . . . . 245 8.5.2 Multifunctional magnetic devices for thermochemotherapy . . . . . . . . . . . 246 8.6 Conclusions and remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 Chapter 9 Magnetic Nanoparticle-based Cancer Therapy . . . . . . . . . . . . 261 9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262 9.2 MNPs-based cancer therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 9.2.1 Magnetic hyperthermia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 9.2.2 Magnetic specific targeting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268 9.2.3 Magnetically controlled drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 9.2.4 Magnetofection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 9.2.5 Magnetic switches for controlling cell fate . . . . . . . . . . . . . . . . . . . . . . . . . . 273 9.2.6 Recently developed therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 9.3 Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 Chapter 10 Composite Magnetic Nanoparticles: Synthesis and Cancer-related Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 10.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 10.2 Controlled synthesis of composite nanoparticles . . . . . . . . . . . . . . . . . . . . . . 292 10.2.1 Dumbbell-like nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 10.2.2 Core@shell nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295 10.2.3 Core/satellite- or flower-like NPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 10.3 Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 10.4 Summary and perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 Chapter 11 Formation of Multifunctional Fe3 O4 /Au Composite Nanoparticles for Dual-mode MR/CT Imaging Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 11.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307 11.2 Synthesis or formation of Fe3 O4 /Au CNPs . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 11.2.1 “Dumbbell-like” structured CNPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 11.2.2 “Core/shell” structured CNPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310

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Contents

11.3 Dual-mode MR/CT imaging applications of Fe3 O4 /Au CNPs . . . . . . . . 314 11.4 Concluding remarks and outlooks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320

Biocompatibility Chapter 12

Using Magnetic Nanoparticles to Manipulate Biological Objects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 12.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 12.2 Protein separation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 12.3 Magnetofection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332 12.4 Manipulation of cellular organelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333 12.5 Separation and detection of bacteria and virus . . . . . . . . . . . . . . . . . . . . . . . 337 12.6 Manipulation of cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341 12.7 Manipulation of organs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344 12.8 Magnetic micro-/nanorobots to interact with multi- scale biological objects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347 Chapter 13 Toxicity of Superparamagnetic Iron Oxide Nanoparticles: Research Strategies and Implications for Nanomedicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352 13.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353 13.2 Mechanism of toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353 13.3 In vitro cytotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355 13.4 In vivo toxicity of SPIONs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 13.5 Blood compatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 13.6 Biodistribution and elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 13.7 In silico assays for nanotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364 13.8 Surface engineering for SPIONs-based nanomedicine . . . . . . . . . . . . . . . . . 365 13.9 Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369 Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379

Introduction

Chapter 1 Nanomagnetism: Principles, Nanostructures, and Biomedical Applications∗ Ce Yanga) , Yanglong Houa)† , and Song Gaob) a)

Department of Materials Science and Engineering, College of Engineer-

ing, Peking University, Beijing 100871, China b)

College of Chemistry and Molecular Engineering, Peking University,

Beijing 100871, China †

Corresponding author. E-mail: [email protected]

Nanomagnetism is the origin of many unique properties in magnetic nanomaterials that can be used as building blocks in information technology, spintronics, and biomedicine. Progresses in nanomagnetic principles, distinct magnetic nanostructures, and the biomedical applications of nanomagnetism are summarized.

1.1

Introduction

The study of nanomagnetism aims to deal with the magnetic properties of materials that have at least one dimension in the size range from 1 nm to 100 nm. A nanomagnetic material exhibits magnetic behaviors that are distinct from those of the bulk form of the same substance [1, 2] because (i) the material’s dimensions are ∗ Project supported by the National Basic Research Program of China (Grant No. 2010CB934601), the National Natural Science Foundation of China (Grant Nos. 51125001 and 51172005), the Natural Science Foundation of Beijing, China (Grant No. 2122022), and the Doctoral Program, China (Grant No. 20120001110078).

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Nanomagnetism: Principles, Nanostructures, and Biomedical · · ·

comparable to the critical lengths of one or more of various physical phenomena, such as the size of the magnetic domains;[3−5] (ii) the translation symmetry is broken, giving rise to specific sites with reduced coordination numbers, broken exchange bonds, and frustration; [6, 7] (iii) the material is in close contact with an exterior system such as the substrate or capping layer in the thin film magnets; [8, 9] (iv) the spin wave spectrum is changed because the spin wave energy is comparable to the thermal energy. [10] As a result of their extraordinary magnetic behaviors, nanomagnets have many practical applications distinct from those of the conventional bulk magnets, such as magnetic recording, giant magnetoresistance (GMR) devices, magnetic resonance imaging (MRI), magnetic hyperthermia and bionsensors.[13−18] In this article, we will introduce several important nanomagnetic effects, and then discuss the magnetic properties of diverse magnetic nanostructures. Finally, the applications of nanomagnetism in biomedicine are also addressed.

1.2 1.2.1

Nanomagnetic effects Single domain and superparamagnetism

The subdivision of a material into distinct magnetic domains is the origin of many unique behaviors of magnetic materials. For example, differing magnetic directions of domains may give rise to the vanishing of the total magnetic moment, or an average magnetization approximating zero. Based on the theory of magnetism, taking an ellipsoid for example, the total energy is contributed by three types of energies, exchange, anisotropy, and magnetostatic energy. With the increase in the size of a magnet, the number of domains will also increase. As a result, there will be a decrease in the magnetostatic energy, while the more numerous domain walls will also raise the exchange and the anisotropy energies. Therefore, the size of the magnet has a great influence on its magnetic behavior, as can be illustrated by considering the coercivity of the magnet. [19] The size-dependent coercivity of magnets is shown schematically in Fig. 1.1[20−22] First, for very small particles whose diameters are smaller than the critical diameter of superparamagnetism (Dspm ), the magnetic moment is not stable, and therefore Hc = 0. Secondly, in the range between Dspm and the critical diameter of a single domain (Dsd ), the moment is stable, and the coercivity enlarges as Dsd increases. Finally, for larger diameters, the multi-domain region appears, and the coercivity declines with increasing particle diameter. Therefore, the magnet has the maximal coercivity when its diameter is equal to Dsd , and it will become superparamagnetic when its diameter becomes smaller than Dspm .

1.2

Nanomagnetic effects

5

In particular, for the single domain magnet, all the magnetic moments are along the anisotropy axis, and the free energy contribution from exchange and anisotropy is zero. Therefore, the magnetostatic energy is the only relevant energy term. Moreover, as shown in Fig. 1.2, the Dsd of magnetic materials has a close relationship with the anisotropy constant K, and for the identical saturation magnetization (Ms ), Dsd is also proportional to the domain wall energy. In addition to that, with the increase of the domain wall energy, the critical single domain diameter Dsd will also increase. [23]

Fig. 1.1

Fig. 1.2

Size dependence of coercivity of magnets.

Relationship between Dsd and the anisotropy constant for magnetic materials. [23]

When the size of the particles is sufficiently small, the thermal energy will be

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Nanomagnetism: Principles, Nanostructures, and Biomedical · · ·

able to overcome the anisotropy energy. Thus, the magnetization is no longer in a stable configuration. The temperature at which the thermal energy can overcome the anisotropy barrier of nanoparticles (NPs) is referred to as the blocking temperature (TB ). [24] The critical diameter Dspm is the maximum size below which, at given temperature, the superparamagnetism behavior takes place. [6, 25] 1.2.2

Exchange-coupling effect

Since the first model of the exchange-coupling effect was introduced by Kneller and co-workers, this effect attracts intense interest. The exchange-coupling effect only takes place at the interphase boundary between hard and soft magnets at nanoscale, [26] and an exchange-coupled magnet can be designed based on the expected properties by choosing various hard and soft phases and tuning the phase ratio. [27] In an exchange-coupled magnet, nanoscale hard and soft magnetic phases are coupled via the interfacial exchange interaction such that the soft phase becomes “hardened” and its high magnetization enhances the energy product (BH)max of the composite (Fig. 1.3). [28] The energy arising from the exchange-coupling effect is given by E= −J · µ1 · u2 cos θ, where µ1 and µ2 are the magnetic moments of the two phases and cosθ denotes the angle between them. Moreover, J represents the exchange-coupling constant, which describes the intensity of the magnetic coupling and is closely related to the arrangements of the magnetic moments.

Fig. 1.3

Typical hysteresis loops: (i) a hard phase, (ii) a soft phase, (iii) the

exchange-coupled nanocomposites made of the soft and hard phases. [28]

1.2

Nanomagnetic effects

Fig. 1.4

7

EELS elemental maps and line scans of Sm–Co (20 nm)/Fe(20 nm) samples

with (a) sputtering temperature at 100 ℃and (b) annealing temperature at 400 ℃. [30]

Recently, the importance of the interphase layer to the exchange-coupling effect is frequently suggested. It is generally accepted that the energy generated from exchange coupling does not depend sensitively on the exchange constant J, but instead depends on the exchange constant and the thickness of the soft phase. [29] In the case of Sm–Co based nanocomposites, Liu and coworkers developed graded interfacial layers in which the material parameters gradually varied by promoting the intermixing of Sm–Co with Fe via thermal treatments at elevated annealing temperatures (Fig. 1.4). [30] Hou and coworkers found that an amorphous intermediate layer appeared in chemically synthesized SmCo5 @Co core-shell nanomagnets (Fig. 1.5). [31] It was found that the magnetization behavior of the modified interface differs notably from that of a sharp interface and relaxes the grain size requirement for optimal exchange–spring properties.[30−32] However, in the case of a series of

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Nanomagnetism: Principles, Nanostructures, and Biomedical · · ·

L10 -FePt based exchange-coupling nanomagnets, Hou and coworkers found that no significant alloying took place at the interface, and a single phase behavior was also displayed with the absence of an interphase layer. [33]

Fig. 1.5

(a) XRD pattern of SmCo5 @Co nanomagnets. (b) and (c) TEM images of

as-synthesized SmCo5@Co magnets. (d) and (e) HRTEM images of (d) the exterior of and (e) an arbitrary interior part of the particle. (f) SAED pattern of the particle shown in panel (c). [31]

In the Nd–Fe–B-based exchange-coupled magnets, however, the interphase gradient does not enhance the ferromagnetic properties, but rather leads to severe deterioration. The introduced magnetic soft phase likely alloys with the hard phase. Unlike SmCo5 based nanocomposites, there are no pinning sites in the Nd–Fe–B phase, and therefore, the coercivity of the exchange-coupled Nd–Fe–B/Fe composite is much lower than that of the Nd–Fe–B magnets. [34, 35] Thus, to avoid this phenomenon, a sharp interphase boundary, with no alloying, is required. By using a Ta layer as an interfacial layer, Hono and coworkers prepared Nd2 Fe14 B/FeCo thin film magnets with an enhanced maximum energy product (BH)max (Fig. 1.6). [36]

1.2

Nanomagnetic effects

Fig. 1.6

9

(a) Coercivity, (b) remanence, and (c) (BH )max dependencies on the number of

layers N in multilayer films of Ta(50 nm)[Nd–Fe–B(30 nm)/Nd(3 nm)/Ta(1 nm)/Fe67Co33 (10 nm)/Ta(1 nm)]N /Nd–Fe–B(30 nm)/Nd(3 nm)/Ta(20 nm). [36]

1.2.3

Exchange bias effect

The exchange bias effect originates in the interaction through the interface between any two of ferromagnetic (FM), antiferromagnetic (AFM), and ferrimagnetic (FI) domains. Generally, this interaction acts as an effective field that changes the behavior of the ferromagnet under an applied magnetic field, which is manifest as a displacement of the hysteresis loop. [19] The effect was first discovered in the studies of field-cooled (FC) oxidized Co particles, in which the relevant interface was that between the Co grains (FM) and the surrounding CoO layer (AFM). [37] The hysteresis loop of exchange bias magnets is shown schematically in Fig. 1.7. [38] Starting from magnetic saturation (a), as the field reverses, the FM moments begin

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Nanomagnetism: Principles, Nanostructures, and Biomedical · · ·

to flip (b), but the AFM atoms exert a local restoring force due to the magnetic field from the interface. Since the AFM atoms exhibit a torque dragging the FM moments to their initial direction, this effect is called unidirectional anisotropy. Note that the resulting displacement of the hysteresis curve is proportional to the effectiveness of the coupling between the two layers. [19]

Fig. 1.7

Schematic diagram of the spin configurations of an FM–AFM bilayer. [38]

Moreover, due to the requirement to overcome the AFM anisotropy during the magnetization reversal in the FM phase, the coercivity of the composite magnet increases. This well known coercivity-increase effect is another important characteristic of exchange bias magnets. Recently, Hadjipanayis and coworkers prepared 4 nm ferromagnetic cobalt nanoparticles (NPs) embedded in either a paramagnetic or an antiferromagnetic matrix, and found that the cobalt cores lost their magnetic moment at 10 K in the first system, while remaining ferromagnetic up to about 290 K in the second one (Fig. 1.8). It was demonstrated that the phenomenon can be ascribed to the specific way that the ferromagnetic NPs couple to the antiferromagnetic matrix. [39] Another phenomenon that shows up in systems with exchange bias is the training effect, i.e., the exchange bias field is found to depend on the number of measurements performed, decreasing as this number increases. [40] Zhang and coworkers observed the exchange bias and the training effect in γ-Fe2 O3 -coated Fe NPs. It was found that the field-cooling hysteresis shifts in both the horizontal and the vertical directions due to the change in spin configuration arising from field cycling during the hysteresis loop measurements (Fig. 1.9). The decrease of the frozen spins along the

1.2

Nanomagnetic effects

11

cooling field direction reduces the effective pinning energy, and thus, the exchange bias field decreases with field cycling. [41]

Fig. 1.8

Temperature dependences of the zero-field cooled (ZFC; filled symbols) and the

field-cooled (FC; µ0 HFC = 0.01 T, open symbols) magnetic moments of 4-nm Co/CoO core-shell particles. Particles were embedded in a paramagnetic (Al2 O3 ) matrix (diamonds), or in an AFM (CoO) matrix (circles). [39]

Fig. 1.9

The ZFC loop, first and sixth FC loops, and aged first and sixth FC loops of gamma-Fe2O3 coated Fe NPs at 5 K. [41]

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Nanomagnetism: Principles, Nanostructures, and Biomedical · · ·

During a field-cooling process, when the temperature is above the N´eel temperature (TN ) of the antiferromagnet and below Curie temperature (TC ) of the ferromagnet, the magnetic moments of the AFM atoms are disordered. However, as TN is reached, the AFM atoms at the interface align ferromagnetically to the FM moments.

1.3 1.3.1

Magnetism of nanomaterials Magnetism of NPs

The Stoner-Wohlfahrt model was the first model to describe the magnetism of small particles and is still used today. [42] In this model, each NP is considered as a homogeneous single domain with an elongated ellipsoid shape. However, the model does not take into account the possibility of thermal excitation to overcome the energy barrier between the two magnetization directions, which means that this model is only suitable at T = 0 K. [19] Moreover, the model is applicable only to NPs with uniaxial anisotropy. For cubic anisotropy, however, a three-dimensional model is required to describe the magnetism. In addition to the single domain magnetism and superparamagnetism mentioned in Section 2.1, another important feature of any NP is its large surface to volume ratio. It has been proposed that the large surface to volume ratio enhances the magnetic moment and the anisotropy. In fact, enhancements in magnetic moments have been observed for Fe, Co, and Ni NPs with several tens to several hundreds of atoms.[7,10,43−45] 1.3.2

Magnetism of nanoplates

Circular magnetic nanostructures, such as nanoplates, are promising materials in the development of higher performance magnetic information storage devices.[46−48] In nanoplates with thickness of several nanometers, the magnetization is almost entirely restricted to the plane of the plate. However, close to the center of the plate, there is a vortex. The equilibrium arrangement for the magnetic moment of the nanoplate is such that the magnetic moment orientation points outward at the center of the plane, which means that a perpendicular component of the magnetization exists at the center of the plate. [49] This vortex core has been detected by magnetic force microscopy (MFM). MFM images show dark or light dots at the centers of the disks, representing upward or downward vortex core magnetization. The Z component of the magnetization of the vortex core can point up and down during the rotation of

1.3

Magnetism of nanomaterials

13

the vortex in clockwise (CW) or counterclockwise (CCW) directions. As a result, the chirality of the vortex can be identified by the combination of vortex core polarity and rotation of the vortex. [50] When an in-plane magnetic field is applied, the chirality can be found from the motion of the vortex core. The motion is generated by the torque on the magnetic moment in the vortex. [51] This unique property has great application potential in the area of recording media. 1.3.3

Magnetism of nanorings

Generally, the magnetism of nanorings is quite similar to that of nanoplates. However, compared with nanoplates, nanorings show superior potential in magnetic recording applications due to the allowance for higher storage density generated from their flux-closed structure and stable magnetic reversal behavior. [52] Three kinds of magnetizations have been observed in nanorings: (A) the moment follows the same rotation direction and forms a vortex; (B) the nanoring is partitioned into two magnetic domains, in which the two moments are opposite in direction (this also called an onion state); (C) the twisted state, or asymmetric onion state, frequently found in nanorings of smaller size. [19] An applied magnetic field in the onion state can move the domain walls to coalesce on the opposite side of the ring, and therefore, forming a new configuration at remanence.[52−54] Sun and co-workers looked into the magnetic properties of Fe3 O4 nanorings. They suggested that there are two kinks in the hysteresis loop near zero-magnetization, revealing that there are two vortex states with opposite directions (insets of Fig. 1.10(a)). The HRTEM image (Fig. 1.10(b)) shows that the Fe3 O4 nanoringshave two directions, h111i and h112i with magnetic vortex states (Fig. 1.10(c)). [55]

14

Chapter 1

Fig. 1.10

Nanomagnetism: Principles, Nanostructures, and Biomedical · · ·

(a) The M –H loop of the Fe3 O4 mnanorings at room temperature.

(b) Off-axis electron hologram of a single Fe3 O4 ring. (c) Direction of the magnetic induction under field-free conditions following magnetization, indicated by colors as interpreted in the color wheel in the inset (red = right, yellow = down, green = left, blue = up). [55]

1.4 1.4.1

Biomedical applications of nanomagnetism T 2 MRI contrast agents

Magnetic resonance imaging is a fundamental diagnostic tool in biomedical fields. MRI contrast agents can help to clarify images, allowing better interpretation. Theoretically, when the nuclei of protons are exposed to a strong magnetic field, their spins are arranged along the magnetic field. During the alignment, the spins process with a particular frequency, called the Larmor frequency (Fig. 1.11(a)). When a pulse with the resonance frequency in the radio-frequency (RF) range is introduced, the protons are excited to the antiparallel state. Then, after the removal of the pulse, the excited nuclei will relax to the initial states through either the so-called T 1 relaxation pathway, which involves the decreased net magnetization (Mz ), recovering to the initial state, or the T 2 relaxation, which involves the induced magnetization on the perpendicular plane (Mxy ) disappearing by the dephasing of the spins (Figs. 1.11(c) and 1.11(d)). [56] When the magnetic pulse is applied, a transverse magnetization perpendicular to the static magnetic field is generated (Fig. 1.11(b)). Thus, the magnetization is composed of Mz and Mxy , which produce the interrelated process of spins. The energy transfer is responsible for the change of Mz , while the reason for the change of Mxy is spin dephasing, which is the randomization of the magnetization of the excited spins that were originally of the same phase coherence immediately after

1.4

Biomedical applications of nanomagnetism

15

the application of the pulse, but the coherence disappeared because of the difference of the magnetic field experienced by the protons. [56, 57, 58] The phase incoherence is largely caused by the magnetic properties of the imaging objects, while the magneticfield difference arises mainly from other different magnetic properties of the imaging objects. The spin–spin interaction between the protons or electrons causes a loss of transverse coherence, which produces the true and characteristic T 2 relaxation of tissues. Moreover, this interaction will also induce local magnetic field gradients, which can also be generated by contrast agents. Thus, the transverse relaxation is affected by external sources, and the total relaxation time T 2∗ is described by 1/T 2∗ = (1/T 2) + γB, where γB represents the relaxation by the field gradients and is called the susceptibility effect. [56] The T 2 relaxivity is highly dependent on both the Ms value and the effective radius of the typically superparamagnetic core. In the motional average regime, the relaxivity r2 (where all of the NP contrast agents are simulated as spheres) is given by µ ¶ 256γ 2 π 2 r2 = κMs2 r2 /D(1 + L/r), 405 where Ms and r are the saturation magnetization and the effective radius of the magnetic nanostructure, respectively, D is the diffusivity of water molecules, L is the thickness of an impermeable surface coating, and κ is the conversion factor. [59]

Fig. 1.11

Schematic illustration of magnetic resonance imaging. (a) Spins align parallel

or antiparallel according to the magnetic field and precess under Larmor frequency ω0 . (b) After induction of the pulse, magnetization of spins changes. Excited spins are relaxed through (c) T 1 relaxation or (d) T 2 relaxation. [56]

16

1.4.2

Chapter 1

Nanomagnetism: Principles, Nanostructures, and Biomedical · · ·

Magnetic hyperthermia

Magnetic NPs with spherical magnetic moments undergo orientational thermal fluctuations due to either Brownian fluctuations or N´eel fluctuations. These fluctuations are the reasons for the magnetization relaxation that takes place in a suspension of superparamagnetic particles when the magnetic field is removed. An external AC magnetic field supplies energy that generates the magnetic moment fluctuations, and this magnetic energy is converted into thermal energy. [60, 61] The heating effects of magnetic NPs under AC magnetic fields are related to several types of loss processes (hysteresis losses, N´eel and Brown relaxations), and which of these processes contribute, strongly depends on the particle size. For NPs within the single-domain range, the magnetization relaxation is governed by the combined effects of the rotational external (Brownian) and internal (N´eel) diffusions of the particles’ magnetic moments. The Brown relaxation is due to thermal orientational fluctuations of a grain itself in the carrier fluid, the magnetic moment being locked onto the crystal anisotropy axis. The N´eel relaxation refers to the internal thermal rotation of the magnetic moment of the particle within the crystal. [60] The specific heat dissipation for monodisperse magnetic NPs is expressed as SLP =

µ0 χ0 H 20 ωτ P = ω 2, ρφ 2ρφ 1+(ωτ )

where χ0 is the static susceptibility, µ0 is the vacuum magnetic permeability, ρ is the density of the material, H0 is the applied field, and ω is the frequency of the applied field. Moreover, τ is given by the relationship 1/τ = 1/τN + 1/τB , where τN is the N´eel relaxation time and τB is the Brownian relaxation time, as will be described below. [60, 61] 1.4.3

Biosensors

In addition to their applications in disease dignoses and therapy, magnetic NPs have been utilized in various biosensors such as those for the detection of proteins, DNAs, and enzymes. Due to the unique chemical and physical properties of magnetic NPs, incorporating them in biosensors can improve the sensors’ sensitivity and reduce their reaction time. In the case of magnetic NP-based MRI T 2 contrast agents, researchers observed a special magnetic phenomenon in the process of the assembly of magnetic nanoprobes under a magnetic field, i.e., the superparamagnetic iron oxide cores of individual NPs were more efficient in dephasing the spins of surrounding water protons, and thus expanding the spin–spin relaxation time.

References

17

Magnetic NPs were proposed as magnetic relaxation switches (MRS). [62] Therefore, by surface modification, a large number of magnetic NPs can be selectively attached to nucleic acids, peptides, proteins, and antibodies. As a result, the change of the relaxation time of protons will be produced by those aggregated NPs and cause the detection of special oligonucleotides, as mentioned above. This method can be further extended in the detection of molecular interactions such as DNA–DNA and protein–protein. [63]

1.5

Conclusion

Magnetic materials are the building blocks to world’s effort of steering towards a sustainable future and transitioning to low emission renewable energy sources. At the same time, the global population aging on one hand speaks the triumph of modern medical technology, on the other hand puts spotlight on early diagnosis and precision medicine, where magnetic materials play a vital role. As such, the fundamental understanding of magnetism and development of new magnetic with enhanced properties have been continuously gathering momentum in both fundamental research and industrial technology development. In this chapter, typical magnetic effects such as distinct vortex states, ex-change coupling and exchange bias effects have been presented. Their application in modern magnetic materials are also demonstrated, which unravels the origin of the unique magnetic properties in those materials. Significant progress has been made in exploring the fundamentals of magnetism as well as in developing magnetic materials, this paved the road for the use of those theories and materials in new devices with extraordinary performance.

References [1] Sellmyer D J, Zheng M and Skomski R 2001 J. Phys.: Condens. Matter 13 R433 [2] Wu C Z, Yin P, Zhu X, OuYang C Z and Xie Y 2006 J. Phys. Chem. B 110 17806 [3] Kim D, Lee N, Park M, Kim B H, An K and Hyeon T 2009 J. Am. Chem. Soc. 131 454 [4] Kovalenko M V, Bodnarchuk M I, Lechner R T, Hesser G, Schaffler F and Heiss W 2007 J. Am. Chem. Soc. 129 6352 [5] Zhang L H, Wu J J, Liao H B, Hou Y L and Gao S 2009 Chem. Commun. 454 378 [6] Knobel M, Nunes W C, Socolovsky L M, De Biasi E, Vargas J M and Denardin J C 2008 J. Nanosci. Nanotechno. 8 2836 [7] Billas I M L, Chatelain A and Deheer W A 1994 Science 265 1682

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Nanomagnetism: Principles, Nanostructures, and Biomedical · · ·

[8] Chen J, Ye X C, Oh S J, Kikkawa J M, Kagan C R and Murray C B 2013 ACS Nano 7 1478 [9] Fedoseev S A, Pan A V, Rubanov S, Golovchanskiy I A and Shcherbakova O V 2013 ACS Nano 7 286 [10] Shen J and Kirschner J 2002 Surf. Sci. 500 300 [11] Yang C, Zhao H B, Hou Y L and Ma D 2012 J. Am. Chem. Soc. 134 15814 [12] Liu F, Jin Y J, Liao H B, Cai L, Tong M P and Hou Y L 2013 J. Mater. Chem. A 1 805 [13] Jin Y J, Liu F, Tong M P and Hou Y L 2012 J. Hazard Mater. 227 461 [14] Takatsu H, Ishikawa J J, Yonezawa S, Yoshino H, Shishidou T, Oguchi T, Murata K and Maeno Y 2013 Phys. Rev. Lett. 111 [15] Yang D Z, Wang F C, Ren Y, Zuo Y L, Peng Y, Zhou S M and Xue D S 2013 Adv. Funct. Mater. 23 2918 [16] Hayashi K, Ono K, Suzuki H, Sawada M, Moriya M, Sakamoto W and Yogo T 2010 Chem. Mater. 22 3768 [17] Das M, Dhak P, Gupta S, Mishra D, Maiti T K, Basak A and Pramanik P 2010 Nanotechnology 21 125103 [18] Polito L, Colombo M, Monti D, Melato S, Caneva E and Prosperi D 2008 J. Am. Chem. Soc. 130 12712 [19] P.Guimar˜ aes A 2009 Principles of Nanomagnetism (Berlin: Springer-Verlag) [20] Hadjipanayis G C 1999 J. Magn. Magn. Mater. 200 373 [21] Luborsky F E 1961 J. Appl. Phys. 32 S171 [22] Chen C H, Knutson S J, Shen Y, Wheeler R A, Horwath J C and Barnes P N 2011 Appl. Phys. Lett. 99 012504 [23] Goll D, Berkowitz A E and Bertram H N 2004 Phys. Rev. B 18 184432 [24] Yang C, Wu J J and Hou Y L 2011 Chem. Commun. 47 5130 [25] Dormann J L, Fiorani D and Tronc E 1997 Adv. Chem. Phys. 98 283 [26] Kneller E F and Hawig R 1991 IEEE T. Magn. 27 3588 [27] Yang C and Hou Y L 2013 Rare Metals 32 105 [28] Balamurugan B, Sellmyer D J, Hadjipanayis G C and Skomski R 2012 Scripta Mater. 67 542 [29] Kim J, Barmak K, De Graef M, Lewis L H and Crew D C 2000 J. Appl. Phys. 87 6140 [30] Jiang J S, Pearson J E, Liu Z Y, Kabius B, Trasobares S, Miller D J, Bader S D, Lee D R, Haskel D, Srajer G and Liu J P 2005 J. Appl. Phys. 97 10K311

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[31] Yang C, Jia L H, Wang S G, Gao C, Shi D W, Hou Y L and Gao S 2013 Sci. Rep. 3 [32] Li W, Li X H, Li L L, Zhang J W and Zhang X Y 2006 J. Appl. Phys. 99 [33] Liu F, Zhu J H, Yang W L, Dong Y H, Hou Y L, Zhang C Z, Yin H and Sun S H 2014 Angew. Chem. Int. Edit. 53 2176 [34] Li W, Li L L, Nan Y, Li X H, Zhang X Y, Gunderov D V, Stolyarov V V and Popov A G 2007 Appl. Phys. Lett. 91 062509 [35] Gabay A M, Zhang Y and Hadjipanayis G C 2004 Appl. Phys. Lett. 85 446 [36] Cui W B, Takahashi Y K and Hono K 2013 Adv. Mater. 25 1966 [37] Meiklejohn W H and Bean C P 1956 Phys. Rev. 102 1413 [38] Nogues J and Schuller I K 1999 J. Magn. Magn. Mater. 192 203 [39] Skumryev V, Stoyanov S, Zhang Y, Hadjipanayis G, Givord D and Nogues J 2003 Nature 423 850 [40] Nogues J, Morellon L, Leighton C, Ibarra M R and Schuller I K 2000 Phys. Rev. B 61 R6455 [41] Zheng R K, Wen G H, Fung K K and Zhang X X 2004 Phys. Rev. B 69 214431 [42] Stoner E C and Wohlfarth E P 1948 Philos. Tr. R. Soc. S. A 240 599 [43] Apsel S E, Emmert J W, Deng J and Bloomfield L A 1996 Phys. Rev. Lett. 76 1441 [44] Bucher J P, Douglass D C and Bloomfield L A 1991 Phys. Rev. Lett. 66 3052 [45] Douglass D C, Cox A J, Bucher J P and Bloomfield L A 1993 Phys. Rev. B 47 12874 [46] Zeng Y, Hao R, Xing B G, Hou Y L and Xu Z C 2010 Chem. Commun. 46 3920 [47] Zhang W D, Xiao H M, Zhu L P and Fu S Y 2009 J. Alloy Compd. 477 736 [48] Lu J, Jiao X L, Chen D R and Li W 2009 J. Phys. Chem. C 113 4012 [49] Suber L, Imperatori P, Ausanio G, Fabbri F and Hofmeister H 2005 J. Phys. Chem. B. 109 7103 [50] Hollinger R, Killinger A and Krey U 2003 J. Magn. Magn. Mater. 261 178 [51] Choe S B, Acremann Y, Scholl A, Bauer A, Doran A, Stohr J and Padmore H A 2004 Science 304 420 [52] Zhu J G, Zheng Y F and Prinz G A 2000 J. Appl. Phys. 87 6668 [53] Chien C L, Zhu F Q and Zhu J G 2007 Phys. Today 60 40 [54] Castano F J, Ross C A, Eilez A, Jung W and Frandsen C 2004 Phys. Rev. B 69 [55] Jia C J, Sun L D, Luo F, Han X D, Heyderman L J, Yan Z G, Yan C H, Zheng K, Zhang Z, Takano M, Hayashi N, Eltschka M, Klaui M, Rudiger U, Kasama T, Cervera-Gontard L, Dunin-Borkowski R E, Tzvetkov G and Raabe J 2008 J. Am. Chem. Soc. 130 16968

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Nanomagnetism: Principles, Nanostructures, and Biomedical · · ·

[56] Na H B, Song I C and Hyeon T 2009 Adv. Mater. 21 2133 [57] Hao R, Xing R J, Xu Z C, Hou Y L, Gao S and Sun S H 2010 Adv. Mater. 22 2729 [58] Henkelman R M, Stanisz G J and Graham S J 2001 Nmr. Biomed. 14 57 [59] Zhao Z H, Zhou Z J, Bao J F, Wang Z Y, Hu J, Chi X Q, Ni K Y, Wang R F, Chen X Y, Chen Z and Gao J H 2013 Nat. Commun. 4 2266 [60] Fortin J P, Wilhelm C, Servais J, Menager C, Bacri J C and Gazeau F 2007 J. Am. Chem. Soc. 129 2628 [61] Rosensweig R E 2002 J. Magn. Magn. Mater. 252 370 [62] Josephson L, Perez J M and Weissleder R 2001 Angew. Chem. Int. Edit. 40 3204 [63] Perez J M, Josephson L, O’Loughlin T, Hogemann D and Weissleder R 2002 Nat. Biotechnol. 20 816

Controlled Synthesis and Modification

Chapter 2 Chemical Synthesis of Magnetic Nanocrystals: Recent Progress∗ Fei Liua) , Jinghan Zhua) , Yanglong Houa)† , and Song Gaob) a)

Department of Materials Science and Engineering, College of Engineer-

ing, Peking University, Beijing 100871, China b)

College of Chemistry and Molecular Engineering, Peking University,

Beijing 100871, China †

Corresponding author. E-mail: [email protected]

Colloidal chemical synthesis of various types of magnetic nanocrystals is discussed with regard to recent discoveries. We first outline the chemical preparation of single-component magnetic nanocrystals with controlled size, shape, and uniformity based on several solution-phase methods, especially thermal decomposition and/or reduction method. Then we discuss the synthetic strategies of multi-component nanocrystals incorporating at least one magnetic component by manipulating heterogeneous nucleation and growth process. finally, approaches for preparing hollow/porous magnetic nanocrystals are highlighted. We believe that the summarized chemical synthesis will pave the way for the future development of extraordinary magnetic nanocrystals. ∗ Project supported by the National Basic Research Program of China (Grant No. 2010CB934601), the National Natural Science Foundation of China (Grant Nos. 51125001, 51172005, and 90922033), the Natural Science Foundation of Beijing (Grant No. 2122022), the Doctoral Program Foundation (Grant No. 20120001110078), the New Century Talent Foundation of the Education Ministry of China (Grant No. NCET-09-0177), the Yok Ying Tung Foundation (Grant No. 122043), and the PKU COE-Health Science Center Seed Fund.

24

2.1

Chapter 2

Chemical Synthesis of Magnetic Nanocrystals: Recent Progress

Introduction

For past decades, magnetic nanocrystals (NCs) have attracted a great deal of interest due to their extraordinary potential for data storage, [1] catalysis, [2, 3] biomedical imaging,[4−8] drug delivery, [9, 10] and environmental remediation. [11, 12] The properties of the NCs strongly depend on their dimensions, and as a result, their physical properties vary dramatically from their bulk counterparts, which offer various opportunities for wide applications. In terms of magnetic materials, the size-effect will result in the NC which possesses a single magnetic domain and shows superparamagnetic behavior when the temperature is above the blocking temperature. [7, 13, 14] Superparamagnetic NCs can be easily saturated in the presence of a field, but the magnetization returns to zero upon removal of the field due to thermal fluctuations. This unique feature has proven to be ideal for a broad range of biomedical applications such as targeted drug delivery, localized heating of cancerous cells (hyperthermia), and magnetic resonance imaging (MRI) because aggregation of such NCs can be effectively avoided.[14−18] On the other hand, properties of nanomaterials can also be tuned by varying their shapes. [19] Therefore, to fully exploit the potential of magnetic NCs with desired properties, synthesis of uniformly sized and shaped magnetic NCs is of significant importance. Recently, synthesis of heterostructured NCs (HNCs) with discrete domains of different materials is becoming an important research direction in nanotechnology.[20−30] Primarily, HNCs incorporating multiple materials, each characterized by unique optical, electric, magnetic, and/or chemical properties, provide multi-functionality that may result in unprecedented applications. [26, 27, 28, 29, 30, 31] Additionally, HNCs possessing artificial interfaces, where electronic communication exists across neighboring material sections, can generate synergistically enhanced and/or tunable chemical– physical responses, or even provide novel functions that are not available in singlecomponent materials or structures.[32−35] In particular, electronic interactions at the interface are present in magnetic HNCs, which may lead to variation of the magnetic properties by magnetic exchange-coupling mechanisms and/or induced extra anisotropy. [33, 34] Therefore, establishing HNCs with effective bonding junctions among dissimilar nanoscale domains offers a promising way to engineer the properties and to achieve optimal performances. Besides HNCs, hollow/porous magnetic NCs have been increasingly investigated in recent years. [36, 37, 38, 39, 40] The hollow interiors and porous shells within the NCs can provide high surface to volume ratio and large pore volume, which are highly attractive for many technological applications. For example, drugs that are initially encapsulated in the void part of the hollow NC can be released either chemically

2.2

Chemical synthesis of single-component magnetic NCs

25

via a pH control or physically through a magnetic stimulation and photothermal activation, offering a new approach for simultaneous diagnostic and therapeutic applications. [41, 42, 43] Compared to the top–down physical processes, colloidal chemical synthetic methods have been found to be highly effective to synthesize uniform magnetic NCs with controlled sizes and shapes by varying the reaction conditions. [44, 45] In this review, we present recent advances in the chemical synthesis of various types of magnetic NCs. General synthesis of single-component magnetic NCs, multi-component magnetic NCs (including core/shell heterostructure, oligomer-like heterostructure, and anisotropically shaped material-based heterostructure), and hollow/porous magnetic NCs are summarized.

2.2

Chemical synthesis of single-component magnetic NCs

To prepare magnetic NCs with controlled sizes and shapes, various methods based on solution-phase colloidal chemistry have been intensively investigated.[46−54] Among them, thermal decomposition and/or reduction approach is one of the most attractive techniques which can meet the requirement of preparing high quality magnetic NCs. In this section, we focus on some recent developments related to the colloidal chemical synthesis of magnetic NCs from metal oxides, metals, alloys, metal carbides, phosphides, and chalcogenides. 2.2.1

Metal oxides

Magnetic metal oxide NCs such as iron oxides are very important for various biological applications, such as MRI, drug delivery, cell tracking, protein separation, and hyperthermia. [55, 56, 57] FeO, γ-Fe2 O3 , and Fe3 O4 , which possess remarkably different magnetic properties, are three typical phases of iron oxides. Co-precipitation of Fe3+ and Fe2+ salts in a basic solution is the simplest method for synthesizing iron oxide NCs. [58, 59, 60, 61, 62] Despite the ease and large-scale producibility of this approach, it is difficult to prepare the NCs with narrow size distribution, high crystallinity, and high magnetization values. Thermal decomposition reaction of an iron precursor in a high-boiling-point organic solvent offers a promising way to synthesize highly monodisperse iron oxide NCs. For example, Sun et al. obtained monodisperse Fe3 O4 NCs with a size range of 4 nm–20 nm by reductive decomposition of iron (III) acetylacetonate (Fe(acac)3 , acac = acetylacetonate) in the mixture of 1,2hexadecanediol, oleic acid (OA), oleylamine (OAm), and benzyl ether (Fig. 2.1). [63] It was found that the type of solvent and reaction temperature determines the size of Fe3 O4 NCs. Additionally, via seed-mediated growth, larger NCs with the size

26

Chapter 2

Chemical Synthesis of Magnetic Nanocrystals: Recent Progress

of 20 nm could be produced (Fig. 2.1(b)). Hyeon et al. developed an ultra-largescale synthetic method to prepare monodisperse iron oxide NCs using iron–oleate complex as the precursor, which can be prepared by the reaction of inexpensive and nontoxic iron chloride with sodium oleate. [64] By slowly heating the mixture of Fe-oleate complex and surfactant to the boiling point (bp) of the solvent, monodisperse iron oxide NCs were produced. The size of the iron oxide NCs could be easily controlled by varying the solvent with different bp. 5-nm, 9-nm, 12-nm, 16-nm, and 22-nm iron oxide NCs were prepared using 1-hexadecene [bp: 274 ℃ ], octyl ether (bp: 287 ℃ ), 1-octadecene (bp: 317 ℃ ), 1-eicosene (bp: 330 ℃ ), and trioctylamine (bp: 365 ℃ ) as solvent, respectively. Cube-shaped Fe3 O4 NCs in the size range from 20 nm to 160 nm could be synthesized by thermal decomposition of Fe(acac)3 in the presence of OA and benzyl ether at 290 ℃. [65] Very recently, Hyeon et al.

Fig. 2.1

(a) Schematic illustration of the synthesis of monodisperse Fe3 O4 NCs through

the decomposition of Fe(acac)3 in the presence of oleic acid, oleylamine, and alkanediol. Transmission electron microscopy (TEM) image of (b) 6-nm and (c) 10-nm Fe3 O4 NCs. (d) A three-dimensional (3D) superlattice of 10-nm Fe3 O4 NCs. Reproduced with permission from Ref. [63]. Copyright 2004 American Chemical Society.

2.2

Chemical synthesis of single-component magnetic NCs

27

reported the preparation of uniform and extremely small iron oxide NCs of less than 4 nm via the thermal decomposition of an iron–oleate complex in the presence of oleyl alcohol. [66] The formation of extremely small iron oxide NCs was ascribed to oleyl alcohol which could lower the reaction temperature by reducing iron–oleate complex. Moreover, by tuning the ratio of oleyl alcohol to OA or changing the temperature, Fe3 O4 NCs could be controlled in the size range from 1.5 nm to 7 nm. The w¨ ustite-type FeO NCs were also prepared via thermal reductive decomposition reactions. Hou et al. synthesized size- and shape-controlled FeO NCs by reductive decomposition of Fe(acac)3 in the mixture of OA and OAm (Fig. 2.2). [67] The size of the FeO NCs was controlled in the range of 14 nm–100 nm and the shapes were either polyhedra or truncated octahedra by varying the molar ratio of OA to OAm. It is worth noting that other types of iron oxide (Fe3 O4 , γ-Fe2 O3 , or γ-Fe2 O3 NCs) could be obtained from the as-synthesized FeO NCs under controlled annealing conditions.

Fig. 2.2

TEM images of FeO NCs with different sizes and shapes: (a) 14-nm spherical,

(b) 32-nm, and (c) 53-nm truncated octahedral. (d) Scanning electron microscopy (SEM) image of 100-nm truncated octahedral NCs. Reproduced with permission from Ref. [67]. Copyright 2007 Wiley-VCH.

28

Chapter 2

Chemical Synthesis of Magnetic Nanocrystals: Recent Progress

Ferrite M Fe2 O4 NCs generated from the partial substitution of Fe2+ with other transition metal M 2+ (M = Mn, Co, Ni, Zn, etc.) in the crystal lattice of magnetite (Fe3 O4 ) have also attracted much attention for their distinct magnetic properties induced by M -doping compared to Fe3 O4 . [68] The approach to the synthesis of monodisperse M Fe2 O4 NCs is similar to that of Fe3 O4 NCs discussed above. Typically, to prepare monodisperse CoFe2 O4 or MnFe2 O4 NCs, a stoichiometric amount of M (acac)2 (M = Co, Mn) and Fe(acac)3 were mixed and heated in a high-boilingpoint solvent in the presence of OA and OAm (Figs. 2.3(a) and 2.3(b)). [63] The size of the NCs can be tuned from 3 nm to 20 nm by varying reaction conditions such as temperature and types of precursors or by seed-mediated growth. Alternatively, Hyeon et al. fabricated spinel M Fe2 O4 NCs (M = Mn, Co or Ni) by means of a hightemperature, nonhydrolytic reaction between divalent metal chloride and Fe(acac)3 in the presence of OA and OAm as surfactants. [69] Cheon et al. synthesized a series of 15-nm sized Zn2+ -doped NCs of (Znx Mn1−x )Fe2 O4 and (Znx Fe1−x )Fe2 O4 (x = 0, 0.1, 0.2, 0.3, 0.4, and 0.8) with single crystallinity and size monodispersity by thermal decomposition of metal chloride precursors and Fe(acac)3 in the solution

Fig. 2.3

TEM images of 14-nm (a) CoFe2 O4 NCs and (b) MnFe2 O4 NCs. Reproduced

with permission from Ref. [63]. Copyright 2004 American Chemical Society. (c) TEM image and (d) high-resolution TEM (HRTEM) image of 15-nm (Zn0.4 Fe0.6 ) Fe2 O4 NCs. Reproduced with permission from Ref. [70]. Copyright 2009 Wiley-VCH.

2.2

Chemical synthesis of single-component magnetic NCs

29

of OA, OAm, and octyl ether (Figs. 2.3(c) and 2.3(d)). [70] The Zn2+ doping level, which was carefully controlled by varying the initial molar ratio of the metal chloride precursors, determined the magnetic properties of the ferrite NCs. For example, the saturation magnetization of (Znx Mn1−x )Fe2 O4 NCs (x = 0, 0.1, 0.2, 0.3, and 0.4) was found to be 125, 140, 154, 166, and 175 emu·g−1 (metal atoms), respectively. Recently, the same group improved the synthetic method for realizing size- and shape-controlled synthesis of zinc ferrite NCs. [71] 22-nm spherical Zn0.4 Fe2.6 O4 NCs were obtained by the reaction of Fe(acac)3 and zinc chloride in the presence of OA, OAm, and octyl ether at 330 ◦ C. To prepare cube-shaped NCs, the precursors were heated in the presence of OA and benzyl ether. By changing the concentration of Fe(acac)3 and zinc chloride, the size of the NCs could be conveniently tailored from 18 nm to 140 nm. 2.2.2

Metals and alloys

Metallic Fe, Co, Ni are typical classes of ferromagnetic (FM) materials with high saturation magnetization. Among them, iron possesses the highest roomtemperature value of saturation magnetization, and has a Curie temperature (Tc ) that is high enough for practical applications. [72, 73, 74] Therefore, iron NCs have attracted a great deal of interest in sensitive MRI and magnetic fluid hyperthermia applications. However, metallic Fe NCs are very reactive and unstable, specifically with respect to water and oxygen, and can be rapidly and completely oxidized in air to form various iron oxide NCs with much reduced magnetizations. Recently, researchers are focusing on the synthesis of metallic Fe NCs that can be stabilized against fast oxidation. [75, 76, 77, 78] The two well-known approaches to monodisperse Fe NCs are the thermal decomposition and chemical reduction of an iron organocomplex. Iron pentacarbonyl, Fe(CO)5 , is generally used to produce Fe NCs via decomposition in organic solutions. In a typical process, monodisperse Fe NCs were prepared by thermal decomposition of Fe(CO)5 in 1-octadeceneand OAm at 180 ℃. [79] To increase the chemical and dispersion stability of the NCs, a crystalline Fe3 O4 shell was created over the core by controlled oxidation of the iron surface via the oxidant (CH3 )3 NO. Interestingly, it was found that the addition of hexadecylamonium chloride could yield body centered cubic Fe NCs with drastically increased magnetization (Fig. 2.4(a)). [78] Concerning the chemical reduction, the complex Fe[N(SiMe3 )2 ]2 (THF) (Me = CH3 , THF=tetrahydrofuran) and Fe[N(SiMe3 )2 ]2 have been chosen as iron sources to produce metallic Fe NCs. Dumestre et al. reported the reaction of Fe[N(SiMe3 )2 ]2 with H2 in the presence of hexadecylamine (HDA) and OA to prepare monodisperse zerovalent iron NCs with controlled sizes

30

Chapter 2

Chemical Synthesis of Magnetic Nanocrystals: Recent Progress

(Fig. 2.4(b)). [77] It is worth noting that the magnetizations of the as-prepared NCs were found close to bulk values. In an improved procedure that argon was used as atmosphere instead of H2 , the reaction of Fe[N(SiMe3 )2 ]2 was held to yield singlecrystalline iron NCs of uniform size and shape with the assistance of ammonium chloride HDA·HCl. [75] Alternatively, by the reduction of the iron–oleate complex at a high temperature of 380 ℃ in the mixture of OA and 1-octadecene, cube-shaped 20-nm iron NCs which is passivated by a thin FeO layer were produced. [64]

Fig. 2.4

(a) TEM image of the 15-nm Fe NCs. Reproduced with permission from

Ref. [78]. Copyright 2011 American Chemical Society. (b) TEM image of 3D superlattice of Fe nanocubes. Reproduced with permission from Ref. [77]. Copyright 2011 Science. (c) TEM image of a two-dimensional (2D) assembly of 9-nm Co NCs. Reproduced with permission from Ref. [84]. Copyright 1999 American Institute of Physics. (d) TEM image of Ni NCs with the size of 12.8±0.7 nm. Reproduced with permission from Ref. [90]. Copyright 2009 American Chemical Society.

Similar as iron, the preparation of cobalt NCs is performed via thermal decomposition or chemical reduction of organometallic precursors. However, Co atoms can crystallize into three types of phases including hexagonal close packed (hcp), facecentered cubic (fcc), or ε-phase with distinct magnetic properties. [80, 81, 82, 83, 84, 85, 86] By varying precursors, surfactant species, and/or reaction temperatures, the size and

2.2

Chemical synthesis of single-component magnetic NCs

31

shape for Co NCs can be efficiently controlled. To synthesize ε-Co NCs, a phase very sensitive to the reaction conditions, Sun et al. reported the reduction of cobalt chloride using lithium triethylborohydride (LiBEt3 H, superhydride) in dioctyl ether with OA and trialkylphosphine as the capping agents (Fig. 2.4(c)). [84] The increase of the reaction temperature from 200 ℃ to 300 ℃ would yield hcp-Co NCs. Besides, the group of Alivisatos developed a method by employing cobalt carbonyl as the precursor, from which monodispersed, stabilized, defect-free ε-cobalt NCs, with spherical shapes and sizes ranging from 3 nm to 17 nm could be produced. [87] Cobalt NCs in the hcp and fcc phase could also be synthesized. Monodisperse hcp-Co NCs could be prepared from cobalt acetate solution in diphenyl ether using a mild reducing reagent (1,2-dodecanediol) at 240 ℃ in the presence of OA and n-trioctylphosphine (TOP). By adjusting the capping groups/metal salt ratio and selecting the degree of bulkiness of the organophosphine stabilizer, the size of Co NCs could be further tuned. [88] Puntes et al. acquired hcp-Co disk-shaped NCs by rapid decomposition of cobalt carbonyl in the presence of linear amines. [89] As selective adsorption of alkylamine might inhibit growth along a unique axis, disk-shaped NCs were formed. The decomposition of Co2 (CO)8 in the presence of stabilizing ligands could also yield multiply twinned fcc-Co NCs with narrow size distributions. Typically, to prepare 8- to 10-nm fcc-Co NCs, Co2 (CO)8 dissolved in dioctyl ether was injected into the mixture of diphenyl ether/OA/tributylphosphine at 200 ℃. [88] Besides Fe and Co, the synthesis of Ni NCs have also been intensively investigated. Based on the chemical reduction of nickel salts Ni(CH3 COO)2 or Ni(acac)2 in the presence of the ligands (OA, TOP or OAm), monodisperse Ni colloidal NCs in the 4 nm–16 nm size range with narrow size distribution were successfully produced (Fig. 2.4(d)). [90] By controlling the synthetic conditions (precursors, ligands and temperature), the size of Ni NCs could be easily tuned. Zhang et al. employed three processes, including direct thermolysis, seed-assisted growth, and hot injection, to synthesize Ni NCs with diameters in the range of 20 nm–60 nm by the decomposition of nickel acetylacetone in OAm. [91] Cordente et al. synthesized nickel NCs of tunable shape from the decomposition of Ni(COD)2 (COD = cycloocta-1,5-diene) in THF in the presence of HDA or trioctylphosphine oxide (TOPO). [92] By increasing the concentration of amine, nearly monodisperse Ni nanorods were formed probably due to the specific coordination of the amine. On the other hand, monodisperse Ni NCs could also be prepared at low temperature with the help of strong reductants. Metin et al. fabricated monodisperse Ni NCs (≈ 3 nm) from the reduction of Ni(acac)2 with the strong reducing agent boranetributylamine (BTB) in OAm and OA. In principle, the crystalline structure of the Ni NCs, which are generated

32

Chapter 2

Chemical Synthesis of Magnetic Nanocrystals: Recent Progress

from the thermal reduction of Ni salts in alkylamines, can be tuned by adjusting the reaction temperature. Chen et al. observed the formation of hcp-Ni NCs at higher reaction temperatures (e.g., > 240 ◦ C) from the reduction of Ni(acac)2 in alkylamines. [93] On the other hand, lower temperatures yielded fcc-Ni NCs. Mourdikoudis et al. reported a similar phase change of Ni NCs based on the thermal decomposition of nickel acetate tetrahydratein primary and tertiaryamines [94] Ni nanostructures with either hcp or fcc crystal structure could be tuned by the reaction temperature, and the size of the particles could be controlled between 5 nm and 120 nm by the additional surfactants such as 1-adaman-tanecarboxylic acid (ACA). The synthesis of nanostructured alloys such as FePt and CoPt have also been intensively studied because of their high magneto-anisotropy and good chemical stability. [1, 95, 96] Nanostructured MPt alloys with the phase of face-centered tetragonal (fct) (also known as L10 phase) are particularly interesting for their extremely high magneto-anisotropy which makes them excellent candidates for ultrahighdensity magnetic storage and the precursor to advanced magnetic materials. Sun et al. first obtained monodisperse FePt NCs by the thermal decomposition of Fe(CO)5 and the reduction of Pt(acac)2 in a mixture of OA and OAm (Fig. 2.5). [1] The size and composition of FePt NCs could be tuned by varying the ratio of precursors and the solvent. Exclusion of additional reducing agent such as 1,2-alkanediol in the reaction mixture can help realize better control of the size of the FePt NCs. [97, 98] To convert as-synthesized FePt NCs with a chemically disordered fcc structure into an fct structure, thermal annealing of fcc-FePt NCs at high temperatures is needed. To obtain dispersible fct-FePt NCs, one can coat the as-synthesized FePt NCs with SiO2 /MgO, or disperse the NCs in NaCl matrix before thermal annealing, and remove the additional chemicals after the fct-FePt is formed.[69,99−103 ] Notably, the direct synthesis of fct-FePt NCs using a wet-chemistry method was also reported. Jeyadevan et al. obtained partial fct-FePt alloys with a particle size of 5 nm–10 nm by the reduction of platinum and iron acetylacetonates in tetraethylene glycol at 300 ℃. [104] Howard et al. acquired partially ordered fct-FePt NCs by the reaction of Na2 Fe(CO)4 and Pt(acac)2 in tetracosane at 389 ℃. [105] Owing to the unique magnetic properties including large permeability and very high saturation magnetization, FeCo alloys are very attractive for self-assembly thin film and biomedical applications. Based on reductive decomposition of Fe(acac)3 and Co(acac)2 in a mixture of OA, OAm, and 1,2-hexadecanediol under a gas mixture of 93% Ar + 7% H2 at 300 ℃, Chaubey et al. successfully obtained bimetallic FeCo NCs with well-controlled particle size and size distribution. [106] By using [Co(η 3 -C8 H13 )(η 4 C8 H12 )] and Fe(CO)5 as organometallic precursors and a mixture of HDA, OA, and

2.2

Chemical synthesis of single-component magnetic NCs

33

stearic acid (SA) as stabilizing agents at 150 ℃ under 3 bars (1 bar = 105 Pa) of H2 , 20-nm monodisperse FeCo NCs, self-organized into millimeter long super-crystals, could be obtained. [107] In an alternative approach, high-magnetic-moment FeCo NCs were prepared via the diffusion of Co and Fe in core/shell structured Co/Fe NCs by raising the solution temperature. [108]

Fig. 2.5

(a) and (b) TEM image of a 3D assembly of 6-nm Fe50 Pt50 NC.

(c) High-resolution SEM image and (d) HRTEM image of 4-nm Fe52 Pt48 assembly after annealing. Reproduced with permission from Ref. [1]. Copyright 2000 Science.

2.2.3

Metal carbides, phosphides, and chalcogenides

Nanosized iron carbides have attracted increasing interest recently due to their good air stability with high magnetization, and excellent catalytic properties in the Fischer–Tropsch synthesis. [109, 110] However, to meet the requirements of wide applications, there still remain big challenges in the synthesis of iron carbide nanostructures with controlled phase, size, and magnetic properties. Compared to the preparation routes of physical pyrolysis, sonolysis, and laser ablation methods, which in-

34

Chapter 2

Chemical Synthesis of Magnetic Nanocrystals: Recent Progress

evitably cause the aggregation of products, solution chemistry methods have shown remarkable advantages in controlling the size and morphology.[111−115] Hou et al. developed a convenient solution phase method to synthesize Fe5 C2 NCs by the reaction of Fe(CO)5 with octadecylamine in the presence of bromide under mild temperatures. [114] It was investigated that bromide in the reaction systems was crucial for the formation of crystalline Fe NCs, which exhibited antioxidized characteristics to proceed to carbonization at high temperature. On the other hand, unsaturated hydrocarbons and cyanides, which were produced by the decomposition of octadecylamine under Fe catalysis, served as carbon source that could react with crystalline Fe to form Fe5 C2 . Owing to the compact organic shell around the NCs built by bulky octadecylamine, the size of the carbide could be effectively controlled. Inspired by the Fischer–Tropsch process, Meffre et al. reported a tunable organometallic synthesis of monodisperse iron carbide NCs based on the decomposition of Fe(CO)5 , which serves as both Fe and carbon precursor, in the presence of preformed Fe NCs at 150 ℃ under 3-bar H2 atmosphere. [115] By carefully altering the surface functional groups of preformed Fe seeds, solvent and Fe(CO)5 concentration, iron carbide NCs with a very narrow size distribution could be obtained (Fig. 2.6(a)). Because of their excellent magnetic properties with tunable magnetic anisotropy, these NCs displayed extremely high efficiency for magnetic hyperthermia. There have been some reports on chemical synthesis of cobalt carbide NCs with interesting magnetic properties. The polyol, which can effectively reduce cobalt salts and generate active carbon, has been exploited to fabricate cobalt carbide NCs.[116−118] Zhang et al. reported the controlled synthesis of cobalt carbide (Co3 C and Co2 C) NCs with high coercivity at room temperature based on a simple one-pot polyol reduction process, in which the shape and size of the cobalt carbide NCs could be controlled by adjusting the category and concentration of the surfactant. [118] The polyol reduction method could be further improved with the help of hydroxide and chloride anions, which could affect the size and phase of cobalt carbide. [117] It is interesting that by varying the concentration of the anions, pure phase Co2 C NCs were prepared. In an alternative process, An et al. performed the reduction of the self-assembled CoO nanorod arrays to form FM Co2 C nanorods arrays. [119] Under H2 atmosphere, CoO was initially reduced to form Co, and reacted with the carbon from the thermal decomposition of the organic surfactant. In spite of the preliminary progress, to develop a reliable method to synthesize high-quality cobalt carbide NCs with pure phase and homogeneous size is still highly desired for practical applications.

2.2

Chemical synthesis of single-component magnetic NCs

35

Based on the reactions carried out in high-boiling-point organic solvents, there have been many efforts in synthesizing colloid nickel carbide NCs. [120, 121] Pure nickel carbide (Ni3 C) NCs, which is characterized as an interstitial solid solution of carbon in the metallic hcp-Ni, have been prepared with particle diameters of 40 nm by thermal decomposition of nickel formate in the presence of OA and OAm. However, due to similar lattice parameters between hcp-Ni and Ni3 C, there remains controversy in examination of the exact phase. Goto et al. demonstrated the thermolysis of Ni(acac)2 in OAm to acquire Ni3 C NCs, and used hard-X-ray photoelectron spectroscopy to clarify that the hcp phase was not a metallic hcp-Ni but a hexagonal nickel carbide. [120] During the process, metallic Ni NCs were first generated by the thermal decomposition of the acetylacetonate, and then were subjected to carbonization to form cubic nickel carbide as an intermediate product before being transformed into hexagonal nickel carbide. By decomposing Ni(acac)2 in the presence of OAm and 1-octadecene, Schaefer et al. synthesized Ni3 C1−x with controlled average carbon content via tuning the reaction time. [121] Their results help to experimentally rationalize the discrepancies in lattice constants and magnetic properties, and effectively bridge prior reports of hcp-Ni and Ni3 C. Magnetic metal phosphides including iron, cobalt, and nickel phosphides, are a class of compounds that have gained increasing interest for their advanced catalytic, electronic, and magnetic properties. [122, 123] Recent studies have been focused to develop general synthetic approaches to synthesize high crystalline magnetic metal phosphides with careful control over both the composition and the morphology.[124−135] In general, the preparation of metal phosphides is based on the reaction between phosphorus containing chemicals (phosphines, phosphorus pentachloride, P(SiMe3 )3 or trictylphosphine) and metal precursors. Perera et al. first reported the preparation of pure FeP NCs from reaction of Fe(acac)3 with P(SiMe3 )3 in TOPO at 280 ℃. [136] Instead of P(SiMe3 )3 , the use of alkyl phosphines, like TOP, as the phosphorus source has proven to be a more general and cheaper route to synthesize magnetic metal phosphide NCs. Henkes et al. described a general strategy for synthesizing various types of transition metal phosphides nanostructures by the conversion of preformed metal NCs into metal phosphides via solution-mediated reaction with TOP. [132] Similarly, the Brock group reported the synthesis of phase-pure Fe2 P and FeP by reacting preformed Fe NCs with TOP at temperatures in the region of 350 ℃–385 ℃. It was found that shorter reaction time/lower temperature favored an iron-rich product (Fe2 P), and longer reaction time/higher temperature favored a phosphorus-rich product (FeP). [124] Ha et al. reported the chemical transformation of ε-Co NC into two phases of cobalt phosphide, Co2 P, and CoP from a reaction

36

Chapter 2

Chemical Synthesis of Magnetic Nanocrystals: Recent Progress

with TOP. [130] Discrete, unsupported NCs of Ni2 P with an average crystallite size of 10.2±0.7 nm have been prepared by using a solution-phase method with Ni(COD)2 as the nickel source and TOP as the phosphorus source in the presence of the coordinating solvent TOPO. [126] Muthuswamy et al. presented controlled synthetic procedures to utilize reaction parameters as levers to tune phase, size, and morphology, enabling phase-pure samples of Ni12 P5 and Ni2 P to be prepared in both solid and hollow morphologies. [125] In order to get anisotropic nanostructures of the metal phosphides, Liu [134] and Hyeon [137] developed the method to promote the growth of anisotropic NCs by multiple or continuous injection of a metal-TOP precursor solution. For example, well-defined FeP nanorods and nanowires were acquired by the multiple injection of iron pentacarbonyl and phosphine mixtures (Fig. 2.6(b)), [134] while uniformly sized magnetic Fe2 P nanorods could be fabricated from the thermal decomposition of continuously delivered iron-phosphine complex using a syringe pump. By controlling the injection rate and by using different surfactants, the diameters and aspect ratios of the nanorods could be conveniently controlled, thus MnP, Co2 P, FeP, NiP nanorods with various dimensions could be successfully obtained (Fig. 2.6(c)). [133] In an alternative process without continuous injection, Li et al. employed a simple and reproducible method to prepare CoP nanowires with a high aspect ratio by the thermal decomposition of Co(acac)2 and tetradecyl phosphonic acid in a mixture of TOPO and HDA. Zhang et al. presented the use of TOPO, an air-stable compound, as both a solvent and a controlled phosphorus source to produce hyperbranched Co2 P NCs that are uniform in size, shape, and symmetry (Fig. 2.6(d)). [135] Magnetic metal chalcogenides are also an important family of interesting materials that have been proven to possess great potentials in many fields due to their magnetic, electrochemical, optical, and electrical properties. By taking advantages of solution-based chemical route, many groups have been challenging the syntheses of magnetic metal chalcogenides with tunable sizes and variable shapes. Notably, from previous studies, the hot-injection method and single-source precursor method have been proven to be highly effective strategies for preparing magnetic metal chalcogenides nanostructures. By employing a single source precursor, [Nn Bu4 ]2 [Fe4 S4 (SPh)4 ], bis(tetra-n-butylammonium)tetrakis[benezenethiolatoµ3 -sulfido-iron], a cubane-type cluster, which can decompose under extended reflux in alkylamines, O’Brien and Vanitha prepared monodispersed superparamagnetic iron sulfide NCs with controlled composition, structure, and dimensions. [138] In the procedures, pyrrhotite type Fe7 S8 NCs were formed at 180 ℃, while Fe3 S4 with a greigite structure was obtained at a higher temperature of 200 ℃. In another

2.2

Chemical synthesis of single-component magnetic NCs

Fig. 2.6

37

TEM image of (a) 13.1-nm iron carbide NCs, (b) FeP nanowires, (c) Ni2 P

nanorods, (d) hyperbranched Co2 P NCs, (e) NiS nanorods, and (f) β-FeSe nanosheets. Reproduced with permission from Refs. [115], [133]– [135], [140], and [141], respectively. Copyright 2012, 2004, 2005, 2011, 2004, 2009 American Chemical Society.

approach, by decomposing a single-source precursor of Fe(Ddtc)3 or Fe(Ddtc)2 (Phen) (Phen = 1,10-phenanthroline; Ddtc = diethyldithiocarbamate) in the mixture solvents of OA/OAm/1-octadecene, Fe3 S4 and Fe7 S8 nanostructures displaying strong FM properties at room temperature have been synthesized with diverse shapes (NCs, nanoribbons and nanoplates). [139] By extending the single source precursor method, rhombohedral NiS (millerite) nanorods and triangular nanoprisms could be synthesized relied on the thermal degradation of nickel thiolate precursors in the presence of octanoate. [140] Owing to solventless environment where interparticle collisions

38

Chapter 2

Chemical Synthesis of Magnetic Nanocrystals: Recent Progress

are rare, and controlled growth process, NiS NCs are achieved with relatively homogeneous size and shape (Fig. 2.6(e)). Raymond E. Schaak and his colleagues made an important contribution in the synthesis of iron chalcogenide via solution chemistry, where by β-FeSe, Te-containing compounds and the compositiontunable β-Fe(Se, Te) solid solution could be acquired by adopting Fe(CO)5 as an iron source and TOPO as solvent (Fig. 2.6(f)). [141] Bi et al. obtained phase pure, highly crystalline cubic FeS2 NCs by using a TOPO assisted hot-injection method. [142] Chen et al. prepared uniform tetragonal b-FeSex square nanoflakes with tunable composition and size by the reaction between ferrous chloride and selenium trioctylphosphine in the presence of OAm and OA. [143] Very recently, onestep colloidal synthetic methods have attracted increasing attention due to the avoidance of complicated procedures and harsh synthetic conditions. In a representative process, Zhang et al. have developed a convenient protocol for synthesizing Fe3 Se4 nanostructures (nanosheets, nanocacti, and nanoplatelets) by the one-pot high temperature organic-solution-phase method. [144] Interestingly, the assynthesized Fe3 Se4 nanostructures exhibit hard magnetic properties, with giant coercivity values up to 40 kOe (1 Oe = 79.5775 A·m−1 ) at 10 K and 4 kOe at room temperature.

2.3

Chemical synthesis of multi-component magnetic NCs

HNCs, which are composed of different inorganic components with various types of interfaces, have recently attracted much attention due to the unique properties and numerous possibilities of applications.[20−22,26−30] In terms of multi-component magnetic nanostructures, the different domains meet at interfaces open an opportunity to adjust the magnetism. In addition, the functional components involved in individual magnetic nanostructures may provide a platform for recyclable catalysis, medical diagnosis and therapy, photonics and electronics. [27, 29, 32, 145] In order to realize the successful application of such nanocomposites, it is extremely important to control their nanostructure, composition, and stability under different conditions. Therefore, in the past years many researchers have devoted themselves to developing reliable synthetic methods to fabricate the magnetic multi-component nanostructures. Among those approaches, nonhydrolytic method was found to be one of the most efficient and controllable ways to obtain the required NCs. In this part, we briefly overview the recent advances in the nonhydrolytic chemical synthesis of magnetic multi-component NCs with different nanostructures including core/shell, oligomer-like and anisotropically shaped material-based heterostructure.

2.3

2.3.1

Chemical synthesis of multi-component magnetic NCs

39

Core/shell heterostructure

In the systems of core/shell nanostructures, the inorganic inner NC “core” is evenly covered with a shell coating, which may be composed of one or more layers of inorganic materials. The magnetism of core and/or shell contributes to the magnetic property of the whole structure. Due to the large area of interfaces and related strong interactions, the physico–chemical properties of the core/shell nanostructures are found to be quite distinct from the individual components. In terms of magnetic NCs, the interactions at the interface always lead to the variation of the magnetism, such as the exchange bias effect and exchange-coupling-caused increase of magnetic energy product.[146−150] In order to successfully obtain the core/shell nanostructures, epitaxial growth is worth consideration. When the core and shell components are characterized by similar crystal structure and/or close matching lattice space, the strain at the interfaces can be minimized, resulting in the formation of core/shell structures, otherwise islands or satellites would finally appear for the decrease of the interface energy. However, the lattice compatibility is not necessary to achieve core/shell nanostructures. For example, the uniform oxidation of the active core NCs is an effective strategy to establish core/shell geometry. Zeng et al. first synthesized bimagnetic FePt/Fe3 O4 core/shell NCs by reductive decomposition of Fe(acac)3 in the presence of monodisperse FePt NCs (Fig. 2.7(a)). [151] The seed-mediated approach was found to be effective for the uniform growth of iron oxide. By adjusting the molar ratio between FePt NCs and the Fe(acac)3 precursor, the shell thickness could be easily tuned. Similarly, magnetic CoFe2 O4 shell could also be achieved by introducing Co(acac)2 into the system. [146] Besides FePt NCs, other metal/alloy NCs could also be used as seeds to generate metal/iron oxide core/shell nanostructures. It was suggested that metal/alloy seeds were generally rich of electrons, which could serve as catalytic centers for the growth of the secondary component. Shi et al. synthesized monodisperse Au/Fe3 O4 core/shell NCs with epitaxial interfaces by decomposing Fe(CO)5 or Fe(acac)3 in the presence of small Au seeds (Fig. 2.7(b)). [152] Co/Sm2 O3 core/shell NCs (Fig. 2.7(c)) obtained from solution phase processing were used as precursors for high-temperature annealing, yielding nanocrystalline SmCo5 with large coercivity. [153] Teng et al. reported the synthesis of Pt/Fe2 O3 core/shell NCs by sequential decomposition of Pt(acac)2 and Fe(CO)5 (Fig. 2.7(d)). [154] FePt/ZnO core/shell NCs could be prepared by the decomposition of zinc acetate at high temperature in the presence of uniform FePt seeds, which offered a good example to combine the magnetism and fluorescence. [155]

40

Chapter 2

Fig. 2.7

Chemical Synthesis of Magnetic Nanocrystals: Recent Progress

TEM images of typical metal/oxide core/shell HNCs prepared by seed-mediated

process. (a) FePt/Fe3 O4 core/shell HNCs. Reproduced with permission from Ref. [151]. Copyright 2004 American Institute of Physics. (b) Au/Fe3 O4 core/shell HNCs. Reproduced with permission from Ref. [152]. Copyright 2006 American Chemical Society. (c) Co/Sm2 O3 core/shell HNCs. Reproduced with permission from Ref. [153]. Copyright 2007 Wiley-VCH. (d) Pt/Fe2 O3 core/shell HNCs. Reproduced with permission from Ref. [154]. Copyright 2003 American Chemical Society.

All-oxides magnetic NCs are also important series of core/shell NCs for wide application potentials. The spinel-phase M Fe2 O4 (M = Zn, Mn, Fe, Co, Ni) are those types of ferrimagnetic (FiM) materials which deserve to be mentioned. The incorporation of both FM (or FiM) and antiferromagnetic (AFM) phase in the core/shell structure brings the signature of magnetic exchange coupling between interfacial spins of the two types of magnetic sections, which may cause horizontal loop shift by an “exchange bias” field, thus resulting in enhancement of the coercivity. [148, 149, 156] In addition, effective interfacial exchange interaction also occurs between soft and hard magnetic phases if the thickness of soft phase is twice the width of domain wall of the hard phase. In this case, soft phase becomes rigidly pinned by hard phase at the interface. [71, 99, 146, 150] This unique effect offers opportunities to tune the mag-

2.3

Chemical synthesis of multi-component magnetic NCs

41

netism of the NCs and therefore to realize ideal performances. The preparation of all spinel phase core/shell NCs is generally easy to carry out due to the similar crystal structures and lattice spaces between the components. Uniform core/shell NCs incorporating all magnetic spinel phases can be obtained with controlled size and shell thickness based on the seeds-mediated process. For instance, to synthesize 15-nm core/shell CoFe2 O4 /MnFe2 O4 NCs, a 9-nm CoFe2 O4 NC was used as a seed and MnFe2 O4 was over-grown onto the surface of the seed particle by thermal decomposition of the MnCl2 and Fe(acac)3 . [99] By tuning the amount of the precursors, the shell thickness of the secondary component could be easily controlled. The AFM phase of MnO could be overgrown onto the spinel ferrite by decomposition of Mn (CH3 CO)2 via a similar seed-mediated method, which generated the FM/AFM interactions at the core/shell interfaces. [157] Another smart family of core/shell NCs, in which the FM (or FiM) core, such as FePt, Fe3 O4 , was covered by the noble metal, such as Au, Ag, for realizing combined functions of magnetism, optics and biocompatibility. Xu et al. reported the synthesis of Au- and Ag-coated Fe3 O4 NCs with controlled plasmonic and magnetic properties. [158] In the chloroform solution of OAm, Au could be coated on the surface of Fe3 O4 seeds by reducing HAuCl4 . Ag shell could be further generated onto Fe3 O4 /Au NCs by adding AgNO3 to the reaction mixture after the seeds were transferred into water. In order to obtain uniform Au (or Ag) shell, it is essential to enhance the surface energy of Fe3 O4 to effectively adsorb Au atoms. Among a variety of strategies, surface modifications of Fe3 O4 by those molecules containing the groups which exhibit strong affinity to Au have been regarded as the most efficient approach. Jin et al. found that in contrast to commonly used primary amines, the imidazole groups are capable of immobilizing Au3+ ions on Fe3 O4 at high packing density. The authors used ploy-L-histidine to modify the outer surface of Fe3 O4 , inducing the uniform Au shell growth by the reduction of Au3+ . [31] Core/shell HNCs incorporating magnetic and semiconducting chalcogenides components are worth mentioning. FePt/CdS were produced by series of reactions in a one-pot procedure, whereby FePt NCs were first formed in the solution and were subsequently allowed to react with sulfur and Cd(acac)2 to generate amorphous CdS shell. Notably, the metastable core/shell structure could be transformed into heterodimers of crystalline CdS and FePt NCs upon heating for eliminating the surface tension between the two components. [159] When using FePt NCs as seeds, they could also prepare FePt/CdX (X = S, Se) core/shell NCs by the sequent addition of Cd(acac)2 and chalcogens, whereby FePt/CdO core/shell intermediates were formed for the successful preparation of the final structure. [160] Monodisperse spherical or

42

Chapter 2

Chemical Synthesis of Magnetic Nanocrystals: Recent Progress

cube-shaped FePt/PbX (X = S, Se) were generated via similar strategy. [161] Magnetic materials enwrapped within a biocompatible and hydrophilic SiO2 shell have attracted increasing interest. The silica shell is beneficial to promote the biocompatibility of the magnetic NCs, such as Fe3 O4 , for the improvement in biochemical applications. The silica shell can also contribute to minimize release of toxic metals to biological environments. In addition, further modification of the silica shell may bring more functions of the system. The main synthetic method to fabricate silica-coated magnetic NCs relies on the reaction in water-in-oil microemulsions. Numerous reports showed that the silica coating could be successfully achieved by microemulsions as nanoreactors, which can efficiently dissolve the precursors and seeds, and control the hydrolysis and condensation reactions. The surfactant, which determines the size of the droplets and in turn strongly affect the coating process, is found to be the key factor to achieve silica-coated magnetic NCs with diverse sizes, shapes, and functions. Though this methodology, FePt/SiO2 , CoFe2 O4 /SiO2 , and other ferrites/SiO2 core/shell NCs could be prepared. [162, 163, 164, 165, 166, 167] For example, with the assistance of the surfactant, Igepal CO-520 (poly(5)ox-yethylene4-nonylphenyl-ether), the FePt NCs were coated with SiO2 by base-catalyzed silica formation from tetraethyl-orthosilicate in a water-in-oil microemulsion. The silica shell could effectively prevent FePt coalescence even at a high temperature up to 850 ◦ C. [164] Another commonly used strategy to generate shell on the magnetic core are redox transmetalation reactions between the reagents without the need for any additional reductants. In terms of metal/oxide systems, the metal core, which is usually chemically active toward oxygen, can be easily oxidized to form metal/oxide core/shell nanostructures with controlled shell thickness. Fe/Fe3 O4 , [79] Co/CoO, [168] and Ni/NiO [169] core/shell NCs can be obtained by air exposure or addictive oxidation of the metal seeds. For example, by exposing OAm-capped Fe NCs to air, amorphous iron shell can be introduced (Fig. 2.8(a)). [79] A crystalline Fe3 O4 shell could be produced by controlled oxidation of the as-synthesized NCs using an oxygen transferring agent (CH3 )3 NO, which effectively made Fe/Fe3 O4 core/shell NCs more stable (Fig. 2.8(b)). Through the sacrificial conversion, the magnetic metal cores (Fe or Co) were able to be coated with those metals which are chemically less active and possess favorable redox potentials (such as Au, Pt, Pd). Lee et al. reported a general protocol for the synthesis of high-quality Co/M (M = Au, Pd, Pt, Cu) core/shell NCs by redox-transmetalation process in the presence of Co NCs. During the process, the metal ions can be reduced on the surface of Co NCs, while the Co atoms were in turn released as Co-ligand complex. The simultaneous core

2.3

Chemical synthesis of multi-component magnetic NCs

43

metal consumption and shell layer formation contribute to the uniformity of the final products (Fig. 2.8(c)). [170] Interestingly, the generation of the AFM shell on the FM core offers a good platform to study the exchange bias effects. Sun et al. prepared FeO/Fe3 O4 core/shell NCs with tunable FeO core size and Fe3 O4 shell thickness via a controlled oxidation process (Fig. 2.8(d)). [156] Alternatively, MnO/Mn3 O4 [171] and even more complex core/shell nanostructures [149] (three-, and four-component multilayers) can be achieved through similar strategy.

Fig. 2.8

TEM images of typical core/shell HNCs prepared based on redox

transmetalation reactions. (a) and (b) Fe/Fe3 O4 core/shell HNCs. Reproduced with permission from Ref. [79]. Copyright 2006 American Chemical Society. (c) Co/Au core/shell HNCs. Reproduced with permission from Ref. [170]. Copyright 2005 American Chemical Society. (d) FeO/Fe3 O4 core/shell HNCs. Reproduced with permission from Ref. [156]. Copyright 2012 American Chemical Society.

Unlike the classical seed-mediated approach, which frequently requires multiple steps to separate the nucleation and growth processes artificially, there have also been successful efforts to develop simplified one-pot single-step methods. In the reaction process, all necessary precursors, which are present simultaneously in the solution, can successively decompose to realize the self-controlled nucleation and

44

Chapter 2

Chemical Synthesis of Magnetic Nanocrystals: Recent Progress

growth. Under appropriate conditions, different materials form at distinct times or temperatures, and the shell can be produced by heterogeneous nucleation on the in-situ formed seeds. Based on the self-controlled nucleation/growth mechanism, Ag/Co, [172] Cu/Ni, [173] Au/Co, [174] and Cr/Fe2 O3 [175] core/shell NCs can be successfully synthesized. For example, in the one-pot preparation of Au/Co core/shell NCs, Au3+ could be first reduced to form Au NCs at low temperature. Afterwards, when the temperature was further increased to 200 ◦ C, the preformed Au seeds were able to catalyze Co nucleation to ensure the continuous shell growth. [174] 2.3.2

Oligomer-like heterostructure

Apart from core/shell NCs, oligomer-like HNCs are also a distinguished family of heterostructured nanomaterials which incorporate distinct domains of materials interconnected through limited small bonding interfaces. To obtain such oligomer-like topologies, the thermodynamically controlled growth is anisotropically centered on one or several sites of the seeds, which is distinct from the case in the preparation of core/shell HNCs. Therefore, by varying the objective materials and/or tuning the synthetic conditions that can promote anisotropic growth, the oligomer-like geometries can be successfully achieved. For example, materials that hardly form alloys and/or are strongly lattice-uncorrelated tend to form oligomers in order to minimize the interfacial energy. In addition, the environmental parameters, such as the seedto-precursor ratio, the solution concentration, the heating profile, and the polarity of the solvent play important roles in developing the oligomers. By tuning the concentration of the precursors below the homogeneous nucleation threshold, heterogeneous nucleation is promoted while homogeneous nucleation is suppressed so that the secondary growth preferentially occurs at accessible sites of the seeds. The heating profile can induce the phase segregation, leading to the formation of oligomer-like heterostructures from core/shell geometries by a surface de-wetting process. The polarity of the solvent can strongly affect the electron distribution on the surface of the seeds and electron transfer at the interface, thus one can conveniently obtain the oligomer-like morphologies rather than core/shell nanostructures. Like core/shell nanostructures, oligomers incorporating magnetic components have received intensive studies. The exchange coupling between the different magnetic domains at the interfaces that are distinct from those of the core/shell NCs, also brings various interesting magnetic phenomenon. Moreover, due to the surface exposure of each component given by the oligomer-like geometries, one can exploit their surface activity to link functional molecules or to make effective catalysis. The magnetic component can not only contribute to magnetically recovery of the cat-

2.3

Chemical synthesis of multi-component magnetic NCs

45

alysts, but also benefit catalytic properties via electron transfer at the interfaces. Such advantages make the magnetic oligomers promising especially in the field of medical diagnosis/therapy and recyclable catalysis. [29, 145, 176] The seed-mediated protocols have been successfully utilized in the preparation of various types of magnetic oligomers. In the presence of preformed NCs, Fe3 O4 X1 (X1 = Au, Pt, Ag, Ni, FePt, AuAg),[176−182] CoO/MnO-X2 (X2 = Au, Ag, Pt, FePt), [148, 179, 180, 183] and FePt-X3 (X3 = CoFe2 O4 , Au, CdS, PbS, [147, 161, 184, 185] oligomers can be produced by thermal decomposition of the PbSe) precursors for growth. For example, to prepare Au–Fe3 O4 dumbbells, Au NCs with different sizes were first synthesized by the reduction of HAuCl4 in OAm. [176, 180] In the growth procedure, iron pentacarbonyl, Fe(CO)5 , was used as the iron source to introduce the iron growth over the surface of the Au seeds. The joint iron component was transformed to Fe3 O4 by the following oxidation process. The size of the Fe3 O4 sections could be tuned by adjusting the Fe(CO)5 /Au ratio (Fig. 2.9). This synthetic approach can be further improved for the preparation of a range Au–Fe3 O4 hybrid NCs owing more interconnected interfaces with controlled sizes and the numbers of Fe3 O4 domains by choosing multiply twinned Au NCs as seeds. [181] Generally, the generation of phase segregation by anisotropic growth can be ascribed to the appreciable difference in lattice parameters of connected materials, which strongly affect the interfacial energy. However, in some cases, the polarity of the solvent is found to determine the number of nucleation sites for growth on the seeds. For instance, when Fe3 O4 is initially nucleated on the Au seeds, electrons will transfer from Au to Fe3 O4 through the interface, leading to electron deficiency on the Au NCs. [176, 177] As long as the electron deficiency is replenished from the electron–donor solvent, multiple nucleation sites can be generated so that flower-like and even core/shell heterostructures can be formed. In contrast, further nucleation events are inhibited caused by the electron deficiency if non-polar solvent is used. Therefore, by modulating the polarity of the solvent, magnetic heterostructures with different topologies can be easily controlled, leading to the potential possibilities for the applications with designed functionalities. In some cases, the morphology of the seeds and the bonding ligand on certain facets were found to be critical to the formation of final heterostructures. [147, 161, 178] If the cubic FePt NCs are chosen as seeds instead of spherical ones, brick-like FePt/CoFe2 O4 can be prepared. [147] In terms of the synthesis of dumbbell-like FePt–PbS nanostructures, extensive washing of FePt seeds is required to recap OAm ligands with less labile oleate ligands. [161] By tuning the reaction temperature, dumbbell-like structures with size-controlled near-spherical and cubic PbS components attached to FePt NCs can be prepared. Notably, core/shell

46

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Chemical Synthesis of Magnetic Nanocrystals: Recent Progress

heterostructures appear if the surface of FePt seeds is extensively treated with an excess of OAm due to more nucleation sites generated by labile amine surfactants. More interestingly, the seed-mediated approach has shown extraordinary effects on achieving more complex heterostructures containing multiple domains by stepwise construction of supplied seeds. This is conceptually analogous to the construction of complex organic molecules, and can be comprehensively understood from a representative example to synthesize M –Pt–Fe3 O4 (M = Au, Ag, Ni, Pd) heterotrimers, and Mx S–Au–Pt–Fe3 O4 (M = Pb, Cu) heterotetramers. [186]

Fig. 2.9

TEM images of the dumbbell-like Au–Fe3 O4 HNCs with the size of

(a) 3 nm–14 nm and (b) 8 nm–14 nm. (c) HAADF–STEM image of the 8 nm–9 nm Au–Fe3 O4 HNCs. (d) HRTEM image of one 8 nm–12 nm Au–Fe3 O4 NC. Reproduced with permission from Ref. [176]. Copyright 2005 American Chemical Society.

Alternatively, oligomers can be formed from metastable core/shell HNCs by thermally driven coalescence/crystallization process. There have been systematic investigations of the formation of oligomer-like heterostructures based on magnetic

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Chemical synthesis of multi-component magnetic NCs

47

(FePt, γ-Fe2 O3 ) and semiconducting chalcogenides (CdS, ZnS, HgS, CdSe, ZnSe, HgSe), [163, 184, 186, 187, 188, 189, 190] revealing the way of topological change governed by the interfacial strain energy. For example, in the γ-Fe2 O3 –CdS system, a highly defective and amorphous layer of CdS was initially deposited onto the γ-Fe2 O3 seeds by the sequential addition of sulfur and Cd reagent. [188, 189] In spite of the appearance of partial aggregations, the core/shell heterostructures maintained at low temperature would transfer into heterojunctions upon heating the solution at elevated temperature. The significant change can be explained by the large lattice mismatch between γ-Fe2 O3 and CdS components after CdS gradually became crystalline. By examining the morphology of the products incorporating other surfides (ZnS, HgS) under similar synthetic conditions, the effects of lattice mismatch at the heterojunctions can be obviously addressed. The yield of heterostructures was found to be lower in the systems with larger mismatch, and even complete particle separation could be observed in the HgS system with the largest mismatch. [189] The topologies of the heterojunctions can be further tuned by varying the seed size and/or the growth rate. In the Fe3 O4 –CdS system, the size of Fe3 O4 seeds has a strong influence on the interfacial strain, leading to the formation of CdS with different sizes and numbers. [190] When the size of Fe3 O4 seeds is small, the strain can be relieved so that CdS NCs are able to grow into relatively large sizes, while for seeds larger than 7 nm, the growth of CdS is inhibited and the addition of excess Cd/S reagents would lead to the formation of multiple heterojunctions. Interestingly, rods-on-dot structures could be produced by carefully separating the stages of junction formation and growth, and controlling the growing rates of CdS. Another attractive approach to get magnetic heterojunctions is based on reactions at liquid/liquid interfaces (Fig. 2.10). [191] In this simple methodology, the organic phase containing NCs (FePt, Fe3 O4 dissolved in dichlorobenzene, dichloromethane, hexane, or dioctyl ether) is mixed with the aqueous phase containing Ag+ to form the microemulsion, i.e. “colloidosomes” in aqueous phase, by ultra-sonification. The micro-emulsion can be stabilized by the NCs that self-assemble at a liquid–liquid interface. Since a few Fe(II) sites on the exposed surface of the NCs act as the catalytic center for the reduction of Ag+ , Ag nucleate and grow continuously to form heterodimers as the reduction proceeds. The formation of the heterodimers, rather than core/shell structures, can be ascribed to the fact that the seeds are only partially exposed to the aqueous phase so that metal deposition is restricted to a small surface region. The general synthetic method offers access to FePt–Ag, Fe3 O4 –Ag, hollow γ-Fe2 O3 –Ag heterodimers, which can be applied for protein binding, molecular imaging, and pathogen detections.

48

Fig. 2.10

Chapter 2

Chemical Synthesis of Magnetic Nanocrystals: Recent Progress

(a) Schematic illustration of the synthesis of Ag–FePt (Fe3 O4 ) heterodimers

based on reactions at liquid/liquid interfaces. TEM images of (b) 8 nm–3 nm and (c) 8 nm–5.5 nm Fe3 O4 –Ag heterodimers. HRTEM images of (d) Fe3 O4 –Ag and (e) FePt–Ag heterodimers. Reproduced with permission from Ref. [191]. Copyright 2005 American Chemical Society.

A simplified one-pot method, in which all the reagents are added into the primary solution at the beginning of the synthesis, has also been developed to synthesize magnetic heterostructures. Compared to the classical seed-mediated approach,

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Chemical synthesis of multi-component magnetic NCs

49

this method, which is based on self-regulated nucleation/growth, has obvious advantages in avoiding complicated procedures comprised of the preparation of seeds, and the subsequent growth. Nevertheless, identification of the experimental conditions, as well as understanding toward the inherent reaction mechanism are still insufficient and challenging. Such a method has been implemented to synthesize FePt–Fe3 O4 , Au–Ni, and Co–Pd sulfide heterostructures. [174, 192, 193] Notably, the report of a comprehensive study to prepare FePt–Fe3 O4 heterodimers via one-pot colloidal approach has represented an advance in this respect. [193] By temperaturedriven sequential reactions in an OAm/OA/1-octadecene environment, which involved the homogeneous nucleation of FePt seeds and the subsequent heterogeneous growth of iron oxide, size-controlled synthesis of the heterodimers can be realized. The FePt NCs were first formed at low temperature, after which Fe complexes in the solution sustained nucleation and growth of iron oxide on preformed FePt NCs upon thermal decomposition at elevated temperature. The size of the starting FePt NCs and the Fe(CO)5 /Pt(acac)2 molar ratio used in the synthesis were found to be critical for the domain dimensions of the heterostructures because they determined the ultimate surface area available for heterogeneous deposition and the growth degree of the iron oxide domain, respectively. Similarly, Au–Ni heterodimers can be obtained by temperature-driven sequential reactions, in which preformed Au NCs could induce the deposition of Ni. [174] There are also a few attempts to prepare oligomer-like heterostructures, especially those high-order hetero-oligomers, which are made by coupling reactions of smaller fragments to form larger oligomers by certain additives. A typical example can be illustrated for the synthesis of Fe3 O4 –Au–Fe3 O4 dumbbells, in which Au–Fe3 O4 heterodimers can be fused together in the presence of sulfur to form ternary dumbbells. [177] Owing to the high affinity to Au, sulfur can be enriched on Au surfaces, and therefore help triggering welding of the Au domains in Au–Fe3 O4 heterodimers. Inspired by such a unique process, Schaak et al. reported the observation of higher-order (Au–Pt–Fe3 O4 )n hetero-oligomers with distinct geometries (linear, bent, and branched nanostructures) by heating Au–Pt–Fe3 O4 heterotrimers to 120 ℃–150 ℃ with a trace amount of sulfur powder in trioctylamine. [186] 2.3.3

Anisotropically shaped material-based heterostructure

Another family of heterostructured magnetic nanomaterials based on anisotropically shaped components is worth mentioning. Heterogeneous growth on anisotropically shaped seeds, such as nanorods, nanowires, and branched NCs, can result in the formation of heterostructures with spatially asymmetric configuration. Notably,

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Chemical Synthesis of Magnetic Nanocrystals: Recent Progress

the facet-dependent reactivity of the seeds for secondary growth becomes rather pronounced to drive the ways of heterogeneous nucleation compared to the cases in the formation of core/shell and oligomer-like heterostructures. Based on the minimizing of the overall surface and interfacial energy of the system, nucleation can occur on apexes and sidewalls of the seeds selectively or nonselectively to form distinct architectures. By varying the synthetic conditions, such as solution supersaturation, reactant diffusion, and reaction atmospheres, spherical, linear, and branched growth can be achieved. Due to the coupling and electron transport across the interface between the different domains, this family of heterostructured nanomaterials can exhibit novel or enhanced physical and chemical properties. So far, there has been considerable progress on preparation of semiconductor-based heterostructures relying on the advance in getting their anisotropic shapes. In terms of magnetic heterostructures, there have also been successful efforts to devise pathways to achieve various architectures with designed functionalities. Based on the controlled growth of Au NCs onto FePt nanorods, tadpole-, dumbbell-, bead-, and necklace-like FePt–Au nanostructures were synthesized. [194] The heterostructures can be tuned by manipulating the reaction atmosphere and the crystallization of FePt seeds. Under an Ar atmosphere, tadpole-like FePt–Au nanostructures were formed from the FePt seeds treated at 300 ℃, while dumbbell- and bead-like heterostructures could be obtained by bubbling forming gas into the solution for different time. Since hydrogen possesses the tendency to be adsorbed onto the surface of FePt to freshen their surfaces and lower the reduction energy of Au, the introduction of H2 can help create more active sites for Au nucleation, otherwise the nucleation preferentially occurs on the tips. To further increase the nucleation sites, FePt that synthesized at low temperature (180 ℃ –220 ℃ ) was used as seeds, from which necklace-like nanostructures were produced under Ar/H2 atmosphere. The heterostructures incorporating semiconductor and magnetic all-oxide components, which can be envisioned to enable exploitation of multifunctional nanomaterials, have attracted much attention. In the synthesis of TiO2 –Fex Oy heterostructures, the rod-like TiO2 seeds with size- and shape-dependent anisotropic reactivity were found to strongly affect the selective heterogeneous nucleation and growth of iron oxide, leading to various final architectures.[195,196,197] Iron oxide with controlled sizes and numbers could be kinetically overdriven toward active regions of the exposed b-TiO2 facets by multi-step hot-injection of Fe(CO)5 /OA/1-octadecene. Compared to anatase TiO2 , brookite seeds with enhanced reactivity were found to be capable to overcome strain-related heteroepitaxial growth constraints. [197] Additionally, for larger TiO2 seeds, multiple depositions of iron oxide were encouraged

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Chemical synthesis of multi-component magnetic NCs

51

so that architectures with more iron oxide domains could be obtained. Further investigations by the same group [196] indicated that under diffusion-controlled growth conditions, iron oxide can be epitaxially grown at either one apex or any location along their longitudinal sidewalls of b-TiO2 nanorods distinguished by a curved shape-tapered profile with richly faceted terminations (Fig. 2.11). By taking advantage of the generation of strain fields during heteroepitaxial growth, heterostructures of iron oxide decorated on the longitudinal facets of TiO2 nanorods have been prepared. It was revealed that the strain played an important role in the formation of the architectures due to the fact that the two domains of TiO2 and iron oxide share a restricted and locally curved junction region, which efficiently accommodates the interfacial strain and retards the formation of misfit dislocations.

Fig. 2.11

(a)–(d) TEM images of matchstick-shaped HNCs based on b-TiO2 nanorod

seeds with different sizes and aspect ratios. Reproduced with permission from Ref. [196]. Copyright 2010 American Chemical Society.

Alternatively, there have been some reports on the syntheses of magnetic-metal/ semiconductor heterostructures based on the domains with anisotropic shape prepared by colloidal methods. In the heterostructures of CdS (CdSe) nanorods decorated with magnetic metals (PtCo, Co), metal nucleation can be successfully realized at both seed apexes in a high degree of selectivity. [198, 199, 200, 201] For example, CdSe/Co nanorod/nanosphere hybrid NCs could be obtained through the selective growth of cobalt on the tips of CdSe nanorods, while the formation CdSe/Co nanorod/nanorod heterostructure could be observed at elevated reaction temperature by inducing anisotropic growth of the initially formed Co nanospheres. [198]

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However, in the presence of nanowires, the metal deposition occurs nonselective, leading to multiple metal domains on apex and any location along the longitudinal sidewalls of the nanowires. [199] In the previous parts, surfactants or ligands that facet-preferentially adhere onto the surfaces of the seeds have been revealed to be critical for preparing core/shell and oligomer-like heterostructures. Similarly, by exploiting anisotropic nanomaterials as seeds, the selective heterogeneous nucleation is also strongly dependent on the molecule attachment of the seeds. In many cases, surfactant concentration is kept at a relatively low value to ensure sufficient heterogeneous nucleation. Due to the large lattice mismatch, the effects of surfactants have been found to be pronounced to incorporate oxide and metal. Size-tailored ZnO nanorods decorated with magnetic Fe-based domains, were synthesized via a colloidal seeded-growth method in a noncoordinating solvent. [202] In surfactant-free 1-octadecene, a variable number of Fe/Fex Oy core/shell NCs with no facet-preferential attachment could be grown onto purified ZnO nanorods by the controlled hot-injection of Fe(CO)5 , followed by air-oxidation. The surfactant-free environment was also exploited to grow Co on CdSe/CdS nanorods and γ-Fe2 O3 tetrapods by Co2 (CO)8 decomposition. [203, 204] In the synthesis of three-component Co/CdSe/CdS nanohybrid, metallic Co could be attached to either apexes of one rod-shaped section due to the peculiar anisotropic reactivity of the noncentrosymmetric CdSe/CdS core/shell nanorods. [203] When γFe2 O3 tetrapods were used as seeds, heterogeneous nucleation, and growth of multiple secondary Co components can be selectively accomplished, leading to tetrapodshaped skeleton of iron oxide functionalized with multiple domains of Co. [204] The heterostructurers incorporating FiM and FM components exhibit various unique magnetic properties based on the exchange coupling effects between different domains. Notably, in both cases discussed above, the delayed addition of OA could not only restrict Co growth but also promote the colloidal stability of the obtained heterostructures. Co-decorated TiO2 nanorods were synthesized by thermal decomposition of Co2 (CO)8 under assistance of octanoic acid and OAm, in which heterogeneous Co nucleation in a tip-preferential or a nonselective way could be altered by varying the octanoic acid/OAm concentration. [205] It was suggested that the decrease of surfactant concentration was key to enhance the reactivity of TiO2 , thus TiO2 seeds were chemically accessible for heterogeneous nucleation. Subsequent addition of OA, which possesses strong affinity to both TiO2 and Co surfaces, would quench any further reaction owing to the compact organic shell built by bulky OA around the heterostructures.

2.4

2.4

Chemical synthesis of hollow/porous magnetic NCs

53

Chemical synthesis of hollow/porous magnetic NCs

Over past decades, researchers have focused on hollow/porous magnetic NCs due to their unique structures and related wide applications. [36, 38, 39, 40, 41, 206] Owing to their hollow interior, porous shell and much higher surface to volume ratio compared to the solid counterparts, hollow/porous magnetic NCs exhibit great potentials in catalysis, water purification, and drug delivery. The interior void can serve as a container for encapsulating active and functional materials, such as NCs, drugs, and proteins, which can be sealed for protection or be made accessible to the outside in many biomedical applications. On the other hand, the porous shell can provide active surfaces for attracting molecules and can offer channels for materials transportation. To synthesize various hollow/porous magnetic NCs, several colloidal synthetic methods have been developed, including the Kirkendall effect, chemical etching, galvanic replacement, and a template-mediated approach. In this part, we briefly review recent advance in the synthesis of hollow/porous magnetic NCs, including Fe-based and Mn-based NCs. 2.4.1

Fe-based hollow/porous NCs

As one of the most popular Fe-based NCs, iron oxide NCs have been intensively investigated for many years due to their relatively high chemical stability and feasibility to obtain. Hollow/porous iron oxide NCs of Fe3 O4 and Fe2 O3 with controlled cavity dimension, shell thickness, and porosity have been developed recently. Among those synthetic strategies, the template-assisted approach is regarded as the most convenient and versatile procedure for the synthesis of hollow nanostructures. To synthesize the hollow nanocapsules of iron oxide with porous shells, a wrap-bakepeel process involving SiO2 -templated growth was applied. [42] The spindle-shaped akagenite (β-FeOOH) nanorods were coated with silica, followed by a heat treatment and silica removal. Since significant volume change occurred when a loose akagenite structure changed to a dense haematite phase, iron oxide was able to become hollow/porous structure. Similarly, the magnetite Fe3 O4 nanocapsules could also be obtained by a simple additional treatment of the hematite/silica nanocomposite at 500 ◦ C under H2 atmosphere. The prepared hematite and magnetite nanocapsules showed typical characteristics of paramagnetism and superparamagnetism, respectively. By using carbon NCs as the template, hollow hematite NCs could also be synthesized via sonochemical method. [207] As the starting materials, Fe/carbon nanocomposites transferred into hollow α-Fe2 O3 NCs upon exposure to air. In the procedure, the iron shell on the carbon NCs was oxidized while auto-ignition of carbon conducted at the same time, leaving the final hollow oxide nanostructures.

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Organic micelles have been also utilized as the template to prepare akagenite (βFeOOH) nanotubes. [208] The uniform hollow nanostructures were achieved when reacting hydrazine with Fe–oleate complex in reverse micelles formed by OA, xylene, and water. Alternatively, the Kirkendall effect can also be utilized to create hollow/porous nanostructures. In 2004, Alivisatos and his co-workers reported the preparation of hollow CoS (CoO) by sulfidation (oxidation) of Co NCs exploiting the Kirkendall effect at the nanometer scale. [206] During the reaction, the outward element diffusion was faster than the inward diffusion, and consequently the void at the center formed. By similar strategy, monodisperse hollow Fe3 O4 NCs can be obtained via solution phase synthesis. [209] The amorphous Fe/Fe3 O4 core/shell NCs were made by thermal decomposition of iron pentacarbonyl, Fe(CO)5 in the presence of OAm and subsequent air oxidation. The controlled oxidation was realized in the presence of oxygen transfer reagent, trimethylamine-N-oxide, Me3 NO. It was observed that in the middle of the reaction process, multiple voids were formed in the particle. During the reaction, the solid NCs were transformed into the core/shell/void, the yolk/shell, and, finally, the hollow structures, which was dominated by the Kirkendall effect. It was revealed that the initial Fe/Fe3 O4 core/shell NCs were essential to create unbalanced interfacial diffusion between oxygen and Fe atoms during the oxidation process, thus resulting in final hollow structures. When the obtained hollow NCs were treated at high temperature, the Fe3 O4 domain in the shell grew into larger crystallites, leading to the change of the crystal boundaries and formation of the porous shell (Fig. 2.12). [210] Since the boundary area was more reactive to be etched away, the pore size could be further controlled readily by acid etching. Through similar controlled oxidation process, colloidal solutions of monodisperse iron/iron oxide core–void–shell nanostructures and hollow maghemite NCs with controllable particle size and shell thickness could be produced under an oxygen atmosphere. [211] Etching is also regarded as one effective approach to prepare hollow/porous nanocrystals. The Hyeon group reported a reproducible and general etching method to synthesize series of hollow oxide NCs with various sizes, shapes, and compositions. [212] The hollow iron oxide of Fe3 O4 and α-Fe2 O3 NCs could be obtained by simply heating initial solid NCs in technical grade TOPO at 300 ℃ for hours. The control experiments revealed that alkylphosphonic acid impurity in TOPO contributed to the diffusion of phosphorus and iron cations in the etching process, which dominated the formation of hollow structures. Besides the hollow/porous iron oxide NCs, other kinds of Fe-based hollow/porous NCs were also reported. The Hyeon group reported the synthesis of a hollow iron nanoframe from the thermal decomposition of the Fe(II)–stearate complex in the

2.4

Chemical synthesis of hollow/porous magnetic NCs

55

presence of sodium oleate and OA. [213] The thermal decomposition of iron salts in the organic solution was generally utilized to synthesize dispersible iron oxide NCs with controlled size, shape, and composition. However, in their process, it was believed that the sodium oleate played an important role in the formation of iron nanoframe due to the fact that sodium molten salt derived from sodium oleate could cause severe corrosion of metallic materials at high temperature. Star-shaped iron nanoframes could also be obtained by decreasing the heating rate. When exposed to air, those iron nanoframes with different structures can be readily transferred to iron oxide nanoframes. Zhao et al. successfully achieved monodisperse iron phosphate nanospheres with nanoporous structure through a solvent extraction route using an acid-base-coupled extractant. [214] The established reverse micelles with micro waterpools inside acted as nanoreactors, which can prevent the particles from aggregation. The novel nanoporous structure of the iron phosphate nanospheres is ascribed to the subsequent extractant removal from the nanospheres by organic solvents like acetone or ethanol.

Fig. 2.12

(a) TEM and (c) HRTEM images of the 16-nm Fe3 O4 hollow NCs. (b) TEM

and (d) HRTEM images of the 16-nm Fe3 O4 hollow/porous NCs. Reproduced with permission from Ref. [210]. Copyright 2009 American Chemical Society.

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2.4.2

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Chemical Synthesis of Magnetic Nanocrystals: Recent Progress

Mn-based hollow/porous NCs

Hollow/porous Mn-based NCs also have important applications in the field of medical diagnosis and therapy. The approach based on etching or Kirkendall effect to hollow/porous Fe-based NCs can be extended to the synthesis of Mn-based NCs. Based on the etching process, An et al. fabricated uniform hollow spherical and dumbbell-shaped MnO NCs in the presence of TOPO and alkylphosphonic acid. [212] It was revealed that the impurities in technical grade TOPO, especially alkylphosphonicacid, played important roles in controlling the etching process dominating the formation of hollow structures. The possible mechanism was suggested to be the opposite diffusion of phosphorus and metal cations within the NCs accompanied by Kirkendall effect. Shin et al. developed hollow manganese oxide NCs as multifunctional agents for simultaneous MRI and drug delivery. [215] Manganese oxide NCs with a diameter of 20 nm stabilized by OA were initially prepared, and then were transformed to water by encapsulated with poly(ethylene glycol) phospholipid. Afterwards, phthalate buffer solution at pH 4.6 was used to create the hollow interior of the NCs by selective etching of the core MnO phase from the NCs. By varying the duration of immersion of the solid manganese oxide NCs in water before the acid treatment, the interior shape of the hollow NCs could be changed. Immersion for one day afforded an interior cavity with roughly spherical shape and a diameter of 12 nm, while immersion for 10 ∼ 40 days yielded two or three irregularly shaped cavities having average diameters of 8 nm–5 nm within a particle. Similarly, Kim et al. obtained silica-coated hollow MnO NCs via an etching process in the mild hydrochloric acid solution (4%) (pH≈2.4). [216] Alternatively, Peng et al. employed a facile method to prepare hollow manganese oxide NCs, wherein the hollow structure was formed by the extrusion of the core MnO via Kirkendall effect with the aid of carboxylate anion. [217] Recently, Hao et al. demonstrated a general strategy to prepare various kinds of hollow/porous Mn-based NCs via directional ion transfer across different solid–liquid interfaces in a one-pot solvothermal process. [218] In a typical procedure, hollow Mn oxide, hollow Mn phosphate, and porous Mn phosphate could be obtained by the reaction of water, Mn(acac)2 , and triethyl phosphate under solvothermal conditions in the presence of OA and OAm. It was found that surfactant (OA and OAm) ratios were essential for the void structure and composition of the hollow/porous NCs, and as a result, hollow Mn oxide NCs were formed without OA, while hollow Mn phosphate and porous Mn phosphate NCs were yielded by increasing the amount of OA. Interestingly, these Mn-based porous/hollow NCs can act as effective multifunctional probes for selective diagnosis with MRI, as well as giving efficient targeted

2.5

Summary and perspectives

57

drug delivery. [219]

2.5

Summary and perspectives

Research into colloidal chemical synthesis of magnetic NCs has made substantial progress over the past decades. The size, shape, and composition of magnetic NCs can be effectively controlled through the judicious selection of precursor, solvent, and capping agent. Additionally, size monodispersity, which is critical for many technologically important applications, can also be successfully realized through solution-phase methods. Among those single-component magnetic NCs, metal oxides, especially iron oxide, have attracted the most attention for their wide application potential. For example, size-, crystallinity-, uniformity-controlled iron oxide NCs can be prepared via colloidal chemical synthesis to meet the requirements of diverse biomedical applications. Owing to the superior biocompatibility, iron oxide NC-based MR contrast agents have already been used in clinical trials, or are undergoing clinical trials. Multi-component magnetic NCs with different levels of complexity have also received many investigations recently. Solution-phase method can be utilized as an efficient tool to construct the architectures for designed functionality and performance by purposefully choosing the seeds, and artificially controlling the secondary growth process. The interactions between the joint domains can also bring various interesting chemical–physical phenomena, resulting in unprecedented properties. Furthermore, chemical synthesis of hollow/porous magnetic NCs is highlighted in this review. Based on strategies including the Kirkendall effect, chemical etching, galvanic replacement, and template-mediated approach, various types of Fe-based and Mn-based ones can be successfully prepared. The fine control of the size, uniformity, void and pore structure, and shell thickness help hollow/porous NCs to be suitable as multimodal nanoprobe/carriers for both drug delivery and bioimaging. However, synthesis of high-quality magnetic NCs practically still remains a challenge. A large scale synthesis of magnetic NCs via green chemistry process is highly demanded. Additionally, extensive studies are needed to maintain the stability of the NCs for a long time without agglomeration or precipitation. For magnetic NCs that are sensitive to air or water, such as metallic Fe, Co, Ni NCs, it is necessary to develop efficient strategies to improve their chemical stability and make the best of their magnetic properties. Nanosized magnetic metal carbides are promising due to their good air stability with high magnetization. Unfortunately, there is no reliable method to control the phase, size, and uniformity of carbide NCs. In the complex HNCs systems, it yet remains a challenge to synthesize elaborate HNCs incorpo-

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rating nonhomologous and/or structurally uncorrelated materials, and understand the compositional, structural, and topological evolution of nanoheterostructures in detail. Moreover, in the reported synthesis of hollow/porous magnetic NCs, understanding of the mechanism in the structural formation, as well as the characterization techniques, needs to be improved. In the future, the development of the chemical synthesis of magnetic NCs with controlled size, shape, composition, and topology will deliver exciting opportunities in practical exploitation of various magnetic nanomaterials. We expect that magnetic NCs will keep occupying important positions in biomedical, catalytic, and magnetic fields.

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Chapter 3 Magnetic Iron Oxide Nanoparticles: Synthesis and Surface Coating Techniques for Biomedical Applications∗ Shengnan Suna) ,

Chao Weia) , Zanzan Zhub) ,

Yanglong Houc) ,

Subbu S Venkatramana)† ,

and Zhichuan Xua)‡ a)

School of Materials and Science Engineering, Nanyang Technological

University, Singapore 639798, Singapore b)

Department of Chemical Engineering, Worcester Polytechnic Institute,

Worcester, MA 01609, United States c)

Department of Materials Science and Engineering, College of Engineer-

ing, Peking University, Beijing 100871, China † Corresponding author. E-mail: [email protected] ‡ Corresponding author. E-mail: [email protected] Iron oxide nanoparticles are the most popular magnetic nanoparticles used in biomedical applications due to their low cost, low toxicity, and unique magnetic property. Magnetic iron oxide nanoparticles, including magnetite (Fe3 O4 ) and maghemite (γ-Fe2 O3 ), usually exhibit a superparamagnetic property as their size goes smaller than 20 nm, which are often denoted as superparamagnetic iron oxide nanoparticles (SPIONs) and utilized for drug delivery, diagnosis, therapy, and etc. This review article gives a brief introduction on ∗ Project supported by Start-up Grant of Nanyang Technological University and Tier 1 Grant of Ministry of Education, Singapore (RGT8/13).

3.1

Introduction

69

magnetic iron oxide nanoparticles in terms of their fundamentals of magnetism, magnetic resonance imaging (MRI), and drug delivery, as well as the synthesis approaches, surface coating, and application examples from recent key literatures. Because the quality and surface chemistry play important roles in biomedical applications, our review focuses on the synthesis approaches and surface modifications of iron oxide nanoparticles. We aim to provide a detailed introduction to readers who are new to this field, helping them to choose suitable synthesis methods and to optimize the surface chemistry of iron oxide nanoparticles for their interests.

3.1

Introduction

Iron oxide nanomaterials have attracted great attention from many research fields. They have been found highly applicable and versatile in lithium ion batteries, [1] supercapacitors, [2] catalysis, [3] tissue-specific releasing of therapeutic agents, [4] labeling and sorting of cells, [5] as well as the separation of biochemical products. [6, 7] Due to their superparamagnetic property and low toxicity, magnetic iron oxide (Fe3 O4 and γ-Fe2 O3 ) nanoparticles are especially interesting to biomedical applications, such as diagnostic magnetic resonance imaging (MRI), [8] thermal therapy, [9, 10] and drug delivery. [8, 11] For these applications, Fe3 O4 and γ-Fe2 O3 nanoparticles are usually smaller than 20 nm, where they exhibit superparamagnetic properties, i.e. a high magnetic saturation moment and nearly zero coercivity at room temperature. The external magnetic field can readily induce magnetic iron oxide nanoparticles towards magnetic resonance, self-heating, and also moving along the field attraction. These behaviors actually highly depend on the quality of the iron oxide nanoparticles, such as crystallization, size, and shape. this indicates the importance of synthesis approaches of iron oxide nanoparticles, i.e. the synthesis approaches that can produce well-crystallized and size-controlled iron oxide nanoparticles that offer more opportunities for these applications. On the other hand, after synthesis, iron oxide nanoparticles need surface modification to make them more compatible in bio-systems for molecular conjugation and functionalization. They also often suffer from chemical corrosion-induced instability. Therefore, the surface modification is a critical post-synthesis step for making iron oxide nanoparticles bio-compatible and stable. Some modifications also introduced additional chemical and/or physical properties onto iron oxide nanoparticles. In this review, we will focus on the synthesis approaches and surface modification techniques of magnetic iron oxide nanoparticles. A detailed comparison of the available physical and chemical syn-

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Magnetic Iron Oxide Nanoparticles: Synthesis and Surface Coating · · ·

thesis methods is given, aiming to help readers who are new to this field to choose appropriate suitable synthesis methods for their research interests. Surface modification with inorganic and organic coatings is presented. The advantages of surface modification are demonstrated with several MRI and drug delivery examples. In addition, we also give a brief introduction on crystal structure of Fe3 O4 and γ-Fe2 O3 , size-dependent magnetism, and the working principles of magnetic nanoparticles in MRI.

3.2

Fe3 O4 and γ-Fe2 O3

For Fe3 O4 and γ-Fe2 O3 , the electron configuration of the Fe3+ ion is 1s2 2s2 2p6 3s2 3p6 3d5 and Fe2+ ion is 1s2 2s2 2p6 3s2 3p6 3d6 . It is the Fe 3d electrons that determine the electronic, magnetic and some spectroscopic properties. In the ground state Fe3+ has five unpaired electrons and Fe2+ has two paired and four unpaired electrons. Magnetite, Fe3 O4 , is a ferrimagnetic oxide with a high Curie temperature (TC = 858 K). It is in an inverse spinel structure with a face-centered cubic (fcc) unit cell (unit cell length a = 0.839 nm) based on 32 O2− ions regularly cubic close packed along the [111] direction. There are eight formula units per unit cell. Fe3 O4 chemically contains both Fe2+ and Fe3+ . The structure consists of octahedral and mixed tetrahedral/octahedral layers stacked along [111]. The formula can be written as Fe3+ (A)[Fe2+ Fe3+ ](B)O4 . A is the tetrahedral site which is occupied by Fe3+ ions surrounded by four O atoms, while B is the octahedral site which is a mixture of Fe2+ /Fe3+ ions surrounded by six O atoms. Thus, Fe3+ occupies both tetrahedral and octahedral sites. [12, 13] Fe atoms in A and B sites are coupled antiferromagnetically and the Fe2+ ions in B site contribute to macroscopic ferromagnetic properties. [14] As shown in Fig. 3.1, the magnetic properties of Fe3 O4 are ascribed to the splitting of the 5d orbitals. The 5d orbitals are split into two subsets due to the oxide ligands and all Fe3+ and Fe2+ ions have four unpaired electrons, respectively. As can be seen, in the octahedral site, Fe3+ and Fe2+ ions are coupled ferromagnetically through a double exchange mechanism. The electron with the spin directing in the opposite direction of the others (in red), can be exchanged between two octahedral coordination sites. On the other hand, the Fe3+ ions in tetrahedral and octahedral sites are coupled antiferromagnetically via the oxygen, implying that the Fe3+ spins cancel out each other and thus merely unpaired spins of Fe2+ in octahedral coordination contribute to the magnetization. Fast electron hopping between the Fe3+ and Fe2+ ions at the B sites can lead to the Fe3 O4 conductivity. [15] The Fe3 O4 can be treated as half metal: a full spin polarization coming from the negative electron spin polarization at the Fermi level. [16, 17] Maghemite, (magnetitehematite), γ-Fe2 O3 , is also a ferrimagnetic oxide, whose structure (a = 0.834 nm)

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is similar to that of magnetite. [18] The difference between γ-Fe2 O3 and Fe3 O4 lies in all or most of Fe in γ-Fe2 O3 is in the Fe3+ state and the oxidation of Fe2+ is compensated by cation vacancies. The unit cell contains 32 O2− ions, 64/3 Fe3+ ions and 7/3 vacancies. Each cation occupies the tetrahedral site and the remaining cations are randomly distributed among the octahedral sites. The vacancies are usually confined to the octahedral sites.

Fig. 3.1

(a) Crystal structure of Fe3 O4 , where green atoms are Fe2+ , brown atoms are

Fe3+ , and white atoms are O. [18] (b) The electron, colored red, whose spin directs in the opposite direction of the others, can be exchanged between two octahedral coordination.

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Size-induced magnetism evolution and application mechanisms

For all materials, the magnetism can be divided into five groups: diamagnetism, paramagnetism, ferromagnetism, antiferromagnetism, and ferrimagnetism. Diamagnetism is a basic property of all substances and it is a tendency to oppose an applied magnetic field. The magnetic susceptibility of a diamagnetic substance is small (−10−6 ), negative and independent of temperature. The diamagnetic material has no unpaired electrons, and the paired electrons have opposite spin directions, so the magnetic moment will be offset. Paramagnetic substances have unpaired electrons whose spins have random magnetic moment directions. When applying a magnetic field, the spins will make themselves align to the applied magnetic field direction. The magnetic susceptibility is positive and small (0 to 0.01). It varies with temperature and its behavior is described by the Curie–Weiss law. [19] Ferromagnetic substances also have unpaired electrons, and they can also make their magnetic moments align to the applied magnetic field. The difference between paramagnetic and ferromagnetic substances lies in the magnetic moment of ferromagnetic substances that will remain the lowered-energy state and parallel to each other, and this state can remain even though the applied magnetic field is removed. An antiferromagnet has a zero net moment because of the intrinsic magnetic moments of neighboring valence electrons having opposite directions. A ferrimagnet has two characteristics 1) it can keep its magnetic moment without external magnetic field; and 2) neighboring pairs of electron spins point in opposite directions with a dominance of magnetic moments in one direction. The detailed magnetism classification can be found in the literature. [20] Bulk Fe3 O4 and γ-Fe2 O3 are ferrimagnetic. They were classified as ferromagnetic materials a long time ago, before N´eel’s discovery of ferrimagnetism and antiferromagnetism in 1948. [21] The research in nanosized magnetic materials has found that the magnetism of materials is highly size-dependent. [22, 23] The general rule is that as the size of ferromagnetic crystals is sufficiently small, they will be like a single magnetic spin, which has a larger response to the applied magnetic field. Below such a size, the substances display the superparamagnetic property. Nanosized Fe3 O4 and γ-Fe2 O3 smaller than 20 nm are often considered in the range of a single domain and exhibit a superparamagnetic property. In the single-domain region, the coercivity decreases with the decrease of the particle size when the size is bigger than Dp (the superparamagnetic critical size). The coercivity will become zero when the particle size is smaller than Dp , which can be attributed to the randomization caused by thermal energy. There is a maximum coercivity that exists at the transition from multi-domains to a single-domain. In the multi-domain re-

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gion, domain wall motion determines the magnetic property, and coercivity decreases when the overall size increases. When the nanoparticles are extremely small, the magnetic moment of nanoparticles is very small, and the magnetization will have a linear relationship with the magnetic field. [24] A high magnetic field will saturate the magnetization. Because of the fluctuation of magnetic moment caused by thermal energy, superparamagnetic nanoparticles do not present any remanence and coercivity.[24−27] A major application of superparamagnetic iron oxide nanoparticles is magnetic resonance imaging (MRI). MRI is a medical imaging technique using a strong magnetic field and radio waves for body diagnosis. Because the human body is largely composed of water molecules containing protons, when the body is placed in the MRI scanner, the magnetic moments of protons will align to the applied magnetic field direction. If a radio frequency (RF) electromagnetic field is applied, proton magnetic moments will change. As this RF electromagnetic field is turned off, the magnetic moments will return to their original state. Most MRI applications rely on detecting a radio frequency signal emitted by excited protons. Since the time or rate of the protons in different tissues return to their equilibrium state after the microwave is removed are different, the diseased tissue can be detected. When the RF electromagnetic field is switched off, the flipped nuclear spins tend to return to a low energy state along the applied magnetic field and thus there will appear two independent processes: the spin-lattice relaxation T1 process and the spinspin relaxation T2 process. They can be used to demonstrate different anatomical pathologies. In the T1 process, the magnetic moments will recover to the low energy state: aligned to the applied magnetic field direction, while in the T2 process, the magnetic moments will decay in the xy-plane perpendicular to the applied magnetic field direction. Thus, the image signal from the T1 process will be brighter because the magnetic moments in the applied magnetic field direction increase, while the image signal from T2 will be darker. In order to accelerate T1 and T2 processes and further increase the contrast, contrast agents are desired to accelerate the relaxation. The contract enhancement can be measured by relaxation rate R = 1/T (s−1 ) and relaxivity r = R/concentration (mM−1 ·s−1 ). If a higher relaxivity is obtained, an enhancement on contrast will be observed. Gd3+ -complexes often serve as the T1 contrast agent, [28, 29] and magnetic nanoparticles (MNPs) are often used as the T2 contrast agent. The contrast effects are determined by (Ms V )2 and d−6 , where Ms is the saturation magnetization, V is the volume of nanoparticles, and d is the distance from the MNP surface to the protons. Therefore, the magnetic nanoparticles with a high Ms , uniform size, and thin surface coating layer will be able to give a shaper contrast. [28, 30, 31] The synthesis and surface modification of magnetic nanoparticles for MRI purposes should follow this rule to reach a higher detection sensitivity.

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In addition, because superparamagnetic iron oxide nanoparticles can be imaged in MRI and also be moved under an applied external magnet, they have great potential to be the carriers of drug molecules for targeted drug delivery. Ideally, the targeted drug delivery [32] technique delivers the medicine directly to the disease parts of a patient. It can increase the local medicine concentration and reduce the dosage intake by the patient. As a result, the usage of the drug can be more efficient with lower side-effects and fluctuation in circulating drug levels. Magnetic nanoparticles can be followed using MRI so that the transportation of the drug with magnetic carriers can also be tracked or guided. [33] Magnetic nanoparticles for drug delivery should not only meet the criteria of an MRI contrast agent, but also need carrying sites for the drug. Because of the limited space on the nanoparticle surface for both targeting agent and drug, surface coating/modification is a major approach for creating loading sites for carrying drugs. [34]

3.4 3.4.1

Synthesis approaches Physical vapor deposition (PVD)

Physical vapor deposition is a vacuum deposition method used to deposit thin films by the condensation of a vaporized form of the desired material on the substrates. It is purely physical processes such as high-temperature vacuum evaporation with subsequent condensation, or plasma sputter bombardment rather than a chemical reaction at the surface as chemical vapor deposition (CVD). Many research groups report to prepare iron oxides using PVD. Various PVD methods such as pulsed laser deposition (PLD), [35, 36] reactive molecular beam epitaxy (MBE) [37] and sputtering [38, 39] have conventionally been used to grow these spinel ferrites. For example, Boho et al. utilized the facing target sputter technique to make Fe3 O4 epitaxial growth on MgO single crystal substrates. [40] Pandya et al. deposited Fe3 O4 nanoparticle film on Si(100) using pulsed DC sputtering under the assistance of an electric field. [41] Since γ-Fe2 O3 has almost the same lattice parameters as Fe3 O4 , XRD cannot distinguish the phase between Fe3 O4 and γ-Fe2 O3 alone. Some researchers used Raman spectra and M¨ossbauer spectroscopy to ensure the phase purity. [41] You et al. reported the preparation of iron/iron oxide core-shell nanoclusters via nanocluster deposition system, which employed a combination of magnetron sputtering and gas-aggregation techniques. The iron nanoparticles were prepared by passivating the Fe surface with MgO in order to retain the high magnetic moments of Fe. [38] However, the method of growing γ-Fe2 O3 nanoparticle films has been limited to reactive MBE and facing target sputtering. [39] Most recently, Yanagihara et al. prepared Fe3 O4 and γ-Fe2 O3 on single crystal MgO (001) using reactive sputtering. When the total gas pressure was 0.5 Pa, and the Ar flow rate was 30 sccm, changing

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the O2 flow rate can be used to choose to grow Fe3 O4 or γ-Fe2 O3 . When the O2 flow rate is controlled between 0.2 sccm to 0.5 sccm, the product is Fe3 O4 ; when the O2 flow rate is bigger than 0.7 sccm, the product is γ-Fe2 O3 . [39] 3.4.2

Chemical vapor deposition (CVD)

Chemical vapor deposition was also reported for synthesizing Fe3 O4 nanoparticles by some groups, but the reports are relatively rare. Rochel et al. used CVD to prepare carbon-coated Fe3 O4 particles by the reduction of Fe2 O3 in methane and nitrogen. [42] The carbon coating is commonly used because of its biocompatibility and chemical stability. [42] Recently, Mantovan et al. synthesized Fe3 O4 thin film via CVD using Fe(C6 H8 )(CO)3 as a precursor. [43] The method improved the stoichiometry degree as compared with carbonyl precursors. [43, 44, 45] The thickness of Fe3 O4 can be controlled by varying CVD pulses. Because of the limitation of approach, both PVD and CVD have been found to not be suitable for producing iron oxide in the nanoparticle form. Even some reports with nanoparticle formation, the postsynthesis treatments, such as scratching powders from substrates and dispersing in solvent by sonication or surface modification, have to be used. These shortcomings limit their biomedical applications in a wet-chemical environment.

3.4.3

Electrodeposition

Similar to vapor deposition, electrodeposition also involves the deposition of precursors onto a substrate to form nanostructures. But the electrodeposition usually can be conducted under room temperature with dissolved Fe2+ or Fe3+ ions as precursors. It is promising to prepare large-scale iron oxide nanomaterials. [46, 47, 48, 49, 50] Evidence from the literature suggests that, in general, changes in deposition potential and electrolyte composition can significantly affect film formation, including crystallinity, grain size, and orientation. [47] Carlier et al. prepared Fe3 O4 by anodic oxidation of Fe2+ at 80 ℃ under N2 atmosphere, and used KCH3 COO and (NH4 )2 Fe(SO4 )·6H2 O as precursors. The gold-coated polycarbonate membrane served as templates. [51] Poduska et al. used the same precursor to prepare Fe3 O4 on metal substrates (Fig. 3.2). The magnetic hysteresis response of Fe3 O4 film can be tuned by changing the applied potential and electrolyte composition. [47] In addition, they found that acetate played an important role in controlling the ratios of Fe3 O4 and γ-Fe2 O3 . At a higher concentration of acetate in the electrolyte, pure Fe3 O4 can be produced.

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Fig. 3.2

Magnetic Iron Oxide Nanoparticles: Synthesis and Surface Coating · · ·

(a) Applied deposition potential vs. time for a sample prepared

galvanostatically at 50 µA/cm2 . Within the first 15 s of deposition, the applied potential stabilizes to a potential at which magnetite is electrodeposited, and no significant variation in potential is observed over 15–90 min of deposition. (b) Scanning electron micrographs show that rounded, columnar crystallites appear in deposits synthesized potentiostatically, in this case at −0.425 V vs. Ag/AgCl reference electrode (Fisher Scientific), from electrolytes with higher acetate concentrations. [47]

3.4.4

Hydrothermal synthesis

Hydrothermal synthesis is one of the most popular wet chemical approaches for synthesis of inorganic nanocrystals, especially for metals and metal oxides. [52, 53] This method often employs a relatively high temperature and a high pressure to induce or affect the formation of nanocrystals. The solubility of reactants and desired products under such a condition is critical. Hydrothermal synthesis has various advantages such as high reactivity of the reactants, facile control of product morphology, and good crystallization of products. In addition, some metastable and unique condensed phases can also be produced under a high pressure condition. Magnetic nanoparticles, [54] nanospheres, [52] nanosheets, [55] nanoplates, [56, 57] nanorods, [58, 59] nanocubes, [60] nanorings, [61] nanowires, [62] etc. have been successfully synthesized

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by the hydrothermal synthetic method. [63] Chen et al. prepared quasi-sphere polyhedron nanoscystalline Fe3 O4 nanoparticles with an average of 50 nm by the hydrothermal method. They employed Na2 S2 O3 as the phase control agent. The ratio of Na2 SO3 /FeSO4 determined whether the Fe3 O4 phase can be produced. [64] Date et al. prepared spherical Fe3 O4 with a size range of 150–200 nm using microwave hydrothermal reaction in 90–200 ℃. The FeSO4 ·7H2 O and FeCl3 served as precursors and NaOH was used as the hydrolysis reactant. It was found that Fe/NaOH was a critical parameter to control Fe3 O4 formation. As compared with other hydrothermal methods, the microwave facilitates the kinetics of reaction. [65] Different from reducing the Fe3+ precursor, Chen et al. prepared Fe3 O4 nanopowders via a hydrothermal process using Fe2+ precursor (FeCl2 ·4H2 O). They used a mixture of NaOH and N2 H4 to react with FeCl2 . N2 H4 is believed to act as an oxidant to partially oxidize Fe2+ to Fe3+ . [66] Zheng et al. reported the synthesis of octahedrallike Fe3 O4 nanoparticles using an EDTA-assisted reaction in mild condition. The starting reactants are FeCl3 , H2 H4 ·H2 O and NaOH and EDTA. The EDTA acted as a surfactant and assisted the shape control. [54] Polyvinylpyrrolidone (PVP) was also used as a surfactant in the hydrothermal method. It was reported that by mixing FeCl3 , FeSO4 ·7H2 O, NaOH with PVP and benzene, the shape of the Fe3 O4 nanoparticles can be controlled. By varying experimental conditions and the amount of PVP, different morphologies of Fe3 O4 can be obtained, such as nanoparticles, nanowires, bundles, and nanorods. [67] A further study revealed that hexagonal, dodecahedral, truncated octahedral and octahedral shapes can also be synthesized by modifying this method. The modification on the recipe was mainly made on the surfactant and precipitation agent selection. L-arginine and CTAB were used as the precipitation agent and surfactant, respectively. [68] Another similar modification was reported by Gai et al. They used FeSO4 ·7H2 O, polyethylene glycol (PEG), NaOH, and KNO3 to synthesize octahedral Fe3 O4 with the size of 200–300 nm. It was found that the ratio of PEG and NaOH was important to the formation of octahedral Fe3 O4 nanoparticles (Fig. 3.3). If a higher concentration of NaOH was employed, PEG would prefer to adsorb on the (111) plane of Fe3 O4 and decrease the growing rate along the [111] axis. [69]

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Fig. 3.3

Magnetic Iron Oxide Nanoparticles: Synthesis and Surface Coating · · ·

SEM images of the Fe3 O4 samples prepared (a) with and (b) without PEG-6000. [69]

3.4.5

Co-precipitation

Co-precipitation is widely used in the aqueous phase synthesis of Fe3 O4 nanoparticles. [70] In general, the method employs an alkaline solution, such as NaOH and NH3 ·H2 O, to precipitate Fe2+ and Fe3+ ions in an aqueous solution. The Fe3 O4 nanoparticles were produced by dehydration from the intermediate iron hydroxides. The surfaces of so-produced iron oxide nanoparticles are rich in OH group and the nanoparticles can be suspended well in an aqueous solution. [71, 72, 73] Refait and Olowe found another formation mechanism that Fe(OH)2 can also serve as an intermediate for Fe3 O4 formation. The mechanism includes the precipitation of Fe2+ by alkaline, the oxidation of Fe(OH)2 by O2 in air to FeOOH, and the combination of Fe(OH)2 and FeOOH to form Fe3 O4 . [74, 75, 76] It indicated that if only Fe2+ was used as the precursor, the co-precipitation method under air could still produce Fe3 O4 nanoparticles and thus there was potentially no need to involve Fe3+ as precursors. Gao et al. used C6 H5 Na3 O7 ·2H2 O, NaOH, NaNO3 , FeSO4 ·4H2 O in an aqueous solution to prepare Fe3 O4 nanoparticles on the gram scale. The diameter range of Fe3 O4 nanoparticles can be tuned from ∼20 nm to 40 nm (Fig. 3.4) by changing the experimental parameters. The citrate ions served as the surfactant, which capped on the surface of Fe3 O4 nanoparticles and prevented them from aggregation by the repulsive force between radical ions. [76] In 2012, Mo et al. prepared Fe3 O4 by injecting NH3 ·H2 O into the Fe3+ and Fe2+ aqueous solution under ultrasonic conditions. [77] Ahmad et al. prepared Fe3 O4 on the exterior surface layer of talc mineral by coprecipitation of FeCl2 and FeCl3 in NaOH aqueous solution. [78] In 2012, Xia et al. reported a novel complex-coprecipitation method to synthesize Fe3 O4 nanoparticles. They used triethanolamine [N(CH2 CH2 OH)3 , TEA] as ligands to govern the quality of the Fe3 O4 nanoparticles. The readily available and cost-effective iron precursors, Fe2 (SO4 )3 and FeSO4 , were used to synthesize the TEA-coated Fe3 O4 nanocrystals. TEA played a role in limiting the Fe3 O4 growing rate due to its chelation to Fe3+

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and Fe2+ . Additionally, TEA can prevent the Fe3 O4 from agglomeration due to the TEA molecules being rooted in the colloid particles. [79] Co-precipitation was also reported for the shape control of Fe3 O4 nanoparticles. Yan et al. reported the synthesis of Fe3 O4 nanowires through NaAc-assisted co-precipitation in an aqueous solution with FeSO4 ·7H2 O, NaAc, and NaOH. The morphology could be controlled by altering the concentration of NaAc. [80] However, because of a polarized environment, the weak bonding between capping agents and the iron oxide surface was often interrupted by the hydrogen bond interactions between the iron oxide surface and the water solvent. It resulted in a limited control over the size and shape in co-precipitation approach.

Fig. 3.4

(a)–(c) TEM images and size distributions of Fe3 O4 nanoparticles synthesized

by co-precipitation in the presence of sodium citrate with the different mean diameters of 20 nm ((a), σ = 16%), 25 nm ((b), σ = 19%), and 40 nm ((c), σ = 10%). (d) As-synthesized hydrophilic Fe3 O4 nanoparticles in powder form. (e) Fe3 O4 nanoparticles dispersed in water, which can be attracted by a magnet. [76]

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3.4.6

Magnetic Iron Oxide Nanoparticles: Synthesis and Surface Coating · · ·

High-temperature (thermal) decomposition of organometallic precursors

As stated above, for the co-precipitation route, it is difficult to optimize the size and size distribution of nanoparticles. It is also difficult to achieve high crystallinity or control the particle shape. This is because most co-precipitation reactions occur at low temperature and their chemical reaction kinetics can only be controlled by rate of adding reactants. It results in limited control over nucleation and growth. The lack of capping agent also results in the difficulty of size control. In addition, the crystallization is usually improved by temperature. The synthesis temperature of co-precipitation in aqueous solution is limited by the low boiling point of aqueous solution and thus so-produced iron oxide nanoparticles are in low crystallization. Thus, it is desirable to develop some high temperature synthesis approaches to prepare high quality Fe3 O4 nanoparticles. [79] In recent years, thermal decomposition of organometallic precursors, such as Fe(acac)3 and Fe-oleate, has been found to be one of the best approaches to produce magnetic iron oxide nanoparticles for biomedical applications. [28, 81, 82] The iron oxide nanoparticles produced by this method are usually well-controlled in size and shape. Due to the high temperature, nanoparticles are also well crystallized with a high saturation moment. The first report using thermal decomposition of Fe(acac)3 was made by Sun et al. in 2002. [15] The method involved the thermal decomposition of Fe(acac)3 in the presence of surfactants, oleylamine and oleic acid. To partially reduce Fe3+ to Fe2+ , a reducing agent 1,2-hexadecanediol was also used. To achieve the high temperature, organic solvents with high boiling point (> 250 ℃ ) of phenyl ether or benzyl ether were used. The method produced Fe3 O4 nanoparticles confirmed by XRD and M¨ossbauer spectroscopy. The size could be controlled between 4–16 nm (Fig. 3.5) and the size of nanoparticles was uniform. By a thermal treatment in O2 , Fe3 O4 nanoparticles could be converted to γ-Fe2 O3 . [15] This thermal decomposition method was further simplified by Xu et al. in 2009. It was found that oleylamine could serve as the solvent, surfactant, and reducing agent. Therefore, the recipe could be simplified to use two or three chemicals. As illustrated in Fig. 3.6, [83] Fe3 O4 nanoparticles were synthesized by heating a mixture of Fe(acac)3 , oleylamine, and benzyl ether. The decomposition of Fe(acac)3 was found beginning at 250 ℃, where the nucleation of small iron oxide clusters was found by TEM. The complete decomposition occurred at around 300 ℃. The size of so-produced Fe3 O4 nanoparticles could be controlled from 7 nm to 10 nm by varying the volume ratio of benzyl ether and oleylamine. As compared with the early method, the recipe is cost effective. Oleylamine is inexpensive and strong enough as a reducing agent to replace 1,2-hexadecanediol, which is more expensive. [83] In

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addition, the surface of so-produced Fe3 O4 nanoparticles is only capped with oleylamine, which is believed to have a weaker bonding with the nanoparticle surface as compared with oleic acid and thus can be easily replaced by other ligands for surface modification. [84]

Fig. 3.5

(a) TEM image of 16-nm Fe3 O4 nanoparticles synthesized by thermal

decomposition of Fe(acac)3 in the presence of oleic acid and oleylamine. (b) HRTEM image of a single Fe3 O4 nanoparticle. [15]

Fig. 3.6

(a) The modified recipe for synthesizing Fe3 O4 nanoparticles capped only by

oleylamine. TEM images of as-synthesized Fe3 O4 nanoparticles using (b) only oleylamine and (c) a mixture of oleylamine and benzyl either. [83]

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Alternatively, Fe-oleate complex was also reported as the precursor for large scale synthesis of high quality iron oxide nanoparticles. Hyeon et al. reported ultralarge scale synthesis, in which a single reaction could produce 40 g of monodisperse magnetic iron oxide nanocrystals. The method used environmentally friendly iron chloride (FeCl3 ) and sodium oleate to prepare iron-oleate complex precursor, and then iron-oleate, oleic acid and 1-octadecene were mixed and heated up to 320 ℃ to synthesize iron oxide nanoparticles. The nanoparticle size could be controlled by varying reaction time, temperature, as well as the solvents with different boiling points (shown in Fig. 3.7). It was also concluded that the composition of iron oxide nanocrystals was Fe3 O4 and γ-Fe2 O3 , and the Fe3 O4 component gradually increased with the increase of the particle size. [85]

Fig. 3.7

TEM images and HRTEM images of monodisperse iron oxide nanocrystals

synthesized using various solvents with different boiling points: (a) 5 nm; (b) 9 nm; (c) 12 nm; (d) 16 nm; and (e) 22 nm nanocrystals. [85]

Fe(CO)5 can be also used as the precursor for iron oxide nanoparticles. The synthesis usually includes the formation of Fe nanoparticles from Fe(CO)5 and then the oxidation into iron oxide nanoparticles. In 2007, Sun et al. prepared monodisperse hollow Fe3 O4 nanoparticles by carefully controlling the oxidation process of Fe nanoparticles by Fe(CO)5 . [86] Because Fe nanoparticles are not chemically stable, they can be oxidized if exposed to air. The oxidation happens from the surface of Fe nanoparticles and thus the Fe/Fe3 O4 core/shell structure can be obtained. It was found that both Fe and Fe3 O4 were in the amorphous state. Instead of oxidation by air, controlled oxidation could be performed using the oxygen-transfer reagent

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trimethylamine N-oxide (Me3 NO), which resulted in a step-by-step formation of hollow Fe3 O4 nanoparticles (as shown in Fig. 3.8). The controlled oxidation gave hollow Fe3 O4 nanoparticles with polycrystalline Fe3 O4 grains. A major advantage is that the hollow Fe3 O4 nanoparticles are low in mass density and it may facilitate the formation of low-density porous nano-structures by self-assembly or surface functionalization. This method was modified later for the synthesis of Fe3 O4 porous hollow nanoparticles (PHNPs) by modifying the synthesis of Fe/Fe3 O4 nanoparticles. [11] The formation of PHNPS went through three steps. The first step was the synthesis of Fe nanoparticles. 1-octadecene, oleylamine, and Fe(CO)5 was maintained at 180 ℃ for 30 min to produce Fe nanoparticles. The second step was to synthesize Fe3 O4 hollow nanoparticles. It is a controlled oxidation process at different temperatures with different heating times. Fe nanoparticles were added to the mixture solution of 1-octadecene and trimethylamine N-oxide at 130 ℃ under argon gas, and then the solution experienced a series of heating processes to produce hollow Fe3 O4 nanoparticles. Finally, the Fe3 O4 PHNPs were synthesized by adding the hollow Fe3 O4 nanoparticles to the mixture of oleylamine and oleic acid and then being heated and treated at 260 ℃ . The porous shell allowed the capsulation of the cancer chemotherapeutic drug cisplatin for controlled release. The encapsulated cisplatin was protected well from deactivation.

Fig. 3.8

(a) Synthesis of core–shell–void Fe–Fe3 O4 and hollow Fe3 O4 nanoparticles from

Fe–Fe3 O4 nanoparticle seeds. TEM images: (b) 13 nm Fe–Fe3 O4 nanoparticle seeds, (c) 16 nm hollow Fe3 O4 nanoparticles. [86]

Using Fe(CO)5 as the precursor, the method can also be optimized to produce

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ultrasmall Fe3 O4 nanoparticles. The nanoparticles (shown in Fig. 3.9) were synthesized by oxidizing the products from the thermal decomposition of iron pentacarbonyl, Fe(CO)5 . 4-methylcatechol (4-MC) served as the surfactant. Moreover, the 4-MC-coated Fe3 O4 nanoparticles (shown in Fig. 3.23) surface could be directly conjudged with peptide, c(RGDyK), which made the nanoparticles stable in the physiological environment. The diameter of c(RGDyK)-MC-Fe3 O4 nanoparticles is about 8.4 nm. [87]

Fig. 3.9

(a) TEM image of 2.5 nm Fe3 O4 nanoparticles. (b) HRTEM image of 4.5 nm Fe3 O4 nanoparticles. [87]

Recently, Cheng et al. reported the synthesis of monodisperse Fe3 O4 nanoparticles using FeO·OH as the precursor. The size of Fe3 O4 nanoparticles could be controlled from 3 nm to 20 nm. The approach showed a large scale capability with a product mass up to 1.0 g. The synthesis was conducted by mixing FeO·OH, oleic acid, and 1-octadecene and then heating to 315 ℃ for 1 h. The size of so-prepared Fe3 O4 nanoparticles has a non-monotonic change when either decreasing the precursor concentration or increasing the molar ratio of oleic acid to FeO·OH. The phenomenon could be explained as that in the “heating-up” process, the generation of monomers experienced a relatively long time and followed the nucleation and growth of the nanoparticles simultaneously. The “heating-up” process is different from “hot injection”, in which “hot injection”-induced monomer supersaturation contributes to a fast homogeneous nucleation reaction. The homogeneous nucleation reaction is followed by a diffusion-controlled growth process. [88] The thermal decomposition method also offers shape control over iron oxide nanoparticles. In terms of the cubic shaped crystal structure, there are some reports on the synthesis of Fe3 O4 and/or γ-Fe2 O3 nanocubes by thermal decomposition. [25, 89] Hyeon et al. reported the synthesis of Fe3 O4 cubic nanoparticles using Fe(acac)3 as precursor. Fe(acac)3 was mixed with oleic acid and benzyl ether and then heated to 290 ℃ for 30 min. The reaction produced cubic-shaped Fe3 O4 nanoparticles

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with a uniform edge length of about 79 nm (Fig. 3.10(a)). With a reduced amount of benzyl ether, the reaction allowed the morphology evolution from the truncated cubes and truncated octahedra (Fig. 3.10(b)) to a perfect cubic shape (Figs. 3.10(c) and 3.10(d)). According to the HRTEM analysis, it can be concluded that the fast growth along the h111i direction resulted in the formation of nanocubes. The surfaces of the nanocubes were {100} planes. It was found that under high monomer concentration, the anisotropic growth was due to kinetically controlled growth. The size of nanocubes could be controlled by adding additional control agents. As 4biphenylcarboxylic acid and oleic acid were used together, the 22 nm-sized nanocubes could be synthesized (Fig. 3.10(e)). [25]

Fig. 3.10

TEM images of (a) 79-nm-sized Fe3 O4 nanocubes (inset: HRTEM image); (b)

mixture of truncated cubic and truncated octahedral nanoparticles with an average dimension of 110 nm; (c) 150-nm-sized truncated nanocubes; (d) 160-nm-sized nanocubes; (e) 22-nm-sized nanocubes. [25]

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Iron oxide nanocubes can also be produced using other precursors. A recent work found an interesting phenomenon that similar to some synthesis of metal nanocubes, halogen ions such as Cl and Br ions also work for the synthesis of cubic-shaped iron oxide nanoparticles in the thermal decomposition method, which has been reported by Xu et al. [90] Cl ions could contribute to the formation of cubic iron oxide nanocrystals (Fig. 3.11). When Cl ions were lacking, there were only spherical iron oxide nanocrystals. Br ions also had a similar function to control the shape of the iron oxide. The halogens played a role in stabilizing {100} facets of magnetic iron oxides, but not in regulating the thermolysis kinetics or serving as the surfactant. This method provides a new way to control the shape of iron oxide nanoparticles. It also simplifies the organic phase synthesis because the metal chloride can be used directly to replace organometallic powder. So it is economical and environmentally benign.

Fig. 3.11

(a) TEM image of spherical Fe3 O4 nanoparticles synthesized without the

presence of Cl ions. (b) TEM image of cubic Fe3 O4 nanoparticles synthesized in the presence of Cl ions. [90]

Octahedral Fe3 O4 nanoparticles can be synthesized using Fe-oleate, Fe(OA)3 as the precursor. Hou et al. developed a method for shape-controlled Fe3 O4 nanoparticles. The thermal decomposition of Fe(OA)3 was conducted at a high temperature in the mixture of tetracosane and oleylamine. The lateral size of as-synthesized Fe3 O4 octahedral nanoparticles was 21±2 nm, as shown in Fig. 3.12. [91] Although high-temperature (thermal) decomposition can produce highly crystalline and uniform-sized magnetic nanoparticles by using organometallic and coordination compounds in non-polar solution, [92] there are also some limitations in this method. First, it needs relatively expensive organometallic compounds as precursors such as Fe(CO)5 , [93] Fe(acac)3 , [94] iron oleate. [95] Fe(CO)5 is also very toxic. Second, the reaction process needs a high temperature and tedious procedure, which

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limits their large-scale production and applications. [63] Furthermore, nanoparticles applicable in biochemistry must have a hydrophilic property and can be dispersed well in water. However, the Fe3 O4 synthesized via thermal decomposition cannot meet these demands. In addition, most bio-environments have a wide pH range (about 5–9), [76, 96] where iron oxide may not be able to survive long if the pH goes

Fig. 3.12

TEM images of self-assembled monolayer patterns consisting of Fe3 O4

nanoparticles with different projection axes. Image projection direction: (a) h110i, (b) h111i. (c) and (d) HRTEM images are projected from h110i and h111i, respectively. (e) and (f) are the models of (c) and (d), respectively. [91]

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lower than 7. Therefore, it is desired to optimize the surface chemistry of iron oxide nanoparticles to protect them from low pH corrosion, while functionalizing their surface for further use.

3.5

Surface coating for biomedical application

Magnetic iron oxide nanoparticles with a bare surface tend to agglomerate because of strong magnetic attractions among particles, the van der Waals force, and high surface energy. [79] Consequently, the agglomerated iron oxide nanoparticles can be rapidly eliminated by the reticulendothelial system (RES). [97, 98] Also, a high local concentration of Fe ions from surface Fe dissolution is toxic to organisms. [99] These can be avoided by coating a shell on the iron oxide nanoparticle surface to make them hydrophilic, compatible to bio-environments, and functionalized. [33, 99, 100] Here we summarize several typical coating methods and materials. Some coating techniques are designed for protecting iron oxide cores from corrosion and some are designed with additional chemical and physical functions for specific applications. 3.5.1

Au coating

The nobel metal coating is a popular method to protect iron oxide nanoparticles from low pH corrosion. The coating with Au or Ag with surface plasmonic property is more interesting since it provides additional optical properties. As a plus, coating with Au can also facilitate the further organic conjugation by Au–S chemistry. There are many reports on the Au coating on magnetic iron oxide nanoparticles. [101, 102, 103] The coating usually is achieved by reducing Au precursor in the presence of iron oxide nanoparticles. The experimental conditions vary according to the properties of iron oxide nanoparticle cores, such as the solubility, surface chemistry, size, etc. Here we introduce some typical examples briefly. Using Fe3 O4 nanoparticles synthesized by thermal decomposition of Fe(acac)3 , Xu et al. synthesized magnetic core/shell Fe3 O4 /Au and Fe3 O4 /Au/Ag nanoparticles by reducing HAuCl4 at room temperature (shown in Fig. 3.13). Due to the incompatible chemistry, the coating of Au over the iron oxide surface is quite difficult. The fast reduction of Au precursor will lead to the growth of Au nanoparticles instead of coating shell. To prevent the fast reduction, the method employed oleylamine as a mild reducing agent to slowly reduce HAuCl4 in chloroform solution of Fe3 O4 nanoparticles. Also, chloroform is a strong solvent and it probably helps desorption of oleylamine, as the surfactant, from the surface of Fe3 O4 nanoparticles, opening the surface for Au shell nucleation and growth. So-prepared Au-coated Fe3 O4 nanoparticles were soluble in non-polar solvent because the surface was still capped by oleylamine. To make them water-soluble, these nanoparticles were dried and mixed with sodium citrate

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and cetyltrimethylammonium bromide (CTAB). The absorption of sodium citrate on a Au shell enabled a negative charged surface, which further led the capping of CTAB with a well-known double layer structure and a stronger capping could be achieved to replace oleylamine. The water-soluble core/shell nanoparticles could serve as seeds for thicker Au-coating by adding more HAuCl4 under the reducing condition, or for Ag coating by reducing AgNO3 . The method not only stabilized magnetic Fe3 O4 nanoparticles from a corrosive environment, but also manipulated the surface plasmonic absorption of magnetic core/shell nanoparticles. [103]

Fig. 3.13

(a) Schematic illustration of surface coating Fe3 O4 nanoparticles (i) with Au

to form hydrophobic Fe3 O4 /Au (ii) and hydrophilic Fe3 O4 /Au nanoparticles (iii); (b) TEM image of the nanoparticles (iii); (c) HRTEM image of part of a single Fe3 O4 /Au nanoparticle from (b). [103]

For Au coating of Fe3 O4 nanoparticles synthesized by thermal decomposition, there is another method reported by Zhong et al. The schematic illustration was shown in Fig. 3.14. [104] The method employed Au(Ac)3 as the precursor and thermally reduced this precursor at 180–190 ℃ in the presence of Fe3 O4 nanoparticles. Oleic acid and oleylamine were used as surfactants and 1,2-hexadecandediol was used as the reducing agent. The desorption of oleylamine and oleic acid from Fe3 O4 nanoparticle surfaces is facilitated by high temperature heating. The method also employed a size selection process by centrifuge to separate uncoated Fe3 O4 nanoparticles, large-sized and small-sized core/shell nanoparticles. The shell thickness was

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determined by TEM and direct current plasma (DCP) composition analysis. After coating, thiol-mediated inter-particle binding was utilized to produce a thin film of core/shell Fe3 O4 /Au nanoparticles. The thin film exhibited a similar surface plasmonic property with pure Au nanoparticle cross-linked thin films, which was used as a medium for gas sensor applications a few years later.

Fig. 3.14

Schematic illustration of the chemistry and processes involved in the synthesis of the Fe3 O4 and Fe3 O4 @Au nanoparticles. [104]

The coating of Au over the iron oxide nanoparticles by co-precipitation synthesis has also been reported with several examples. The iron oxide nanoparticles by the co-precipitation method are usually water-soluble and their surfaces are rich in OH groups. Such a surface chemistry is difficult for Au or other metal coatings. Surface modification by organic linkers is necessary. An example is to use (3-aminopropyl)triethoxysilane (APTES) to functionalize the surface with amine groups, which are affinitive to Au3+ ions. A small amount of HNO3 was also used to make functionalized surface positively charged. The sonication of a mixture of APTES functionalized iron oxide nanoparticles, HAuCl4 , and sodium citrate finally resulted in Au-coated iron oxide nanoparticles. Li et al. also reported a method to modify the surface of iron oxide nanoparticles with small Au nanoparticles (Fig. 3.15). The difference is that the method used chemical linkers to immobilize the pre-made Au nanoparticles onto iron oxide nanoparticles. The chemical linkers are O-benzotriazole-N,N,N’,N’-tetramethyluroniumhexafluorophosphate (HBTU) and triethylamine. The covalent binding between amine and OH groups linked HBTU with iron oxide nanoparticles. The thiol group on HBTU bonded with

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Au nanoparticles. These Au modified iron oxide nanoparticles were used for separating arginine kinase from cell lysate. The separation was achieved by applying external magnet attraction, and arginine kinase persists the catalytic activity after separation. [102]

Fig. 3.15

Illustration of the synthetic chemistry for Fe3 O4 /Au nanoparticle preparation. [102]

3.5.2

SiO2 coating

SiO2 coating is often used in colloid surface modification. The density of silica shell can be tuned by changing the reaction conditions to either porous or dense. The SiO2 shell surface is compatible with many chemicals and molecules for further bio-conjugation. [99, 105] In addition, small molecules like dyes and drugs, and even quantum dots can be incorporated into the silica shell during its formation. Due to these advantages, the SiO2 coating has been popular for magnetic iron oxide nanoparticles, and a silica surface can covalently attach to various ligands and biomolecules to target organs via antibody-antigen recognition. [99, 106, 107, 108] Silica coating is usually made by alkaline hydrolysis of tetraethyl orthosilicate (TEOS) in the presence of core nanoparticles. The recipe can be modified for most nanoparticles in either an organic solution or an aqueous solution. For magnetic iron oxide nanoparticles, core-shell Fe3 O4 @SiO2 nanoparticles have been widely reported. It is interesting to note that the silica-coated iron oxide nanoparticles usually are stable and can be easily dispersed in an aqueous or organic solution, even without surfactants. Gao et al. used 20 nm hydrophilic Fe3 O4 nanoparticles as seeds to prepare Fe3 O4 @SiO2 nanoparticles , and by changing experimental conditions, the thickness of the SiO2 shell can be tuned from 12.5 nm to 45 nm. The reaction time, the concentration of Fe3 O4 seeds and the ratio of TEOS/Fe3 O4 were found to be critical for controlling SiO2 shell thickness. [99] Xia’s group reported a sol–gel method to coat iron oxide nanoparticles with silica. [109] Because the iron oxide surface has a strong affinity to silica, the coating of silica can be achieved without intermediate steps to promote the adhesion of silica to the iron oxide surface. Commercial iron oxide nanoparticles (EMG 340) dispersed in water were directly mixed with ammonium and TEOS in 2-propanol.

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The reaction proceeded at room temperature under stirring for 3 h. The hydrolysis of TEOS was catalyzed by ammonium hydroxide and the affinity between iron oxide and silica made silica grow over the iron oxide surface. So-produced core/shell Fe3 O4 /SiO2 nanoparticles dispersed well in water without surfactants. The concentration ratio of iron oxide nanoparticles to TEOS had to be carefully optimized to avoid the homogeneous nucleation of silica. This ratio was also a parameter for controlling the shell thickness. They further modified the procedure by adding dye molecules to make fluorescent core/shell Fe3 O4 /SiO2 nanoparticles. Two fluorescent dyes, 7-(dimethylamino)-4-methylcou-marin-3-isothiocyanate (DACITC) and tetramethylrhodamine-5-isothiocyanate (5-TRITC), with thioisocyanate functional group were selected. The thioisocyanate group could be coupled with the amine group of 3-aminopropyl-triethoxy-silane. A covalent bond formed between the two groups stabilized the fluorescent dye molecules into the silica shell. The fluorescent core/shell Fe3 O4 /SiO2 nanoparticles could form chain-like structures along the applied magnetic field. Due to the fluorescent dyes, they were visible under fluorescent microscopy (shown in Fig. 3.16).

Fig. 3.16

(a) A typical TEM image of silica-coated Fe3 O4 nanoparticles synthesized by

the sol–gel method. (b) A close view of a single silica-coated Fe3 O4 nanoparticle. (c) and (d) Fluorescent microscopy images of chain-like structures formed by silica-coated iron oxide nanoparticles in the presence of an external magnetic field. The silica shell was incorporated with DACITC (c) and 5-TRITC (d) with APS precursor. The insets are TEM images of core/shell Fe3 O4 /SiO2 nanoparticles with dye molecules. [109]

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Besides dye molecules, small nanoparticles can also be incorporated into the silica shell. Ying et al. incorporated quantum dots CdSe into the silica shell and produced silica coated gamma-Fe2 O3 /CdSe composite nanoparticles (shown in Fig. 3.17). [110] Magnetic iron oxide nanoparticles and quantum dots were firstly synthesized separately. A reverse microemulsion medium using polyoxythylene nonylphenyl ether and Igepal CO-520 was employed for controlled coating silica. The silica was produced by adding ammonium hydroxide and TEOS after dispersing iron oxide nanoparticles and quantum dots into the reverse microemulsion solution. This method successfully combined magnetic and fluorescent properties into one nanoparticle. The quantum efficiency of incorporated CdSe particles was found to be lowered as compared to bare CdSe. A thicker silica shell may further weaken the quantum efficiency. However, the magnetic saturation moment normalized by iron oxide mass persisted, without drop. The silica shell protected both iron oxide and CdSe nanoparticles and such a bi-functional nanoparticle is very promising for diagnostic imaging by either MRI or fluorescence.

Fig. 3.17

(a) The procedure for synthesis of silica coated magnetic γ-Fe2 O3 and CdSe

nanoparticles. (b) The TEM image of a single core/shell nanoparticle. (c) The HRTEM image of γ-Fe2 O3 and CdSe nanoparticles in the silica. [110]

Au nanoparticles with surface plasmonic absorption are also introduced into the silica-modified iron oxide nanoparticles. An example is by Hyeon et al. They successfully synthesized magnetic gold nanoshells (Mag-GNS), where Au and Fe3 O4 nanoparticles formed a shell over silica nanospheres. The dense Au surface could be readily conjugated with cancer-targeting agents (Fig. 3.18). To immobilize Fe3 O4 and Au nanoparticles, the surfaces of the silica spheres were firstly modified with

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3-aminopropyltrimethoxysilan, which enable the surface to become rich in amine groups. Fe3 O4 and Au nanoparticles were subsequently attached onto silica spheres. The further growth of Au nanoparticles resulted in a dense Au shell with Fe3 O4 embedded. This method is quite interesting because this Au shell has NIR absorption around 700 nm. It enables photothermal therapy against cancer cells. Additionally, magnetic Fe3 O4 nanoparticles are well-protected inside the Au shell and can be used for MRI. Lung and breast cancer cells can be clearly imaged after being targeted with these nanoparticles under T2-weighted MRI. The continuous-wave laser gives an effective local heating by the near infrared (NIR) absorption of Au shell and cancer cells can be killed under optimized power. [9]

Fig. 3.18

(a) Synthesis of the magnetic gold nanoshells (Mag-GNS). TEM images of (b)

amino-modified silica spheres, (c) silica spheres with Fe3 O4 (magnetite) nanoparticles immobilized on their surfaces, (d) silica spheres with Fe3 O4 and gold nanoparticles immobilized on their surfaces, and (e) the Mag-GNS. [9]

3.5.3

TaOx coating

Nanosized TaOx is a low cost CT contrast agent. It has been used for clinical applications [111, 112] similar to Au [113] and Bi2 S3 . [114] Hyeon et al. developed core/shell Fe3 O4 /TaOx nanoparticles as a bifunctional agent for CT and MRI (Fig. 3.19). [115] CT can clearly give images of newly formed blood vessels in the tumors, while MRI detects the tumor microenvironment, such as the hypoxic and oxygenated regions. The complementary information from CT and MRI provides a great potential for accurate diagnosis of cancer. The TaOx coated Fe3 O4 nanoparticles were synthesized by thermal decomposition of iron oleate precursor and subsequently a fast hydrolysis of tantalum ethoxide in a mixture of Igepal CO-520, NaOH, and other organic solvents. The elemental mapping image from TEM showed Fe3 O4 was

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indeed coated with a thin layer of TaOx . This shell could be made thicker if longer hydrolysis was applied. The TaOx shell was further conjugated with rhodamineB isothiocyanate (RITC) functionalized silane and poly(ethylene glycol) silane to enable fluorescence capability, colloidal stability, and bio-compatibility. [115, 116]

Fig. 3.19

(a) Schematic illustration of synthesis and modification of Fe3 O4 /TaOx

Core/Shell nanoparticles. (b) TEM image of Fe3 O4 nanoparticles. (c) TEM image of Fe3 O4 /TaOx Core/Shell nanoparticles. The inset is the elemental mapping image with Fe in red. (d) T phantom images at various concentrations of Fe3 O4 /TaOx core/shell nanoparticles and (b) HU values in CT. [115]

3.5.4

Polymer coating

Incorporating magnetic iron oxide nanoparticles into a polymer has also been developed. Similar to silica coating, a polymer coating can also give a protective and bio-compatible organic surface for functionalization. Its synthesis is similar to the hydrolysis synthesis of silica-coated Fe3 O4 nanoparticles. Usually the coating can be synthesized by polymerization of precursors in the presence of iron oxide nanoparticles. Hyeon et al. developed a multifunctional polymer nanomedical platform with three functions: cancer-targeted MRI, optical imaging, and magneticallyguided drug delivery at the same time (Fig. 3.20). It has four parts: biodegradable poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles served as a matrix for loading and controlling release of hydrophobic therapeutic agents into cells. Fe3 O4 and CdSe/ZnS nanoparticles were incorporated into the PLGA matrix: Fe3 O4 nanoparticles were used for both magnetically guided delivery and T2 MRI contrast agent,

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and CdSe/ZnS nanoparticles were used for optical imaging. Doxorubicin (DOXO) was used as a therapeutic agent for cancer. Finally, cancer-targeting folate was conjugated onto the PLGA nanoparticles by PEG groups to target KB cancer cells. With the increase of PLGA(MNP/DOXO) nanoparticles, the intensity of MRI signal decreases and r2 increases. The external magnetic field during incubation can make the image darker. It also indicated that PLGA(MNP/DOXO) nanoparticles could serve as cancer-targeted, T2 contrast agents in MRI. Additionally, the combination of folate targeting groups and an external applied magnetic field could contribute to enhancing the cancer targeting efficiency. [8]

Fig. 3.20

(a) Synthetic procedure for the multifunctional polymer nanoparticles; (b)

TEM image of PLGA(MNP/DOXO) nanoparticles embedded with 15 nm Fe3 O4 nanocrystals; (c) a close view on a single PLGA(MNP/DOXO) nanoparticle. [8]

Polymer coatings are very popular in making colloidal nanoparticles water-soluble and biocompatible. Dextran, dendrimers, polyethylene glycol (PEG), and polyethylene oxide (PEO) are the most commonly used. As for iron oxide nanoparticles, PEG has been found to be effective to protect the iron oxide in a hydrophilic environment. PEG is an amphiphilic polymer and is commonly regarded as a non-specific interaction reducing reagent. It has been widely used for the conjugation with proteins to extend their circulation time. An early study by Sun et al. investigated the effect of chain length to the hydrodynamic size of PEG-capped Fe3 O4 nanoparticles as well as

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the stability in buffer solutions (phosphate buffered saline (PBS)+10% fetal bovine serum (FBS)). [117] It was found that PEG could be anchored onto Fe3 O4 nanoparticles by covalent bonding. After coating, Fe3 O4 nanoparticles could be well-stabilized in cell culture media with negligible aggregation (Fig. 3.21). The non-specific uptake by macrophage cells was also found to be reduced greatly. It should be highlighted here that dopamine was used to replace the surfactants, oleic acid and oleylamine, on the surface of Fe3 O4 nanoparticles. The dopamine moiety was proven to have a high affinity to the iron oxide surface. [118, 119] Many other surface modifications have been developed based on dopamine-PEG chemistry.[120−122]

Fig. 3.21

(a) Hydrodynamic sizes of the Fe3 O4 nanoparticles coated with different

surfactants. The sizes were measured from the aqueous solution of the nanoparticles by dynamic light scattering (DLS). (b) Hydrodynamic size changes of the DPA-PEG coated Fe3 O4 nanoparticles incubated in PBS plus 10% FBS at 37 ℃ for 24 h. [117]

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Besides dopamine, phospholipid was also combined with PEG for surface modification and stabilization of iron oxide nanoparticles. Hyeon et al. reported polyethylene glycol-phospholipid (PEG-phospholipid)-coated iron oxide nanocubes as an MRI contrast agent. Iron oxide nanocubes were synthesized via thermal decomposition of Fe(acac)3 in a mixture of oleic acid and benzyl ether, and then coated with PEG-phospholipid, which could transform the hydrophobic nanoparticles to hydrophilic and biocompatible nanoparticles, and prevent extensive agglomeration. These PEG-phopholipid-coated magnetic nanoparticles were found to be capable of labeling many kinds of cells with high relaxivity. [123] However, these particles were found in low colloidal stability and the in vivo applications were limited. The MRI of single cells at high tesla MRI was found to be highly efficient. The use in imaging pancreatic islets at clinical MRI was also demonstrated. The imaging function of these particles persisted for nearly 150 days in pancreatic islets (Fig. 3.22). The work indicates that PEG based coating is a promising way to protect iron oxide from corrosion in a hydrophilic bio-environment. The chemistry can also be varied by conjugating PEG with many active groups/molecules. Some research works tried to embed magnetic iron oxide nanoparticles into polymer hydrogels to make a “smart” platform for drug delivery. Hydrogels have been extensively studied in various biomedical applications, such as soft contact lenses, intravascular devices, wound dressings, drug delivery, and lubricants for surgical gloves. An interesting property of hydrogels is that they can swell or shrink with a volume change up to 1000 times in response to small changes in environment temperature, pH level, electric fields or solvent and ionic composition. For example, Poly (N-isopropylacrylamide) (PNIPA) hydrogel is temperature sensitive. When immersed in water, the PNIPA hydrogel has a low critical solution temperature of 34 ℃. It is swollen at temperatures below 34 ℃, but collapses at 34 ℃ and above. [124] Because of this low critical temperature for volume change in aqueous media, PNIPA hydrogel can be used for drug delivery. The drug molecules are encapsulated in the hydrogel and they can be released during this collapse transition. To generate temperature change, Ang et al. incorporated magnetic iron oxide particles and employed hyperthermia to increase the temperature within the PNIPA hydrogel (Fig. 3.23). [125] A magnetic field with a frequency of 375 kHz and the strength varying from 1.7 kA/m to 2.5 kA/m was used. The concentration of Fe3 O4 particles was varied to investigate the temperature induced by this magnetic field. It was found that the temperature in the hydrogel induced by the magnetic field increased with the concentration of Fe3 O4 particles. The optimal concentration was found 2.5 wt.% Fe3 O4 in the PNIPA-Fe3 O4 hydrogel, which took 4 min to be heated to 45 ℃.

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Surface coating for biomedical application

Fig. 3.22

99

(a) TEM image of iron oxide nanocubes synthesized by thermal decomposition of

Fe(acac)3 in a mixture of oleic acid and benzyl either (scale bar, 100 nm). These nanocubes were then capped by PEG-phospholipid through ligand exchange. (b) Trypsinized MDAMB-231 cells. The iron oxide nanoparticles are visible as dark spots inside the cells. (c) MRI of four labeled cells sandwiched between two Gelrite layers. (d) Fluorescence image of cells stained with calcein-AM. (e) Merged image of corresponding region of (c) and (d). The dark spots in the MRI matched exactly with the green spots in the fluorescence image. In vivo MRI of intrahepatically transplanted syngeneic islets. T2 MRI of rat liver infused with ∼3000 pancreatic islets for 4 (f) and 150 (g) days after transplantation. The hypointense spots representing labeled islet persisted up to 150days after transplantation. [123]

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Fig. 3.23

Magnetic Iron Oxide Nanoparticles: Synthesis and Surface Coating · · ·

(a) Temperature vs time for PNIPA-Fe3 O4 at H = 2.5 kA/m. (b) Heating of PNIPA hydrogel at 34 ℃as a function of time. [125]

3.5.5

Small molecular coating

Iron oxide nanoparticles have also been directly coated or surface-modified with small molecules to avoid a large hydrodynamic size. This is to overcome a shortcoming that the magnetic nanoparticles with a hydrodynamic size over 50 nm have a very limited extravasation ability and can be easily uptaken by RES, which further leads to a poor targeting specificity. Xie et al. developed a protocol to synthesize small Fe3 O4 nanoparticles using thermal decomposition of Fe(CO)5 followed by oxidation under air. The synthesis employed 4-methylcatechol (4-MC) as the surfactant, which could be directly conjugated with a peptide, c(RGDyK), through the Mannich reaction. The protocol is illustrated in Fig. 3.24. The overall diameter of the c(RGDyK)-MC-Fe3 O4 nanoparticles was about 8.4 nm, including the Fe3 O4 core size of 4.5 nm. The c(RGDyK)-MC-Fe3 O4 nanoparticles were stable and could target specifically to integrin αv β3 -rich tumor cells. After being accumulated preferentially in tumor cells, these nanoparticles enhanced the MRI contrast for tumor cell detection. As a plus, these RGD-coated Fe3 O4 nanoparticles were found stable in aqueous

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solution for months. In addition, they proved the accumulation of c(RGDyK)-MCFe3 O4 nanoparticles was mediated by integrin αv β3 binding. Although there were some deposition seen in spleen and liver, only rarely c(RGDyK)-MC-Fe3 O4 nanoparticles were seen in kidneys and muscles, which indicated the nanoparticles could last enough circulation time for targeting. [87]

Fig. 3.24

(a) The protocol for producing small c(RGDyK)-MC-Fe3 O4 nanoparticles. MRI

of the cross section of the U87MG tumors implanted in mice: (b) without nanoparticles, (c) with the injection of 300 µg of c(RGDyK)-MC-Fe3 O4 nanoparticles, and (d) with the injection of c(RGDyK)-MC-Fe3 O4 nanoparticles and blocking dose of c(RGDyK); and Prussian blue staining of U87MG tumors in the presence of (e) c(RGDyK)-MC-Fe3 O4 nanoparticles and (f) c(RGDyK)-MC-Fe3 O4 nanoparticles plus blocking dose of c(RGDyK). [87]

Liposome-structured coatings were also developed for encapsulating both iron oxide nanoparticles and molecular therapeutics. A major advantage of liposomes is that it can encapsulate both hydrophobic and hydrophilic molecules very well by its closely packed phospholipid bilayer. As a result, the local dilution and the interaction with microenvironment can be prevented for encapsulated drugs.

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Georgy et al. encapsulated magnetic iron oxide nanoparticles into PEG-modified liposomes (Fig. 3.25). [126] The water soluble iron oxide nanoparticles were made by mechanochemical synthesis using saline crystal hydrates. The magnetic liposomes were prepared by mixing the iron oxide nanoparticles with L-a-phosphatidylcholine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]. These magnetic liposomes were found to be very effective to target the cathepsin inhibitor JPM-565 to the peri-tumoral region of mouse breast cancer, which resulted in a significant reduction in tumor growth. The work also found that magnetic liposomes could act as a drug carrier with the ability of encapsulating many

Fig. 3.25

(a) Preparation procedure of magnetic Fe3 O4 liposomes. (b) Anti-tumor effect

of magnetically targeted Fe3 O4 -liposomes containing cysteine protease inhibitor JPM-565. The treatment experiment with cells from the transgenic (Tg) MMTV-PyMT mouse with multifocal tumors. (c) Tumor volumes for each treatment day for the different treatment groups. [126]

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different types of cargos. As a plus, iron oxide nanoparticle cores could act as an MRI contrast agent and provide non-invasive, real time in vivo MRI detection. 3.5.6

Carbon coating

Carbon coating is not widely reported because the formation of carbon shell usually needs a high temperature annealing process, which carbonizes hydrocarbon precursors but will also result in the reduction of iron oxide. An example can be found in the synthesis of carboncoated FeCo nanoparticles. [127] The synthesis was conducted by a CVD method at 800 ℃ under nitrogen gas protection. The precursor iron and cobalt ions were reduced to FeCo under this condition. A method to avoid this reduction is to use pre-synthesized Fe3 O4 nanoparticles and low temperature annealing. Zhu et al. embedded magnetic Fe3 O4 nanoparticles into a carbon substrate using an ethylene glycol based photoresist as the carbon source (Fig. 3.26). [128] They synthesized Fe3 O4 nanoparticles by the thermal decomposition method and then used layer-by-layer assembly to make Fe3 O4 nanoparticles embedded photoresist on a silicon substrate. The following low temperature annealing induced a carbon coated silicon substrate, where the carbon layer was embedded with Fe3 O4 nanoparticles. Such a substrate was found to be effective for the growth of nerve cell PC12 and with the increase of Fe3 O4 concentration, the substrate exhibited a higher adhesion ability for these cells. This approach is interesting to further studies with a combination of hyperthermia and MRI techniques for cell culture related research. Most recently, a study revealed that the Fe3 O4 nanoparticles synthesized by the thermal decomposition method may have a thin carbon shell on their surface. [129] Iron oleate was used as the precursor and various solvents like octadecane, docosane, eicosane, and octadecene were used to adjust the thermal decomposition temperature. The highest temperature could be achieved as high as 365 ℃ using docosane. The work presented the evidence from HRTEM and Raman spectra, where thin carbon layers can be seen on individual Fe3 O4 nanoparticles, and D band and G band for sp2 carbon were found. The thin carbon coating layer was probably formed by the slight carbonization of oleate ligands. These particles were tested for their cytotoxicity to several cells including HeLa Kyoto, human osteosarcoma U2OS (GFP-53BP1), NIH 3T3 fibroblasts, and Macrophages 7442. The research found that carbon coated Fe3 O4 nanoparticles with the size range of 9.7–20.3 nm gave similar cytotoxicity results, but different uptake behaviors. The cells can uptake both single nanoparticles and small nanoparticle clusters, which may affect the evaluation of the cytotoxicity. However, the carbon coating was not found to be influential on the cytotoxicity. It is probably because the carbon coating layer was too thin to actively prevent the iron oxide from contacting with the microenvironment.

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Fig. 3.26

Magnetic Iron Oxide Nanoparticles: Synthesis and Surface Coating · · ·

Neurite length pictures of rat pheochromocytoma PC12 cells attached on

carbon substrates with different Fe3 O4 concentrations: (a) 0 mg/mL, (b) 1.2 mg/mL, (c) 3.0 mg/mL, and (d) 4.8 mg/mL. [128]

3.6

Conclusions and perspectives

Magnetic iron oxide nanoparticles Fe3 O4 and γ-Fe2 O3 have been extensively studied in terms of their synthesis approaches, characterizations, surface modifications, and biomedical applications. There are many research articles published in this field and a lot of significant progress has been made in recent years in the world. This review article attempts to highlight the most popular and efficient synthesis approaches for magnetic iron oxide nanoparticles, which can be used in biomedical fields, such as MRI and drug delivery. Due to the bio-environment, to obtain iron oxide in colloidal form and soluble in an aqueous solution is a major consideration when choosing synthesis approaches. Wet-chemical approaches, such as co-precipitation in an aqueous solution and high temperature thermal decomposition of organometallic precursors, meet this criterion. Although co-precipitation can make water-soluble iron oxide nanoparticles directly, the poor crystallization and the lack of size control have limited its use. Most researchers selected thermal decomposition of organometallic precursors like Fe(acac)3 , Fe(CO)5 , and Fe-oleate to produce magnetic iron oxide nanoparticles. This method produces iron oxide nanoparticles with a high crystallization due to the high temperature employed. Involving surfactants provides a good control over the size and shape. The particles can be well-controlled into a size range from several nanometers to several tens of nanometers, where they can be stabilized in colloidal form and be superparamagnetic

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for MRI, hyperthermia therapies, targeting cells, and drug delivery. A shortcoming of these iron oxide nanoparticles is their hydrophobic surface chemistry, which makes them only soluble in non-polar solvents like hexane and toluene. Therefore, much effort in the last few years has been made in converting their surface chemistry into hydrophilic and bio-compatible. Various surface modification techniques have been developed. We summarized several typical surface modification techniques, including noble metal coating, silica coating, polymer coating, small molecular coating, and liposome coating. Indeed, to make these nanoparticles applicable in bio-systems, surface modification is a critical step. It not only provides a bio-compatible surface chemistry for bio-conjugation and functionalization, but also offers additional physical properties, such as optical response and CT contrast. To date, the synthesis approaches for magnetic iron oxide nanoparticles, have been well-established. The size and shape can be controlled effectively by tuning synthetic conditions. The surface modification techniques have also been well-explored. However, the interface of nanoparticles and the bio-microenvironment is very complicated. The challenges remain in the tuning of surface chemistry of iron oxide nanoparticles. One of the future research focuses should be exploring the protocols for enhancing specific bonding for a dense functional conjugation, while lowering the non-specific bonding of unwanted biomolecules in a microenvironment. It is important to improve the targeting efficiency of iron oxide nanoparticles for tumor/cancer cells. Another issue is that exposing iron oxide into a bio-environment leads to the degradation of iron oxide nanoparticles. This will cause, for instance, the loss of MRI contrast. The dissolution of iron metal ions into the microenvironment will also result in a toxicity effect. Therefore, the techniques for building a strong, but bio-compatible surface protection layer are highly desirable. In addition, building smart structures with the abilities of diagnosis and therapeutics based on magnetic nanoparticles and other functional materials are always welcome.

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Chapter 4 Surface Modification of Magnetic Nanoparticles in Biomedicine∗ Xin Chu,

Jing Yu,

and Yanglong Hou†

Department of Materials Science and Engineering, College of Engineering, Peking University, Beijing 100871, China † Corresponding author. E-mail: [email protected] Progress in surface modification of magnetic nanoparticles (MNPs) is summarized with regard to organic molecules, macromolecules and inorganic materials. Many researchers are now devoted to synthesizing new types of multifunctional MNPs, which show great application potential in both diagnosis and treatment of disease. By employing an ever-greater variety of surface modification techniques, MNPs can satisfy more and more of the demands of medical practice in areas like magnetic resonance imaging (MRI), fluorescent marking, cell targeting, and drug delivery.

4.1

Introduction

Magnetic nanoparticles (MNPs) have shown enormous potential in disease diagnosis and therapy. Due to their superior magnetic properties and high specific surface, MNPs are perceived as promising materials for magnetic resonance imaging (MRI) agents, biomedical drug carriers, magnetic hyperthermia, etc. [1, 2, 3] Based ∗ Project supported by the National Natural Science Foundation of China (Grant Nos. 51125001 and 51172005), the Natural Science Foundation of Beijing, China (Grant No. 2122022), the Science Fund for Creative Research Groups of the National Natural Science Foundation of China (Grant No. 81421004), and the Doctoral Program of the Education Ministry of China (Grant No. 20120001110078).

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113

on the interaction between protons and surrounding molecules of tissues, MRI is already a key tool for medical imaging diagnosis of cancer and is considered one of the most efficient imaging techniques in medical practice. Colloidally stable MNPs, which display strong magnetization, now attract much attention for their great potential in MRI. In particular, they can be used as contrast agents in MRI, inducing hypo-intensities on T1 /T2 and T1 /T2∗ -weighted MRI maps. Drug delivery is another medical application for MNPs. Magnetic drug delivery is a method to target drugs to the diseased area in the body. The drug is attached to an MNP and injected into the blood flow. A magnetic field located close to the diseased area is used to capture the MNPs in the target area. Under the influence of the magnetic field, the MNPs move irregularly in the target area which accelerates the release of drugs. Apart from pharmaceutical therapy, MNPs are also widely used in magnetic hyperthermia therapy. On account of excellent magnetic properties, metal carbide nanoparticles, especially ferromagnetic NPs, can induce strong attractive forces between the dipoles of neighboring NPs, and aggregate under a static magnetic field. While the efforts to develop new engineered MNPs and constructs continue to grow with new chemistry and synthesis approaches every year, the importance of specific functionalization designs has been increasingly recognized. Because the surface of MNPs is the interface of nanomaterials and patients’ bodies, surface biocompatibility is a prerequisite to the medical application of nanomaterials. [4] As a convenient and quick approach to adjust the properties of MNPs, surface modifications have become a vital component of a great many medical applications of MNPs, due to various requirements to add non-magnetic surfactants. Cell phagocytosis of MNPs has expanded the applications of contrast enhanced MRI beyond vascular and tissue morphology imaging, and enabled many novel applications of MNPs for MRI diagnosis of liver diseases, cancer metastasis to lymph nodes, and in vivo MRI tracking of implanted cells and grafts. [5] The magnitude of contrast effects also needs to be improved for higher sensitivity to minimal changes in a disease and for biomarker-specific detection. Therefore, surface modifications of MNPs are developed to meet the increasing interests in non-invasive in vivo imaging of the molecular and cellular activities that characterize a disease. Surface modifications can inhibit MNPs’ reactions and agglomeration in aqueous phase, which is a precondition for medical applications and endows MNPs with multifunctional properties such as fluorescent marking, cell targeting, drug loading and so on. [6, 7, 8] Furthermore, the addition of non-magnetic surfactants can influence the magnetic performance of MNPs. Surface modifications are accomplished mainly via two approaches, ligand ex-

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change and ligand adsorption. In this case, ligand exchange means changing a hydrophobic ligand into a hydrophilic one. Generally, these ligands consist of hydrophilic groups and linking groups. The linking groups can combine with the surface of the MNPs, whereupon the hydrophilic groups are exposed to the surrounding environment and make the MNPs disperse in the aqueous solution. The key to designing a successful ligand exchange is to select linking groups that have the strongest combination with the surface of the MNPs. “Ligand adsorption” in this case mainly means to adsorb amphiphilic molecules, which have a hydrophilic portion on one side and hydrophobic part on another side. By means of hydrophobic forces, the hydrophobic portion can combine firmly with a hydrophobic surfactant on the MNPs and the hydrophilic portion is exposed so that the MNPs disperse in aqueous phase. In addition, chemical reaction is a third approach to surface modification. In these three strategies, organic molecules, macromolecules and inorganic materials are usually used. In this review article, we will summarize the progress in surface modification of MNPs by considering the principal types of surface materials one by one.

4.2

Surface modification with organic molecules

For organic molecular agents, only a single approach (ligand exchange or ligand adsorption) can be chosen for a given application because of the simple structure. In ligand exchange, monodentate ligand is the simplest ligand. Due to ease of preparation, simple structure and other advantages, monodentate ligands are widely used in ligand exchanges. Since there is only one ligand, the binding force between monodentate ligands and MNPs is weak and the combination process is reversible. To deal with this problem, researchers need to screen the ligands for strong coordination ability. Carboxyl, [9, 10] sulfydryl, [11] silane, [12] and some inorganic ions [13, 14, 15] are most commonly used in monodentate ligand exchange. Murray et al. used nitrosonium tetrafluoroborate (NOBF4 ) to replace the organic ligands attached to nanocrystals’ (NCs) surface (Fig. 4.1). [16] The replacement by inorganic BF− 4 anions enabled NCs to be fully dispersible in polar, hydrophilic solvents without changing the particle size and shape. After surface modification, the NCs were readily further functionalized by various capping molecules that greatly enrich the surface function of NCs. Although monodentate ligands have simple structure and react fast with an MNP surface, the resulting MNPs are not stable in aqueous phase, due to the reversibility of the coordination process. This problem is preferably solved by the application of polydentate ligands. Polydentate ligands have a plurality of coordinating groups

4.2

Surface modification with organic molecules

115

that significantly enhances the force of binding with the MNPs. Therefore, these surface-modified MNPs have high stability constant and exhibit favorable aqueous solubility. The polydentate ligands are diphenols, [17, 18, 19] polyacids, [20] polyols and their derivatives. [21, 22, 23] For all of those, catechol and its derivatives are most commonly used. With its benzene ring structure as electron-donor, catechol and its derivatives can be intensely coupled with metal ions. [18] Hou et al. invented a rapid ligand-exchange method to make hydrophobic Fe3 O4 NPs water-soluble, employing dihydroxybenzoic acid as a ligand (Fig. 2.2). [24] Another common polydentate ligand is dimercaptosuccinic acid (DMSA). A small molecule, DMSA has notably superior hydrophilicity, biocompatibility and coordination ability due its double sulfhydryl and double carboxyl structure. [25, 26, 27]

Fig. 4.1

Schematic illustration of surface modification of MNPs via the ligand exchange

process with NOBF4 . [16] Reproduced with permission from Ref. [16]. Copyright 2011 American Chemical Society.

Fig. 4.2

Ligand exchange process with dihydroxybenzoic acid. [24] Reproduced with

permission from Ref. [24]. Copyright 2013 Royal Society of Chemistry.

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Recently, a new class of dual-modality imaging agents were reported, based on the conjugation of radiolabeled bisphosphonates (BP) directly to the surface of superparamagnetic iron oxide (SPIO) nanoparticles. [28] By linking 99m Tc-dipicolylamine (DPA)-alendronate with SPIO, the dual-modality imaging agents exhibit good performance in single photon emission computed tomography (SPECT) imaging and magnetic resonance imaging (MRI). Some organic molecules are amphipathic. Their structures combine a hydrophilic portion with a hydrophobic portion that is able to attach to the surface of hydrophobic MNPs. The hydrophilic portion is usually long chains hydrocarbons, but the hydrophobic portion has different structures. In addition to enhancing the dispersibility of MNPs in aqueous solutions, optical dyes, targeting agents and therapeutic agents, amphipathic compounds are useful in the ligand adsorption process that helps endow some MNPs with multifunctionality. [29] In combination with organic dyes, some MNPs have a dual-mode imaging property that contributes to disease diagnosis (Fig. 4.3).[30−32] Among the organic dyes, near-infrared fluorescent (NIRF) dyes may be the best choice, due to their low interference and excellent deep penetration of tissues. [33] Likewise, surface modification with a targeting agent or therapeutic agent can strengthen the diagnostic capacity of an MNP. [34] Manuel et al. synthesized biocompatible, multimodal, theranostic functional iron

Fig. 4.3

Schematic of surface modification of MNPs via the ligand absorption process

with DMSA and fluorescent dye. [30] DMSA is coupled to the particle and the fluorescent dye is coupled to DMSA. The coupling between DMSA and the fluorescent dye can be made before or simultaneously with the one between DMSA and the magnetic particles. Reproduced with permission from Ref. [30]. Copyright 2006 American Chemical Society.

4.3

Coating modification with macromolecules

117

oxide nanoparticles that exhibit excellent properties for targeted cancer therapy and both optical and magnetic resonance imaging. [35] Using a novel water-based method, they finished the encapsulation of both near-infrared dyes and anticancer drugs and realized successful theranostics. [36] In recent research, a novel method to synthesize Gd-NPs was reported wherein a Gd-based MR contrast agent self-assembled into gadolinium NPs under the action of furin proteins. These NPs can be used to locate the right position for treatment. [37]

4.3 4.3.1

Coating modification with macromolecules Polymer coating

For macromolecular agents, due to their complex structure with numerous functional groups, the two approaches ligand exchange and ligand adsorption are usually applied together to form a more stable structure. By ligand exchange or ligand adsorption, polymers with multiple functional groups can be expediently combined with MNPs. Because of the same reaction process, polymer coating usually needs the help of active terminal groups. Various monomeric species, such as bisphosphonates, DMSA and alkoxysilanes, have been evaluated to facilitate attachment of polymer coatings on MNPs. [19, 38] In polymer coatings, polymers form a barrier among MNPs to avoid agglomeration and provide varieties of surface properties. Most biocompatible MNPs developed for in vivo applications need to be stabilized and functionalized with coating materials. The coating moieties can affect the relaxation of water molecules in various forms, such as diffusion, hydration and hydrogen binding. [5] In the research, these coatings also serve to link MNPs with biomolecules or to change the surface charge or chemical environment. Moreover, polymer coatings improve the colloidal stability of NPs. [39] Due to the complex structures of polymers, there are many aspects that affect the surface performance of MNPs (for example, the molecular weight, the properties of terminal groups and the conformation of the polymers). Quite a few natural and synthetic polymers have been demonstrated in polymer coating of MNPs. [2, 23, 40, 41] The glycans such as dextran or chitosan are widely used in polymer coatings. [42, 43] Chitosan, a biodegradable natural polymer, is derived by deacetylation of chitin obtained from the shells of crustaceans. It has many biological applications because of its biological activities, biocompatibility, high charge density, low toxicity toward mammalian cells and ability to improve dissolution. Weissleder and his group do research on dextran coated iron oxide nanoparticles and derivative magnetic nanoparticles. Their work on monocrystalline iron oxide nanoparticles

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(MION) [44] and cross-linked iron oxide (CLIO) nanoparticles [45] found that dextrancoated superparamagnetic iron oxide nanoparticles were a very suitable platform for the synthesis of multifunctional imaging agents. [46] Hyeon et al. developed chitosan oligosaccharide-stabilized ferrimagnetic iron oxide nanocubes (Chito-FIONs) as an effective heat nanomediator for cancer hyperthermia. [47] The Chito-FIONs’ magnetic heating ability is superior to that of commercial superparamagnetic iron oxide nanoparticles, enabling eradication of cancer cells through caspase-mediated apoptosis. Another frequently-used polymer is polyethylene glycol (PEG). [48, 49, 50] PEG is a flexible water-soluble polymer. The high hydrophilicity of PEG chains can render the MNP core soluble and stabilized in aqueous media. PEG has been demonstrated to reduce uptake by macrophages [31] sharply, so as to increase the blood circulation time in vivo. By changing the molecular weight of PEG, the thickness of the coating can be controlled. [49, 51] PEG-derivative modified MNPs were prepared by post-synthesis coating. With increasing molecular weight, increasing number of branched chains and functionalities, higher stability and better dispersion can be attained. Sun et al. synthesized heterobifunctional PEG ligands using 3-(3,4-dihydroxyphenyl) propanoic acid and PEG as reactants (Fig. 4.4). [52] They successfully modified porous hollow NPs (PHNPs) of Fe3 O4 via this ligand and achieved targeted delivery and controlled release of the cancer chemotherapeutic drug cisplatin. However, a PEG shell is unfavorable for uptake of MNPs by most cells. To solve this problem, these MNPs can be modified by hyaluronic acid (HA), a targeting moiety, for uptake by stem cells. [53] A recent study reported that different terminal groups partly affected the MRI images of MNPs. [54] Other polymers such as cellulose, poly (ethylene oxide) (PEO), poly (vinyl alcohol) (PVA), poly(acrylic acid) (PAA) and poly (lactide-co-glycolide) (PLGA) are also used for polymer coatings of MNPs. PLGA and cellulose are Food and Drug Administration (FDA) approved for a variety of uses in humans and commonly employed for drug delivery and oral formulations. Xu et al. used a single emulsion method to obtain oleic acid-stabilized iron oxide NPs (10 nm core size) encapsulated in PLGA. [55] The PLGA coating gave the NPs a much higher r2 relaxivity than normal SPIO nanoparticles. Hong et al. synthesized novel polymeric nanoparticles (YCC-DOX) composed of poly (ethylene oxide)-trimellitic anhydride chloridefolate (PEO-TMA-FA), doxorubicin (DOX) and superparamagnetic iron oxide. [56] These NPs show unusually high MRI sensitivity, comparable to a conventional MRI contrast agent, despite their lower iron content. Lin et al. prepared PAA modified GdVO4 NPs by filling PAA hydrogel into GdVO4 hollow spheres. The PAA@

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Coating modification with macromolecules

119

GdVO4 NPs can act as a dual mode agent for MRI and up-conversion imaging and be applied for pH-dependent drug release due to their hollow structure. [57]

Fig. 4.4

Schematic of surface modification of hollow NPs with heterobifunctional PEG

ligands. [52] Reproduced with permission from Ref. [52]. Copyright 2009 American Chemical Society.

To gain specificity and reduce side effects and toxicity, biomarker targeted functional proteins or peptide fragments, such as RGD targeting αv β3 integrin, HER2/neu antibodies, urokinase type plasminogen activator (uPA) amino-terminal fragments (ATF), and single chain anti-epidermal growth factor receptor (EGFR) antibodies, have been conjugated on the surface of MNPs, so that the nanoprobes would be recognized and internalized by tumor cells expressing a specific receptor. Other applications in polymer coatings are also beneficial. To simplify the coating procedures, researchers have developed “one-pot” methods, a series of copolymers can now be used to accomplish in situ coating of MNPs. [58] Nevertheless, the growth of nanocrystals can be influenced as a result of the presence of polymers, leading to abnormal structures and surfaces of MNPs (Fig. 4.5). [59] Polymers or

Fig. 4.5

Schematic illustration of the encapsulation process for DOX-SPIO. [50]

Reproduced with permission from Ref. [50]. Copyright 2008 Elsevier Ltd.

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macromolecules such as peptides or PEG have the conformation to form a monolayer by self-assembly; [60] consequently polymer coatings can be formed by self-assembly on the surface of MNPs.[59,61−64] Polymer coatings’ effects on NP magnetic properties is also a research field. [43, 65, 66] Gao et al. reported novel multifunctional polymeric micelles composed of a chemotherapeutic agent doxorubicin (DOXO) and a cRGD ligand. [65] They demonstrated that each micelle loaded a cluster of superparamagnetic iron oxide (SPIO) nanoparticles inside, allowing the micelles to be tracked by ultrasensitive MRI detection of the MNPs. 4.3.2

Liposome and micelle encapsulation

As one of the earliest tools for drug delivery in nanomedical practice, liposome techniques have been developing for a long time. Liposome are composed of a lamellar phase lipid bilayer, so they are usually biocompatible. Having a bilayer structure, amphipathic liposomes can encapsulate MNPs and can have diameters ranging from 100 nm to 5 µm. Thus, another advantage of liposome encapsulation is to gather a certain number of MNPs for collective delivery to the target. For these reasons, liposome complexes are an ideal platform for delivery of contrast agents in MRI. [67, 68] Polymeric micelles offer the advantage of multifunctional carriers that can serve as delivery vehicles carrying nanoparticles, hydrophobic chemotherapeutics and other functional materials and molecules. Stimuli-responsive polymers are especially attractive since their properties can be modulated in a controlled manner. Due to its large encapsulation range, molecules, proteins, DNA and MNPs can all be encapsulated by liposome as one unit. [69]

4.4 4.4.1

Coating modification with inorganic materials Silica coating

Coating MNPs with inorganic agents is generally accomplished by chemical reaction. Silica is most widely used for surface modification via an inorganic coating. Silica-coated MNPs always form core-shell structures. Silica has many advantages over organic coatings. Silica-coated NPs are robust, water-soluble, colloidally stable and photostable. [70, 71] Serving as protective coatings, silica shells are easy to synthesize with controlled size. The general method to produce silica coating can be divided into two types: classical Stober method [72, 73, 74] (in aqueous phase) and sol-gel method [75, 76, 77] (in both aqueous and oleic phase).

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121

The functionalization of silica shells is similar to ligand adsorption. This inevitably makes the diameter of the modified MNPs too large, which affects the biocompatibility, fluidity, stability and magnetic performance of the MNPs. To control the thickness of the silica shell, researchers have utilized tetraethoxysilane (TEOS) as the source of silica, controlled reaction conditions very carefully, and finally obtained diameters from 10 nm to 1 µm. [77, 78, 79] Zhang et al. studied the regulation of the controlled synthesis of Fe3 O4 @SiO2 core-shell nanoparticles via a reverse microemulsion method. [80] They found that the thickness of the silica shell increased with the size of the aqueous domain. This result can guide us to avoid the formation of core-free silica particles (Fig. 4.6).

Fig. 4.6

The coating mechanism of SiO2 on the surface of Fe3 O4 NPs. [80] Reproduced

with permission from Ref. [80]. Copyright 2012 American Chemical Society.

With controlled size, silica shells are appropriate for encapsulation of NPs and organic molecules like dyes or drugs. Salgueirino-Maceira et al. encapsulated Fe3 O4 NPs and CdTe quantum dots within composite silica spheres. [81] These silica spheres can serve as both luminescent and magnetic nanomaterial. Zhu et al. accomplished the same function by embedding a dye molecule inside the silica shell. [82] Researchers also focus on the synthesis of various other core-shell structures. Deng et al. synthesized superparamagnetic microspheres with an Fe3 O4 @SiO2 core and a perpendicularly aligned mesoporous SiO2 shell (Fig. 4.7). [83] The microspheres possess very high magnetization, large surface area, large pore volume, and uniform, accessible mesopores. Wu et al. reported a silica nanoshuttle as a drug delivery system with a nanoscale PEGylated-phospholipid coating and a 13-(chlorodimethylsilylmethyl)

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heptacosane-derived mesoporous silica NP. [84] The therapeutic and imaging agents were trapped and ligand-assisted targeted delivery was achieved through surface functionalization of the phospholipids. Recently, silica shells with foamed or porous structures have received more attention do to the convenience of loading and releasing drugs. [85, 86]

Fig. 4.7

Synthesis route of Fe3 O4 @nSiO2 @mSiO2 . [83] Reproduced with permission from Ref. [83]. Copyright 2008 American Chemical Society.

Having a robust core-shell structure, silica coated MNPs can be functionalized with various biomolecules. The silica shell tends to adsorb molecules, but silane coupling agents can significantly inhibit this process. [87, 88] These agents always consist of siloxy (linking with silica shells) at one side and biocompatible groups like amino, sulfydryl and so on (linking with biomolecules) or even biomolecules themselves that already incorporate a silane group at another side. Biomolecules can easily be added to the outer shells by using alkoxysilanes with active groups, such as aminopropylsilane (APS) or mercaptopropylsilane (MPS). [89, 90, 91, 92] 4.4.2

Metal element coating

The metallic elements used for surface modification are relatively inert in order to act as a protective layer. The coating metal and MNPs are tightly coupled through a chemical reaction process. The metal coating is more easily bio-functionalized than the bare surface of MNPs. Gold is the major element among noble metal coatings. Due to strong conjugation with sulfur, gold offers remarkable advantages in sulfydryl-containing surface coatings. [93, 94] Because of the chemical inertness of gold, forming gold shells is difficult, so gold coated MNPs are completely stable. Zhong et al. produced gold-coated iron oxide nanoparticles via a reduction of gold precursors on iron oxide nanoparticles of selected sizes as seeds. [94] Williams et al. synthesized gold-coated iron oxide NPs via iterative hydroxylamine seeding. The gold-coated particles exhibit a surface plasmon resonance peak that blue-shifts from 570 to 525 nm with increasing Au

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Coating modification with inorganic materials

123

deposition and the magnetic properties of NPs are largely independent of Au addition. In addition to core-shell structures, Au-coated MNPs with heterostructures are widely used in medical practice (Fig. 4.8). [95, 96] Gold also has a good photothermal property. Kim et al. fabricated a new gold nanorod (GNR) conjugated with MNP composite. [97] The GNR-MNP performed very efficiently as a photothermal agent for repeated cycles of photothermal ablation of bacteria.

Fig. 4.8

Synthesis process of Au-Fe3 O4 nanoparticles. [95] Gold nanoparticles are

attached to the surface of Fe3 O4 nanoparticles. Reproduced with permission from Ref. [95]. Copyright 2007 American Chemical Society.

Silver is another element among noble metal coatings. Silver coating makes MNPs germicidal, [98] because silver has very strong sterilization ability. The study of silver coating is very similar to that of gold. Silver can also form both core-shell structures and heterostructures. [99, 100] Chen et al. synthesized Fe3 O4 @C@Ag hybrid nanoparticles. [101] Owing to the carbon and silver on its surface, this nanoprobe, synergistically combining NIR-controlled drug release and the two imaging modes of MRI and two-photon fluorescence (TPF) imaging, could lead to a multifunctional system for medical diagnosis and therapy. Sometimes researchers utilize gold and silver together, looking for better biomedical properties. [102] Some rare earth elements can be also be used in surface modification via the formation of core-shell structures. For example, an Fe3 O4 @NaLuF4 :Yb,Er/Tm coreshell nanostructure with multifunctional properties was developed by step-wise synthesis (Fig. 4.9). [103] Comprising an Fe3 O4 core and a NaLuF4 shell, this class of nanoprobes combines the merits of three imaging modes, upconversion luminescence (UCL), MR and computed tomography (CT), and is suitable for various applications

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requiring different spatial resolutions and imaging depths.

Fig. 4.9

Synthesis process of Fe3 O4 @NaLuF4 nanoparticles. [103] Reproduced with permission from Ref. [103]. Copyright 2012 Elsevier Ltd.

4.5

Conclusions and outlook

This review presents the surface modification of MNPs by discussing separately three groups of surface modification agents and investigating the processes of applying them. With regard to ligand exchange and ligand absorption, two key modes of surface modification, an enormous variety of MNPs are discussed. Moreover, MNPs can be a multifunction platform for medical practice, in both diagnosis and therapy, after modifying the particles’ surface with optical dyes, targeting agents, therapeutic drugs or other functional molecules. Presently, the study of MNPs is developing rapidly. Some very encouraging nanotechnological methods such as nanotransfer printing, molecular-ruler technique, nanoskiving have been currently used to fabricate different magnetic nanostructures, which present more possible approaches of surface modification to improve the functionalities of MNPs. Researchers tend to attain MNPs that combine multiple functions that are much needed in clinical practice. However, the total full performaces of MNPs like stability, safety, economy and efficiency rather than only multifunctionality must be measured and considered if it is suitable that the MNPs can indeed be applied in medical practice. Besides, aspects such as biocompatibility, toxicity, in vivo and in vitro targeting efficiency, and long-term stability of the functionalized MNPs are also important in clinical translation of MNPs. Because those index of MNPs is closely bound up with the various types of surface modifiction,

References

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there is an immense requirement for surface-modification materials that are convenient,efficient, biocompatible and stabilized. It takes an average of 12 years for a new drug to advance from invention to clinical application with FDA approval, and biosafety remains a critical aspect of this process. Therefore, further development of surface modification is expected to realize the union of diagnosis and therapy at nanoscale, and with ever-improving techniques of surface-modification engineering, research in multifunctional MNPs is sure to remain a frontier of biomedical science.

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Diagnosis and Therapy

Chapter 5 Magnetic Nanoparticle-based Cancer Nanodiagnostics∗ Muhammad Zubair Yousafa) , Jing Yua) , †

Yanglong Houa) , and Song Gaob) a)

Department of Materials Science and Engineering, College of Engineer-

ing, Peking University, Beijing 100871, China b)

College of Chemistry and Molecular Engineering, Peking University,

Beijing 100871, China † Corresponding author. E-mail: [email protected] Diagnosis facilitates the discovery of an impending disease. A complete and accurate treatment of cancer depends heavily on its early medical diagnosis. Cancer, one of the most fatal diseases world-wide, consistently affects a larger number of patients each year. Magnetism, a physical property arising from the motion of electrical charges, which causes attraction and repulsion between objects and does not involve radiation, has been under intense investigation for several years. Magnetic materials show great promise in the application of image contrast enhancement to accurately image and diagnose cancer. Chelating gadolinium (Gd III) and magnetic nanoparticles (MNPs) have the prospect to pave the way for diagnosis, operative management, and adjuvant therapy of different kinds of cancers. The potential of MNP-based magnetic resonance ∗ Project supported by the National Natural Science Foundation of China (Grant Nos. 51125001, 51172005, and 90922033), the Research Fellowship for International Young Scientists of the National Natural Science Foundation of China (Grant No. 51250110078), the Doctoral Program of the Education Ministry of China (Grant No. 20120001110078), and the PKU COE-Health Science Center Seed Fund, China.

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(MR) contrast agents (CAs) now makes it possible to image portions of a tumor in parts of the body that would be unclear with the conventional magnetic resonance imaging (MRI). Multiple functionalities like variety of targeting ligands and image contrast enhancement have recently been added to the MNPs. Keeping aside the additional complexities in synthetic steps, costs, more convoluted behavior, and effects in-vivo, multifunctional MNPs still face great regulatory hurdles before clinical availability for cancer patients. The trade-off between additional functionality and complexity is a subject of ongoing debate. The recent progress regarding the types, design, synthesis, morphology, characterization, modification, and the in-vivo and in-vitro uses of different MRI contrast agents, including MNPs, to diagnose cancer will be the focus of this review. As our knowledge of MNPs’ characteristics and applications expands, their role in the future management of cancer patients will become very important. Current hurdles are also discussed, along with future prospects of MNPs as the savior of cancer victims.

5.1

Introduction

Diagnosis gives insight into a patient’s disease. Early medical diagnosis is a key to successful treatment and can save lives. Cancer is among the deadliest diseases around the globe, and its incidence is increasing alarmingly. [1] Regardless of the rapid progress in diagnostic procedures and treatments, the survival rate of cancer victims has shown little progress over the past three decades. [2] There is a need, therefore, to extend novel methodologies and technological advances for the accurate detection of early stages of cancer and for targeted therapies based on cancer-specific markers, which could lead to personalized medicine. Rapid growth in diagnostic nanotechnology has opened new horizons both in clinical care and in the laboratory, suggesting a dramatic future. The published work regarding the application of magnetic nanoparticles (MNPs) purely for in-vivo and in-vitro cancer diagnoses is limited. So, here in this review, we will discuss how MNPs can be employed to yield diagnostic insights for different cancers. MNPs have been widely used in a variety of molecular or clinical imaging modalities as they are biocompatible, have controllable sizes, and can be easily conjugated to functional groups or ligands in both in-vivo and in-vitro biological systems. The effectiveness of an imaging technique depends not only on its ability to image quantitatively both morphological and physiological functions of the tissue, but also on the contrast agent used to communicate with biomolecules. Several types of contrast media are used in medical imaging, and they

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Introduction

135

can roughly be categorized based on the imaging modalities where they are used. The use of contrast agents of nanometer scale has become commonplace in medical diagnosis. MNPs have fascinated scientists for over a century and are now heavily utilized in biomedical sciences and engineering as they have long been known to communicate effectively with biomolecules (Fig.5.1)[3] . Today these materials can be synthesized and modified with various chemical functional groups, which allow them to be conjugated with antibodies, ligands, and drugs of interest, and thus opening a broad range of potential advancements in biotechnology, and more importantly in diagnostic medical imaging via magnetic resonance imaging (MRI) coupled with computed tomography (CT), ultrasound (US), and positron emission tomography (PET). These imaging modalities differ not only in resolution, but also in the instrumentation and the type of nanoparticle (NP) that can be employed as its assistant. We try to sum up the huge published literature that portrays unique and non-conventional experimental and physical aspects of various types of MNPs, including the fabrication and design of targeted contrast agents to achieve high quality diagnostic applications. Advances in nanobiotechnology require a profound base and a comprehensive knowledge of biology, engineering techniques, imaging modalities, physics, chemistry, and especially the knowhow of their possible integration in nanoscale. This kind of multi-disciplinary association in the research field has enormous prospects for screening, early diagnosis, and most importantly personalized medicine.[4−7]

Fig. 5.1

The scheme illustrates two strategies to fabricate multifunctional MNPs and their potential applications. [3]

Practically speaking, the materials synthesized at nanoscale that can attain a high level of response from very small targeted agents are excellent candidates to be

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used as probes. Up to now, almost all types of nanomaterials have been investigated in various fields of research like bio-sensing, separation, imaging, and therapy, much more than their bulk counterparts. Various parameters like the high volume/surface ratio, surface tailorability, and multi-functionality of nanobiomaterials pose many new promises for biomedicine. Also, the magnetic, intrinsic optical, and/or electrical properties of nanomaterials offer significant prospects in diagnosis when it comes to the complicated and always changing biological settings within the body. Target-specific molecules are now the major players for ultrasensitive detection at the molecular level, and this target-specificity is extremely exploited through the large surface area of nanomaterials, enabling them to attach and bind to a great number of small targets, which in turn make them potentially useful both in-vitro and in-vivo diagnostics. MNPs are employed in nanotechnology applications to meet the demands of diagnostics for improved sensitivity and speedy detection in complex environmental and biological systems. Finally, we have cited some of the best biomedical and clinical applications of the developed MNP-based diagnostic architecture, including MRI and diagnostic magnetic resonance (DMR). Toward the end, we describe some ways and means by which this field could be more helpful and practical in the coming years.

5.2

Magnetic resonance imaging

MRI is a noninvasive diagnostic tool that employs magnetic fields to detect the varied water composition in organisms.[8,9,10] Different water proton relaxivity rates translate into contrasting images of different cells. MRI can be enhanced by reducing the longitudinal and transverse relaxation time of the water protons. [10] It employs non-ionizing electromagnetic radiation and is considered safe. Excellent crosssectional images of the internal structures of the body in any plane are produced by radio-frequency (RF) radiation when the body is exposed to carefully controlled magnetic fields. The procedure of image construction in MRI is very simple. A large magnet is applied, which induces a strong external magnetic field causing the nuclei of hydrogen atoms in water to align with the magnetic field. The energy released from the body in response to the RF signal is in turn used by a computer for image construction. [11] It took over 32 years for MRI to become a technique with immense potential for primary diagnostic investigation. MRI is better for cancer screening than magnetic resonance spectroscopy (MRS) and radionuclide techniques, as it can detect cancer at an early stage and with a relatively high spatial resolution. MRI of magnetic nanoparticle-labeled molecular targets has been demonstrated to be able to provide enhanced imaging contrast because the nature and the property of the

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Magnetic resonance imaging

137

MNPs can significantly shorten T2 relaxation time (Fig.5.2)[12] . Several emerging imaging techniques adopt another contrast mechanism, the magnetomotive effect, to actuate embedded MNPs to move periodically inside tissues by applying a controllable external time-varying magnetic field. These tiny mechanical movements can be measured by a sensitive imaging system to form images. Here are some advantages of MRI: a) It provides detailed images of soft tissues in-vivo, unlike other imaging techniques like X-ray, ultrasound, etc. b) MRI contrast agents (CAs) can be directly correlated with local biochemical processes or metabolic activities like blood flow and neuropsychology. c) MRI allows dynamic studies to be performed, like imaging of the beating heart, transport in the vascular system, the movement of joints, and the response of the central nervous system (CNS) to external stimuli. [13] These advantages influence the commercial manufacture of better and improved MRI scanners, where methods for the controlled growth, stabilization, and functionalization of nanostructures have been imported from the nanotechnology sector to produce a wide range of responsive and smart MRI-detected agents that can be applied to the biomedical field. [14, 15]

Fig. 5.2

5.2.1

Categories of MRI contrast agents based on NPs. [12]

MRI contrast enhancement using MNPs

Different characteristics of magnetic materials like superparamagnetism, high saturation field, and high field irreversibility enable them to show their potential from nanoscale up to bulk. With many advantages in diagnostics and biomedicine, the convenient scale of MNPs makes them subject to easy optimization of size and properties. The movement manipulation by an external magnetic force provides tremendous advantages

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for diagnosis in different locations of the body. MNPs’ contrast enhancement ability is based on the signal of magnetic moment of a proton captured by resonant absorption. [3] The unique properties of magnetic nanomaterials to detect tumors, pathogens, proteins, and other active biomolecules have attracted much research interest. [16] Different kinds of MNPs are currently being synthesized by various methods and have previously been reviewed in detail.[17−25] Contrast agents for MRI are chemical substances that are introduced to the part of the body being imaged. These agents improve the resolution of MRI by increasing or decreasing the brightness between different tissues or between normal and abnormal tissues. Through the use of MRI contrast agents, it is possible to detect smaller tumors, leading to earlier detection of cancer and enhanced treatment, avoiding invasive therapeutic methods. MNPs are excellent candidates for MRI contrast enhancement. Due to their size, they can be easily transported and diffused around the body, and do not require extensive chelating to render them biocompatible, unlike the gadolinium based contrast agents currently used. Also, iron oxide NPs are the only commercial T2 or negative contrast agents, due to their ease of synthesis and biocompatibility. For T2 contrast, healthy tissues/cells take up the NPs while tumor tissues/cells do not. When subjected to MRI, as a result of the presence of iron oxide NPs, the healthy tissue darkens, leaving the tumor tissue white, enabling the detection of cancer. However, iron oxides are weakly magnetic, as a result, their contrast enhancement for MRI is limited, and they are limited to detecting superficial tumors just under the skin. The magnetic resonance relaxation time of water in the tissue is altered by the presence of CAs surrounding the tissue, resulting in the increased intensity of water inside the tissue. Gadolinium complexes are used as positive contrast agents or signal enhancement, compared to gadolinium chelates such as diethylene triamino pentacetic acid (Gd-DTPA) and MNPs, and are considered more efficient as relaxation enhancers, exhibiting higher relativity and, in particular, a good negative contrast or signal suppression. Their effect on the relaxation measurable at nanomolar concentrations makes nanoparticulate agents in many ways complementary to the gadolinium agents. In addition, the advantages of these nanoagents, such as biocompatibility, selective uptake, targeted delivery, removal from the body, easy adjustment by changing the size and the nature of the surface coating of NPs, are imperative for in-vivo medical applications (see Fig. 5.3).[12] MNPs can be easily functionalized with molecules, may possess a range of hydrophobic and hydrophilic coatings, which themselves may influence bio-distribution, enabling a wide range of drugs and fluorescent compounds, all of which can be targeted to a specific area or tissue in the body. Proteins or antibodies

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Magnetic resonance imaging

139

can be targeted to the surfaces at a molecular, cellular, and/or tissue/tumor level in the body. [26] Moreover, extra potential offered by the magnetic moments can be applied to guide and trap NPs at the target site, where they may be used for a temperature-based response (Fig. 5.2)[12] . Noteworthy efforts have been directed to develop smart contrast agents that allow the very early detection of various cancers (serving as pre-symptomatic diagnostics) and would potentially be combined with highly effective targeted therapy. [17, 23, 26, 27]

Fig. 5.3

Biocompatible NP synthesis strategy: (a) reaction scheme for monodisperse

NPs by thermal reaction under surfactant, (b) surface modification of hydrophobic NPs. [12]

MRI contrast agents are based on different structures. They can be small chelates or may act as macromolecular systems. They could be based on iron oxide NPs. Chemical exchange saturation transfer (CEST) and hyperpolarization agents have previously been discussed along with their magnetic status, composition, biodistribution, and imaging applications. [28] It is very well known that the expression

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level of tumor specific molecular markers is very low in normal cells. Specific markers in tumor vessels are particularly well suited for targeted imaging because molecules at the surface of blood vessels are readily accessible to circulating compounds (see Fig. 5.4). [29]

Fig. 5.4

Mechanisms of tumor targeting. (a) Probes that distinguish only tumor cells may

accumulate better at a tumor compared to a non-targeted probe. (b) Probes that identify tumor vessels build up in the tumor but do not enter the tumor, using passive mechanisms. (c) Probes that show the combined effectiveness of the two targeting mechanisms to identify both the vessels and tumor cells. (d) Tumor-penetrating targeting probes. [29]

5.2.1.1

Gadolinium (III) based MRI contrast agents

As depicted in Fig. 5.5, Gd(III) based contrast agents, the first type to be used in MRI, are of different type depending upon the desired contrast enhancement, like extracellular fluidic agents (ionic or neutral), blood pool agents (albumin-binding gadolinium complexes or polymeric gadolinium complexes), and organ specific agents (hepatobiliary), mostly used in the chelated form[30] . The Gd(III) chelates do not

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Magnetic resonance imaging

141

pass the blood-brain barrier because they are hydrophilic. Thus, they are useful in contrast-enhancing lesions and tumors where the Gd(III) leaks out. In the rest of the body, Gd(III) initially remains in the circulating blood but is then distributed into interstitial spaces or eliminated by the kidneys. [28] Presently, nine different types of gadolinium-containing contrast agents are available globally. [28] As a free water-soluble ion, gadolinium (III) is somewhat toxic, but is generally regarded as safe when administered as a chelated compound. In animals, the free Gd(III) ion exhibits a 100–200 mg/kg 50% lethal dose (LD50), but the LD50 is increased by a factor of 100 when Gd(III) is chelated, so its toxicity becomes comparable to iodinated X-ray contrast compounds. [31] The chelating carrier molecules for Gd for MRI CA use can be classified by whether they are macro-cyclic or have a linear geometry and whether they are ionic or not. Cyclical ionic Gd(III) compounds are safe as they are considered the least

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Fig. 5.5

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Magnetic Nanoparticle-based Cancer Nanodiagnostics

(a) Structures of the Gd(III)-based MRI contrast agents currently used in the

clinical practice, [30] (b) examples of macromolecule-based Gd(III) contrast agents. [30]

likely to release the Gd(III) ion. However, the use of some Gd(III) chelates in persons with renal diseases is linked to a rare but severe complication, nephrogenic fibrosing dermopathy, [8] also known as nephrogenic systemic fibrosis (NSF). Right now, the NSF has been found to be linked with four gadolinium-containing MRI contrast agents. The World Health Organization (WHO) issued a restriction on the use of several gadolinium contrast agents in November 2009, stating that there is a high risk in using Gd-containing CAs in liver transplant patients and newborn babies.[30−33] The augmentation is pragmatic when the chelated gadolinium [10] or super-paramagnetic iron oxide is used. [9] It is well known that the gadolinium diethylene triamine pentacetate acid (Gd-DTPA) [34] (Tables 5.1 and 5.2) has been used more extensively for MRI than any other material. Gd(III) gives contrast and DTPA serves as a chelating ligand forming a complex with Gd(III) to minimize the leaching of the

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143

cytotoxic, ionic Gd(III) into the cellular milieu. They can enhance the contrast, but the imaging application of Gd-DTPA is still vulnerable by their rapid renal clearance. [35, 36] Table 5.1

List of Gd(III) based commercially available CAs (adapted from http://www.emrf.org/ and http://www.mr-tip.com/).

Drug name

Active ingredient(s)

Original approval

GASTROMARK

FERUMOXSIL

6-Dec-96

MAGNEVIST

GADOPENTETATE

2-Jun-88

DIMEGLUMINE OMNISCAN

GADODIAMIDE

8-Jan-93

OPTIMARK

GADOVERSETAMIDE

8-Dec-99

OPTIMARK

GADOVERSETAMIDE

8-Dec-99

GADOFOSVESET

22-Dec-08

IN PLASTIC CONTAINER ABLAVAR

TRISODIUM EOVIST

GADOXETATE DISODIUM

03-Jul-08

Drug name

Company

Marketing status

Application

GASTROMARK

AMAG PHARMS INC

prescription

gastrointestinal

MAGNEVIST

BAYER

prescription

lesion visualization

HEALTHCARE OMNISCAN

GE HEALTHCARE

prescription

neuro/ whole body

OPTIMARK

MALLINCKRODT

prescription

neuro/ whole body

OPTIMARK

MALLINCKRODT

prescription

neuro/ whole body

IN PLASTIC CONTAINER ABLAVAR

LANTHEUS

prescription

MEDICAL

angiography, capillary permeability

BAYER

prescription

EOVIST

liver lesions

HEALTHCARE

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The second most common benign hepatic tumor is known as focal nodular hyperplasia and can be diagnosed employing liver-specific contrast-enhanced MRI. Multiple and confluent lesions are diagnosed by using gadolinium-dimeglumine as the MRI CA. It is pertinent that focal nodular hyperplasia could be managed successfully and non-invasively, avoiding unnecessary surgery. [37] Extracellular CT and MRI contrast media are found to be reproducible when gadoxetic acid-enhanced MRI is employed. Contrast accumulation in hepatocellular adenomas (HCAs) could be present during the hepatobiliary phase of gadoxetic acid. True hyperintense HCAs during the hepatobiliary phase are rare but in the vast majority of cases are significantly fewer than that in the liver. [38]

Fig. 5.6

Illustration of folate receptor-targeted bimodal liposomes containing Gd(III) chelates for MR imaging of ovarian cancer. [39]

The pH of media also plays a role in nanodiagnostics. In acidic media, the GdDTPA complex in the nanoprobe’s polymeric coating causes a dequenching of the nanoprobe, with a corresponding increase in the T1 -weighted MRI signal. An increase in the 1/T1 signal in a folate-conjugated nanoprobe (Fig. 5.6) is observed as a result of its degradation by a HeLa cell’s lysosome acidic (pH 5.0) environment in an intracellular release of Gd-DTPA complex with subsequent T1 activation[39] . Also, the co-encapsulation of anti-cancer drug (Taxol) along with the Gd-DTPA within the folate receptor results in the T1 activation of the probe, which in turn concurs

5.2

Magnetic resonance imaging

145

with the drug release and the cytotoxic effect in-vitro, ensuring that T1 nanoagents show promise for pH based diagnosis of tumors and evaluation of drug targeting by MRI. [40] Early hepatocellular carcinoma (HCC) and benign hepatocellular nodules are often intermingled, leading to false diagnosis with gadoxetic acid-enhanced MRI (Gd-EOB-MRI). A study of Gd-EOB-MRI was conducted, imaging 34 patients with 29 surgically diagnosed early HCCs and 31 surgically diagnosed benign hepatocellular nodules. Criteria like diffusion-weighted imaging (DWI), the signal intensity at each sequence, the presence of arterial enhancement and washout were noted, led to better diagnostic performance when compared to the conventional imaging criteria (arterial enhancement and wash out). A comparative analysis confirmed that specificity was 100.0% for both criteria, ensuring that diagnostic criteria for Gd-EOB-MRI may help to improve the discrimination of early HCC from benign hepatocellular nodules. MRI findings of T1 hypointensity, T1 hyperintensity, DWI hyperintensity on both low and high b-value images (b = 50 s·mm−2 and 800 s·mm−2 , respectively), arterial enhancement, late wash out, and hepatobiliary hypo intensity were chosen as the diagnostic criteria. Lesions were supposed to be malignant if they satisfied three or more of the above criteria. The higher sensitivity via Gd-EOB-MRI confirmed its superiority as a diagnostic tool over the conventional method, which is based on the arterial enhancement and washout alone (58.6% vs 13.8%, respectively; p = 0.0002). [41] MR and optical imaging based on hyaluronic acid-ceramide (HACE) has also been reported as a conjugating DTPA with HACE for the chelation of gadolinium as an MR contrast agent. The conjugation of Cy5.5 to the HACE shows a homogeneous distribution when particle sizes and shapes are considered during the self-assembly of an HACE-based nanoprobe, found to be non-toxic in both U87-MG (low expression of CD44 receptor) and SCC7 (high expression of CD44 receptor) cells. SCC7 cells’ uptake efficiency is better than that of 87-MG cells. An HACEbased nanoprobe is found to be better than a commercial formulation (Magnevist), both in-vitro and in-vivo. An improved accumulation of the nanoprobe in the tumor region as monitored by an NIRF imaging study ensures that the HACE-based dualimaging nanoprobe is possibly the best choice to diagnose the cancer, employing passive as well as active tumor targeting. [89] A tumor’s extracellular matrix has an abundance of cancer-related proteins that can be used as biomarkers for cancer molecular imaging. Generation 1 lysine dendrimer interacts with CLT1-dL-(Gd-DOTA)(4) that is blended by conjugating four Gd-DOTA monoamide chelates to produce a CLT1 peptide. The T − 1 relaxivity of

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CLT1-dL-(Gd-DOTA)(4) is 40.4 mM−1 · s−1 per molecule (10.1 mM−1 · s−1 per Gd) at 37 ◦ C and 1.5 T. High binding specificity of CLT1 was observed in orthotopic PC3 prostate tumors in mice. Improved tumor contrast enhancement in male athymic nude mice bearing orthotopic PC3 prostate tumor xenografts at a dose of 0.03 mmol Gd/kg confirmed that the peptide-targeted MRI contrast agent has potential for more sensitive MR imaging. [90] Table 5.2

Types of Gd(III) based MRI CAs with category, engineered methodology, and the cancer diagnosed.

Gd(III) based con-

Sub-category

trast agent type Macromolecular

Engineering

Cancer diagnosed

Reference

methodology chelates

Gd-DTPA

brain Tumor

[42]

Gd(III) chelates /

Gd-DTPA-P846

brain Tumor

[43]

complexes based

Gd-DTPA-P792

breast Tumor

[44]

albumin (Gd-

blood and tissue

[45], [46]

DTPA)

prostate cancer

[47]– [49]

colorectal cancer

[50]– [52]

vascular tissues

[53], [54]

PAMAM propy-

vasculature liver

[55], [56]

lene imine PLL

tumor

[57]– [60]

bio-degradable

polydisulfide

breast tumor

[63]– [66]

PEG liposome core

encapsulated core

solid tumors liver

[67], [68]

protein based

linear polymer based polylysine dextran dendrimer based

[61], [62] Liposomal based

surface conjugated tumor brain tumor

Gd(III) based

encapsulated core

glioma brain tumor

dual-mode

[69] [70], [71] [72] [73]

Targeted Gd(III) based tumor Based protein based dendrimer based

liposomal based

cyclic-RGD

liver cancer vascu-

[74]

CLT1&2

lature

[75]

HER2 EGFR

breast cancer

[76, 77]

glioma

[78]

antibodies peptides ovarian tumor

[79]

folate

breast cancer brain

[80], [81]

tumor

[81], [82]

epithelial cancer

[83]

solid tumors

[84]

ovarian cancer

[85]

antibodies peptides malignant

[86]– [88]

folate

[39], [62]

melanoma breast cancer solid tumors

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147

Ultra small paramagnetic Gd2 O3 NPs (mean diameter < 5 nm) have the highest Gd density of all paramagnetic contrast agents and can act as contrast agents in MRI, especially in T1 -weighted MRI. High relaxivities and signal enhancement modulated by the interactions of water molecules with Gd2 O3 are due to the optimal surfaceto-volume ratio. Gd2 O3 nanocrystals coupled with polyethylene glycol (PEG) by grafting procedures are lengthy and less effective in recovering losses. One-pot synthesized Gd2 O3 coated with PEG, found to be colloidally stable in aqueous media, provides high longitudinal relaxivities and small r2 /r1 ratios (r1 = 14.2 mM−1 · s−1 at 60 MHz; r2 /r1 = 1.20) for T1 -weighted MRI. F98 glioblastoma multiforme cells labeled with the contrast agent, implanted in mice brains, emerged positively contrasted at least 48 h after implantation, showing the development of the brain tumor in each one of the implanted mice. The comparison of PEG-Gd2 O3 with the commercially available iron oxide NPs shows them as a strong positive contrast enhancement in T1 -weighted imaging both in-vivo and in-vitro. [91] A retrospective study showed the results of about 1802 imaging studies of MRI of oncology patients performed between March 2009 and July 2012 in the Radiology and Nuclear Medicine Departments of Acıbadem Adana Hospital, Adana, Turkey. On MRI, skeletal muscle metastases mostly revealed an iso-intense signal on T1 -weighted images, a heterogeneous high signal with peri-tumoral edema on T2 -weighted images, and extensive enhancement with central necrosis on gadoliniumDTPA enhanced images. They concluded that extensive tumoral enhancement, central necrosis, and peri-tumoral edema are highly acceptable features of skeletal muscle metastasis. [92] Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is mostly employed in accordance with other prognostic factors in rectal cancer diagnosis. Gadolinium contrast-enhanced T1 -weighted DCE-MRI with a 3 Tesla scanner of 29 patients with rectal cancer was performed prior to surgery. A time-signal intensity curve with four semi-quantitative parameters (i.e., steepest slope, time to peak, relative enhancement during a rapid rise, and maximal enhancement) and the morphologic prognostic factors (i.e., T stage, N stage, and histologic grade) were noted in addition to tumor angiogenesis. But no significant correlations were found between DCE-MRI parameters and T stage, K-ras mutation, or microsatellite instability that affirms that DCE-MRI is useful in prognostic information regarding angiogenesis and histologic differentiation in rectal cancer. [93] Gadolinium diffusivity can also quantify the tracer transport in tumors. Fourteen different human xenografts were implanted in 14 mice that were subjected to dynamic contrast-enhanced MRI. Estimations of tracer concentration can be calcu-

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lated by using a k-means clustering algorithm to clearly identify the perfused and necrotic tumor regions exhibiting delayed and slow enhancement. [93] Chow et al. [94] investigated the feasibility of detecting and characterizing liver fibrosis using CLT1 peptide-targeted nanoglobular contrast agent (Gd-P) with dynamic contrast-enhanced magnetic resonance imaging in an experimental mouse model of liver fibrosis at 7 T. Differential enhancements were observed and characterized between the normal and the fibrotic livers using Gd-P at 0.03 mmol/kg, when compared with non-targeted controls (Gd-CP and Gd-C). For Gd-P injection, both the peak and the steady-state ∆R1 of the normal livers were significantly lower than those after 4 and 8 weeks of CCl4 dosing. Liver fibrogenesis with an increased amount of fibronectin in the extracellular space in insulted livers were confirmed by histological observations. Their results indicated that dynamic contrast-enhanced magnetic resonance imaging with CLT1 peptide-targeted nanoglobular contrast agent can detect and stage liver fibrosis by probing the accumulation of fibronectin in fibrotic livers. The work on gadolinium chelators linked to various substrates to develop MRI contrast agents with high relaxation efficiency spans almost three decades now. Ligand based compounds already used in clinics are approved contrast agents, while new bifunctional chelators, based on complexes, have been reported recently. They show a powerful relaxation effect, quicker complexation kinetics, and simpler synthetic procedures. Some new synthetic strategies have shown great promise recently for bifunctional chelator applications in MRI. [95] It is reported that about 40% of patients subjected to MRI receive Gd(III)based CAs. Also the safety and effectiveness for the improved cancer diagnosis is progressing. The relaxivities of Gd(III) chelates can be significantly increased by conjugating biocompatible macromolecules and NPs. The flow of Gd(III) chelates on the NPs and macromolecules after the MRI examinations can be aided by attaching biodegradable structures. Gd(III) CAs that specifically bind to tumor markers can produce significant tumor contrast enhancement at reduced doses, as shown by preclinical studies, and they also demonstrate improved contrast enhancement for MRI as compared to currently available clinical CAs in animal models. Detailed toxicological and pharmaceutical evaluations are still required to determine the safety of the agents and enable further steps in clinical development. [30] 5.2.1.2

Iron oxide NP-based MRI contrast agents

Various NPs have been investigated as MRI contrast agents. Iron oxide NPs have been widely used as MRI contrast agents due to their feature to shorten T2∗ relaxation time in different body parts and organs like spleen, liver, and bone marrow.

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Magnetic resonance imaging

149

Currently, superparamagnetic iron oxides (SPIO) and ultra-small SPIO (USPIO) are used extensively (Table 5.3)[96] . Some of them have been approved by the FDA and commercially available (Abdoscanr , GastroMARKr , Resovistr , Feridexr ) while some are in different clinical phases (Supravistr , Combidexr , Clariscanr ). [97] SPIOs and USPIOs have even been used for lymph-node imaging, can be functionalized with Table 5.3

List of iron oxide based NPs approved for use as MRI CAs.

(Modified from http://www.emrf.org/ and http://www.mr-tip.com/). [96] Short name

Generic

Trade name

Signalb)

namea) AMI-227

ferumoxtran-

Combidex/sinerem positive ornegative

10 (USPIO) AMI-25

ferumoxides

Feridex/endorem

negative

(SPIO) Code 7228

ferumoxytol

positive

(USPIO) SH U 555 A

ferucarbotran

Resovist/cliavist

negative

Supravist

positive

Clariscan

positive

(SPIO) SH U 555 C

ferucarbotran (USPIO)4

NC-100150

PEG-feron (USPIO)

Short name

Status

Size/nm

Bolus injection

Developer

AMI-227

development

30

no

AMAG Pharmaceuticals Inc. (USA) Guerbet, SA (EU)

AMI-25

for sale

100

no

AMAG Pharmaceuticals Inc. (USA) Guerbet, SA (EU)

Code 7228

development

30

yes

SH U 555 A

for sale (EU,

62

yes

AMAG Pharmaceuticals Inc.

Australia,

Bayer Schering Pharma AG

Japan)/development (USA) SH U 555 C

development

25

yes

Bayer Schering Pharma AG

NC-100150

development

20

yes

Amersham Health

(discontinued) a)

Short description; b) high local concentrations and/or appropriate pulse sequence parameters,

negative contrast can be achieved (e.g., first-track bolus).

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a variety of bio-materials, and facilitate targeted imaging via the site-specific buildup of NPs at specific targets. As far as the preparation of SPIOs and USPIOs is concerned, the reduction and co-precipitation reactions are the conventional methods that employ a mixture of ferrous and/or ferric salts, a hydrophilic polymer in aqueous media, while uniform ferrite NPs with high crystallinity have also been reported, employing the thermal decomposition method of metal precursors using surfactants in organic media. Ligand exchange with water dispersible ligands and encapsulation with biocompatible shells are some of the methods developed to make them water-soluble and biocompatible. Modified uniform ferrite NPs, with improved relaxation properties, have successfully been employed as new T2 MRI contrast agents. Recently, extensive research has been conducted to develop nanoparticle-based T1 contrast agents to overcome the drawbacks of iron oxide nanoparticle-based negative T2 contrast agents. [12] SPIO and ultra small SPIO NPs SPIO, already approved for clinical use within the human circulatory system, is the main MRI contrast agent for imaging various pathological subjects.[24,98−105] The reduced toxicity and increased biocompatibility of MNPs have been the main aspects of improvement since their use in biomedicine. It is relevant that a lot of work has already been done by different scientists to modify the surface of SPIO NPs in a number of different ways. SPIO nanoparticles’ (SPIONs) signature is easily sensed by MR detection, and the particles are non-toxic and approved for clinical use. [106] They were at first restricted to the neuro-axis. Today, SPIONs are one of the most widely used CAs that can cover all the body regions, providing a better imaging for diagnostic decisions by the physicians. Even so, it is believed that better understanding of its utilization in combination with other techniques or alone to maximize the diagnostic certainty may open still other horizons in the diagnostic world. One of SPION’s best capabilities is to shorten T2∗ relaxation time in the liver, spleen, and bone marrow. Ferrite NPs are uniform, and they show high crystallinity and improved T2 MRI contrast relaxation properties. They can also be ornamented with targeting agents, leading to a site-specific build up of NPs at desired pathological locations within the body. The development of NP-based T1 contrast agents to overcome the drawbacks of iron oxide nanoparticle-based negative T2 contrast agents is still being explored. [12] Under this heading we will discuss how MRI contrast enhancement, using different kinds of MNPs and nanostructures, could be more useful than ever. Nakamura et al. [107] compared different contrast agents and found that SPIOMRI tumor detection results were similar to those found by dynamic CT and plain

5.2

Magnetic resonance imaging

151

MRI, but lower than those attained by Gd-based MRI. Different combinations were analyzed with the conclusion that better results were obtained in some combinations than in others. The plain MRI and SPIO-MRI combination should be useful for assessing tumor maturity and for choosing a therapeutic modality, because it is based on blood flow patterns. For the combination of Gd dynamic MRI and SPIO-MRI, the effectiveness varies with intra-tumor blood flow patterns. On the other hand, another study concluded that contrast-enhanced ultrasonography is an important system to forecast the grading pattern of HCC patients and may be considered as an alternative to SPIO-enhanced MRI. [108]

Fig. 5.7

In-vitro targeting based on antigens and SPIO: ELISA plates were coated with

mouse IgG at selected protein concentrations. The wells coated with mouse IgG were incubated either with antibody conjugated horseradish peroxidase or the SPIOs at 37 ◦ C for 1 h. (a) Wells were incubated with goat anti-mouse IgG conjugated with horseradish peroxidase. Horseradish peroxidase activity was detected by 2,2’-azino-bis(3-ethylbenzothiazoline-6sulphonic acid) (ABTS). (b) Wells were incubated with SPIOs conjugated with goat antimouse IgG. Iron content of bound SPIOs was measured using the ferrozine method. (c) and (d) The plate was loaded with designated amounts of 5 nm or 14 nm SPIOs suspended in 50 µL of water and imaged with a 7 T MRI instrument using spin-echo sequence with echo times of 12 ms and 60 ms, respectively. (e) The T2 effect calculated based on MRI images. [109]

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By PEG coating SPIOs, the T2 relaxivity per particle can be increased more than 200-fold. In-vivo tumor imaging results have demonstrated the potential of SPIOs for clinical applications. Although a quick removal of SPIOs from the circulation may be beneficial for minimizing the background signal generated from unbound SPIOs, longer-circulating SPIOs may increase the chance of binding to the target molecules, thus an enhanced contrast. Adding free coating molecules to an injected SPIO solution can significantly prolong its blood circulation. Additional studies are being conducted on the circulation and bio-distribution of DSPE-PEG coated SPIOs to obtain a better understanding of their pharmacokinetics and the methods to modulate their bioavailability (see Figs. 5.7 and 5.8). [109]

Fig. 5.8

In-vivo tumor imaging. MRI experiments were performed using a spin-echo

sequence. (a) Arrow shows the location of the subcutaneous tumor. (b) and (c) MR images of tumor before probe injection. (d) and (e) MR images collected after 1 h following the injection of 14 nm SPIONs conjugated with antibodies against mouse VEGFR-1. Red dotted lines in panels (b) and (d) outline the tumor. Scale bar represents 5 mm. [109]

The theoretically predicted maximum of r2 relaxivity is achieved by optimizing the overall size of ferri-magnetic iron oxide NPs. Water-dispersible ferri-magnetic iron oxide nanocubes (WFIONs) with an edge length of 22 nm, encapsulated with PEG-phospholipids, exhibit high colloidal stability in aqueous media. In addition, WFIONs do not affect cell viability at concentrations up to 0.75 mg Fe/ml. In comparison with the commercialized T2 MRI contrast agents, such as Feridex, the in-vivo MR tumor imaging using a clinical 3-T MR scanner with intravenous 22-nm-sized WFIONs injection of enhanced colloidal stability and high r2 relaxivity (761 mM−1 ·s−1 ) is found to exhibit superior T2 contrast effect. The combination of suitable targeting ligands with WFIONs will open the doors to take part indecisive roles in the early diagnosis of tumor metastasis (see Figs. 5.9–5.11). [110]

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Fig. 5.9

153

(a) TEM image of 22 nm WFIONs dispersed in water. The average size of

WFIONs is 22 ± 2.6 nm, and their shape is cubic (inset: HRTEM image). (b) Picture showing high colloidal stability of WFIONs in water. The NPs are not aggregated even in an external magnetic field. (c) DLS data for WFIONs in water. Hydrodynamic diameter of WFIONs is 43±10 nm. (d) The M –H curves of magnetic iron oxide NPs. Whereas the saturation magnetization is independent of the nanoparticle size, the remnant magnetization and coercivity decrease with the decreasing size. [110]

Two intravenous formulations with nanoscale SPIO particles, ferumoxides and ferucarbotran, are approved specifically for liver MRI. They may be cleared from the blood by phagocytosis, accomplished by a reticuloendothelial system (RES), so that uptake is observed in the normal liver, spleen, bone marrow, and lymph nodes. After the intracellular uptake, SPIOs are metabolized in the lysosomes into a soluble, the non-superparamagnetic form of iron that becomes a part of the normal iron pool (e.g., ferritin, hemoglobin). [111, 112]

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MR contrast effect of ferri-magnetic iron oxide NPs on changes in size. (a) The

T2 -weighted MR images of ferri-magnetic iron oxide NPs at various concentrations of iron at 3 T, (b) the corresponding color-coded images. (c) Plots of R2 values of ferri-magnetic iron oxide NPs and (d) comparison of their r2 values. [110]

SPIO-enhanced MRI images are more accurate in the characterization of focal hepatic lesions than the review of SPIO-enhanced images alone. [113] In one study, Feridexr -enhanced T2 -weighted images revealed additional lesions not seen on the unenhanced images in 27% of cases and additional lesions not seen by the conventional (non-spiral) CT scans in 40% of cases; the additional information would have changed the therapy in 59% of cases. [114] The metastasis detection with SPIO CA is also related to the presence or absence of lesions in cancerous cells/tissues and the surrounding cells/tissues. Undifferentiated HCC generally demonstrates no change in signal intensity when compared with T2 /T2∗ -weighted images in unenhanced and SPIO-enhanced imaging, resulting in an enhanced contrast-to-noise ratio of the lesion. [115] It is pertinent to mention that some problems in clinical use may arise due to the relative contradiction in the amount of reticuloendothelial cells in focal nodular hyperplasia and hepatic ade-

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noma.

Fig. 5.11

(a) In-vitro cytotoxicity test of WFIONs. The viability of the B16F10 cells

was determined by an MTT assay after incubation with various concentrations of WFIONs for 24 h (n= 3). (b) The T2 -weighted MR image of dispersed cells in agarose. The cells were incubated with various concentrations of WFIONs for 24 h. [110]

The conjugation of iron oxide NPs and holo-transferrin, and an increased receptor level can affect MRI signals considerably. [115] SPIONs and protein combination may detect apoptotic cells successfully as exhibited both in-vivo, in a tumor treated with chemotherapeutic drugs and in-vitro, with isolated apoptotic tumor cells and drugs. [116] Recently, monodisperse SPIONs conjugated to amphiphilic copolymers synthesized from methyl methacrylate and PEG methacrylate by atom transfer radical polymerization were conjugated with folic acid. SPION micelles were biologically evaluated by employing MTT in HeLa cells, confirming the potential application of these nanoplatforms for cancer theranostics. [117] Feridex-labeled cells depicting dual-modality (MR and terahertz (THz) imaging) were assessed using SKOV3 cells at variable concentrations, like 0 mM, 0.35 mM, 0.70 mM, and 1.38 mM. MR and THz images were taken 1 , 3, 7, and 14 days after

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the inoculation of mice. It was shown that the signal intensities of both THz images and T2∗ -weighted MR images of Feridex-labeled SKOV3 increased with increasing r concentration in a similar pattern, but the signal intensities of in-vivo Feridex° MR and THz images from mice decreased over time. More cellular and molecular studies are needed to further standardize and improve this non-invasive multimodal imaging method as the leading imaging modality. [118] The concept of using USPIONs is not new. Both SPIO and USPIO have shown exceptional hepatic uptake for MRI. However, USPIO preparations may aid in the further characterization of focal liver lesions, as they have displayed greater T1 effect in the liver and in some focal liver lesions. [119] Lots of different methods have been reported for their synthesis, characterization, and potential applications in the diagnosis of different cancers via MRI.[120−124] 5.2.1.3

Mn based MNPs

Paramagnetic chelates and ferro MNPs are developed as MRI contrast agents to effectively improve the tissue contrast by altering the relaxation rates of water protons in the tissue of interest. Although Gd(III)-based CAs are widely used, they are associated with nephrogenic systemic fibrosis (NSF), a disease affecting a small percentage of kidney deficient patients who have a history of exposure to Gd(III)based contrast agents.[125−127] Due to the problem of NSF, effectual non-gadolinium contrast agents with lesser toxicity may replace Gd(III)-based MRI contrast agents. An alternative class of MRI contrast agents is paramagnetic manganese (II) chelates or compounds. Manganese-based contrast agents have a distinct biodistribution pattern and an efficient contrast enhancement in the liver myocardium and brain. An oral formulation of MnCl2 (lumaEnhance) and an intravenous formulation of mangafodipir trisodium (MnDPDP) are commercially available for clinical use. [128, 129] An increased dose is desirable to produce enough contrast enhancement, but it may lead to toxicity. Therefore, their relatively low relaxivity is the area of concern that needs to be addressed either by chemical modification or by improving their relaxivities and optimizing their pharmacokinetics and bio-distribution.[59,130−133] Recently, polydisulfide Gd(III) chelates, biodegradable macromolecular MRI contrast agents, were introduced to tackle the safety issue associated with other macromolecular contrast agents. They have prolonged circulation, increased relaxivity, and preferential tumor accumulation as compared to small-molecular Gd(III) chelates. [64, 65, 134, 135] After degradation into oligomeric Gd(III) chelates, they can be excreted via kidneys just after imaging. [136] Manganese (II) and polydisulfides in combination have a better contrast enhancement at a relatively low dose and are

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very important as far as the safety and toxicity are concerned. After the in-vivo contrast enhancement of the agents were evaluated in female nu/nu athymic mice bearing MDA-MB-231 breast cancer xenografts, it was concluded that polydisulfide Mn (II) complexes could serve as non-gadolinium biodegradable macromolecular MRI contrast agents (see Figs. 5.12–5.14). [137]

Fig. 5.12

(a) MR images of MnCl2 , Mn-DTPA cystamine copolymer (MDCC), and Mn-

EDTA cystamine copolymer (MECC) in water as a solvent at the concentrations of 0.2 mM, 0.4 mM, 0.6 mM, and 0.8 mM. (b) The 1/T1 versus concentration plot of MnCl2 , MDCC, and MECC for the calculation of the longitudinal relaxation rate R1 . [137]

Manganese-enhanced MRI (MEMRI) has been evaluated using human tumor cell proliferation. The relationship between proliferation and calcium influx was explained, and it was found that the MEMRI as a non-invasive method is a better option for investigating this link. The MEMRI is appropriate for the in-vivo examination of human prostate cancer. [138] Different combinations of Mn porphyrins-MRI probes, like Mn(III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP5+) and Mn(III) meso-tetrakis (N-n-hexylpyridinium-2-yl) porphyrin (MnTnHex-2-PyP5+), are used to identify prostate cancer. They imitate powerful superoxide dismutase, peroxy nitrite scavengers and modulators of cellular redox-based signaling pathways through adjunctive anti-neoplastic activity. Phantom studies have shown that they are potentially ap-

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plicable as novel diagnostic imaging probes as they have 2–3 fold higher T1 for both metalloporphyrins in comparison to the commercially available gadolinium chelates. MnTE-2-PyP5+ and MnTnHex-2-PyP5+ have shown MR relaxation changes in prostate tumor xenografts just after a single injection. The capacity of metalloporphyrin for prostate malignancy diagnosis by MRI is proved by the results that show six-fold improvements in contrast enhancements in prostate tumors when compared to surrounding noncancerous tissues. [139]

Fig. 5.13

Three dimensional coronal images before (0 min) and at 2 min, 5 min, 10 min,

30 min, and 60 min after the injection of MnCl2 , Mn-DTPA cystamine copolymers, and Mn-EDTA cystamine copolymers at a dose of 0.05 mmol Mn(II)/kg. [137]

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Magnetic resonance imaging

Fig. 5.14

159

Two dimensional spin-echo images of the tumor before (0 min) and at 2 min,

5 min, 10 min, 30 min, and 60 min after the intravenous injection of MnCl2 , Mn-DTPA cystamine copolymers, and Mn-EDTA cystamine copolymers at a dose of 0.05 mmol Mn/kg. [137]

Although agglomerates are more efficiently internalized by HT-1080 cells, no clear difference in signal is measured between USP-MnO and SP-MnO-labeled cells at similar concentrations of Mn per cell. Compared with iron oxide particle suspensions in which the agglomeration in aqueous media results in large changes of relaxometric ratios and drastic decreases of signal intensity, the suspensions of MnO particles preserve their MR signal enhancement properties upon agglomeration. These properties could be exploited for more quantitative cell labeling and tracking applications with MRI, using more complex cell cultures such as stem cells, Langerhans islets, or immune cells (See Figs. 5.15–5.17). [140]

Fig. 5.15

(a) and (b) TEM image and modeling (120 keV) of mono-disperse MnO par-

ticles used for relaxometric and cell labeling studies. (c) Dilutions of DMSA-PEG-coated SPMnO, imaged with a T1 -weighted MRI spin-echo sequence. [140]

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The T1 -weighted MR images of HT-1080 cells labeled with (a) SPMnO (0.38 mM),

(b) USPMnO (0.49 mM), and (c) Mn2+ (0.27 mM). The number under each pellet indicates the mass of Mn detected per cell. (d) Mn uptake in labeled cells, depending on the concentration of Mn in the incubation medium. [140]

Fig. 5.17

TEM of HT-1080 cells incubated with ((a),(b)) SPMnO and ((c),(d)) USPMnO. [140]

Manganese oxide (MnO) NPs have been proposed as a promising positive MRI contrast agent for cellular and molecular studies. Mn-based contrast agents could enable T1 -weighted quantitative cell tracking procedures in-vivo based on the signal enhancement. It is well known that manganese can go into cells via different transport systems, regulated by the plasma membrane calcium sensing receptor (CaSR), so the biological activity of Mn2+ ions and their MR contrast agent ability have opened up the possibility of using manganese-enhanced MR imaging (MEMRI) to image functions and pathology of tissues.

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161

Magnetic heterostructures

To overcome the disadvantages of Gd-complex based T1 MRI contrast agents, the development of nanoparticulate T1 contrast agents that contain Gd3+ or Mn2+ ions has been intensively pursued in recent years.[141−143] Gold NPs coated with a monolayer of Gd-complexed, DTPA-based ligand may increase in relaxivity (as compared to small-molecule analogues), presumably due to the limited restriction of rotational diffusion of the nanoparticle-attached Gd ions. The relaxivity can be further increased by self-assembling a polyelectrolyte on the Gd-studded NPs, and NPs can be readily functionalized, as illustrated by co-adsorbing a biotin-based recognition unit. [141] Recent efforts have shown that nanoscale materials, specifically, metal-based NPs, are promising for the expansion of multi-functionalities together and make available the processes and mechanisms to figure out the combination of both drugs and contrast agents in specific organs, tissues, and cells. Based on the specific sub-cellular locations via DNA hybridization to intracellular targets, Gd(III)-modified DNA-TiO2 semiconducting NP constitutes a novel nanosystem that can target exact DNA sequences. In addition, Gd(III)-modified DNA-TiO2 nanoparticles can also simultaneously be detected via MR imaging in cells (see Figs. 5.18 and 5.19). [142]

Fig. 5.18

Synthesis programming leading to methodology: (a) dopamine-modified MR

contrast agent (DOPA-DO3A), (b) functionalization of TiO2 NPs. [142]

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Bimetallic MR contrast agents like Au3 Cu1 are hollow nanostructures capable of enhanced signal contrast both in T1 -weighted and T2 -weighted imagings at lower doses. The increased brightness of T2 -weighted MR images has resulted in the potential development of this agent for MR angiography.

Fig. 5.19

MR images (T1 -weighted). The scale bar represents 0.5 mm (at 14.1 T within

an FOV of 20 mm and a slice thickness of 0.5 mm). The T1 values are calculated via the student t tests at a 95% confidence level. (a) Control PC3M cells (T1 = 3527 ± 48 ms); (b) PC3M cells incubated with 0.001 mM DNA-DOPA-DO3A NPs with 1.8% 1:TiO2 active site coverage (T1 = 2178 ± 88 ms); (c) PC3M cells incubated with 0.001 mM DNA-DOPADO3A NPs with 4.4% 1:TiO2 active site coverage (T1 = 2356 ± 100 ms). [142]

The porous, hollow morphology of the NPs is believed to be linked to the cooperativity originating from the NPs and the large surface area of the water. Amine groups provide an opportunity for the attachment of biological signals on the outermost PEI polymer shell, offering great prospects for multi-modality nanostructures, especially composite capsules. The current study has shown that the conception of a different type of non-Gd- and non-iron oxide-based bimetallic contrast agents is as practical as other contrast agents (see Figs. 5.20 and 5.21). [144] Recently, the surface of spherical, nonporous silica NPs (SiO2 -NPs) was modified with gadolinium complexes, fluorophores, and cell-penetrating peptides to achieve the multifunctionality of a single particle. The Gd surface concentrations were 9–16 µmol/g, resulting in nanomaterials with high local longitudinal and transversal relaxivities (similar to 1 × 105 mm−1 ·s−1 ·NP−1 and 5 × 105 mm−1 ·s−1 ·NP−1 , respectively). Rapid cellular uptake was observed in-vitro; however, larger extracellular agglomerates were also formed. An in-vivo administration revealed a fast distribution throughout the body followed by a nearly complete disappearance of fluorescence in all organs except the lungs, liver, and spleen after 24 h. Such NPs have the potential to serve as efficient multimodal probes in molecular imaging. [145] SPIOs and manganese chloride (MnCl2 ) are being used for in-vivo diagnosis and have shown great promise. The evaluation of therapeutic agents always depends on the efficacy of diagnostic agents for the characterization of early tumor development, especially in MRI. MnCl2 and SPIOs are used to label prostate cancer cells, both

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in-vitro and in-vivo, and visualized under 1 T MRI for tracing labeled cells and 7 T MRI for tracking in-vivo. The respective tumor volumes and tumor masses are histologically examined. MnCl2 is found to be non-toxic. In-vivo MnCl2 labeled cells are detectable from day 4–16, while SPIO labeling allows detection until 4 days after the subcutaneous injection. MnCl2 labeled cells are found to be highly tumorigenic in NOD/SCID mice, and the tumor volume measurement is characterized in a time dependent mode. It is evident that the amount of injected cells is always directly correlated with tumor size and disease progression. In addition, the histological analysis of the induced tumor masses confirms the characteristic morphologies of prostate adenocarcinoma. So, the direct in-vitro MnCl2 labeling and 7 T-based invivo MRI tracing of cancer cells in a model of prostate cancer imply that MnCl2 labeling is suitable for in-vivo tracing and may allow long detection stages. High tumorigenic potential, both in-vivo and in-vitro, makes MnCl2 and SPIOs as ideal candidates for cancer diagnosis. It is noteworthy that this kind of model can also be applied to diagnose other types of cancers. [146]

Fig. 5.20

Scheme for Au3 Cu1 nanocapsules used as contrast agents in animal MR imaging. [144]

Measured and confirmed using a vibrating sample magnetometer, non-toxic polymerbased superparamagnetic NPs (P80-TMZ/SPIO-NPs) of 220 nm with a narrow hydrodynamic size distribution serve as a theranostic agent for brain cancer and exhibit high drug loading, encapsulation, and efficient drug release performance for 15 days.

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Techniques like fluorescence microscopy, Prussian blue staining, and atomic absorption spectrophotometer (AAS) have confirmed their cellular uptake in C6 glioma cells both qualitatively and quantitatively. Also, MRI results have confirmed that Polysorbate 80 coated temozolomide-loaded PLGA-based super-paramagnetic NPs are promising as a multi-modal theranostic carrier for brain cancer. [147]

Fig. 5.21

In-vivo MRI imaging in male BALB/c mice after injection of Au3 Cu1 nanocap-

sules: (a) T1 -weighted and (b) T2 -weighted images at the indicated temporal points (preinjection, immediately post-injection, and 2 h post-injection). The arrows in panel (b) indicate the increase in signal intensity and show visualized vessels for the thorax and liver regions in T2 -weighted images (coronal view). [144]

5.3

Diagnostic magnetic resonance

The concept of personalized medicine is appealing, as it provides important modalities like disease diagnosis, malignancy monitoring, and therapy efficacy eval-

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uation in a single shot that in turn depends on the sensitive measurement and quick diagnosis of relevant biomarkers or pathogen/cells in biological samples. When it comes to clinical settings, an assay utilizing the molecular measurement of markers must satisfy some criteria like increased sensitivity and specificity, ease of preparation with a small sample volume, and multiplex based simultaneous recognition of a number of diverse target molecules of interest. We know that the conventional detection strategies based on scattering, absorption, and auto-fluorescence in optical imaging are often problematic, requiring all-embracing sample purification. The impression of bio-sensing using MNPs offers exclusive advantages over the conventional diagnosis and screening methodologies and has attained popularity in the recent past because biological samples lack a magnetic background; thus using MNPs can obtain extremely sensitive and specific measurements in spite of the murky and muddy appearance of some biological samples. Presently, the attention in research is focusing on structuring MNPs that would be usable in bio-sensing, especially in-vitro. DMR modulates the spin-spin relaxation time of water molecules surrounding molecularlytargeted NPs that serve as proximity sensors to produce specific in-vitro diagnostic data for cancers. Improvement in DMR detection limits for various target moieties depends on utilizing a broad range of targets like DNA/mRNA, proteins, small molecules/drugs, pathogens like bacteria and viruses, and tumor cells for developing more effective MNP-based biosensors. Miniaturized nuclear magnetic resonance detectors, better MNPs, and novel conjugation methods are examples of the advanced DMR technology. But still there is a dire need to develop DMR based techniques capable of producing accurate results using a minute quantity for a sample. In addition, features like portability, economics, and efficient bio-molecular detection within a biomedical setting are particularly important for the DMR technology to become a highly attractive platform in cancer diagnostics. DMR takes advantage of targeted MNPs to adjust the spin-spin T2 relaxation time of biological samples. Magnetic relaxation switching (MRSw) assay is a kind of DMR that is aimed at small molecular targets with sizes less than or comparable to that of the MNPs. It can detect and quantify the analyte much more precisely and accurately than the conventional methods. The cross linkings of MNPs with metabolites, oligonucleotides, drugs, and proteins support the relaxation switching a lot. MRSw assays can utilize forward switching, a method whereby molecular targets act as cross-linking agents to bring MNPs together into clusters, causing a corresponding decrease in T2 ; whereas in the reverse switching of MRSw, the enzymatic cleavage or competitive binding of molecular targets disassembles preformed clusters, increasing T2 relaxation. It is noteworthy that

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MRSw assays are conducted without unbound MNPs being removed. [148]

5.4

Multifunctional MNPs for multimodal probing

Nanostructures provide an excellent platform to integrate different functional nanocomponents into one single nanoentity to exhibit multifunctional properties. Assembling different NPs into a single entity as a novel building block is exciting and holds great potential. As briefly discussed in the following sections, based on the MNPs, one can combine QDs to exhibit magnetic and fluorescent properties, sequentially grow metallic nanocomponents or form exotic nanostructures, such as yolk-shell NPs for the exploration of nanomedicine. Intracellular exploitation of MNPs for biological applications offers a practical tool to explore the difference between the apical and basolateral domains in polarized cells by the asymmetric localization of MNPs ornamented with specific ligands. To realize these promises, the fluorescent MNPs should have fast response to a magnetic force, which is yet to be improved.

Fig. 5.22

Schematic map for the synthesis of water-dispersible QD-FVIOs. The branched PEI is drawn as simple line for clarity. [149]

A new class of magnetic-fluorescent nanoprobes, QD-FVIOs with elevated luminescence and a magnetic vortex core, have been successfully developed. The bio-

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compatible and multicolor QD-FVIOs have a much stronger effect on T2∗ -weighted MRI signals than the conventional SPIO-based multifunctional NPs. Available results from exploratory experiments of multiphoton fluorescence imaging and cell uptake indicate that QD-FVIOs are rapidly internalized by endocytosis and are initially stored in vesicles, followed by slow endosomal escape and release into the cytoplasm. These insights suggest that QD-FVIOs could serve as an excellent dualmodality imaging probe for intracellular imaging and therapeutic applications (see Figs. 5.22–5.24). [149] The features of nanomaterials like high sensitivity, target specificity, stability, and most importantly, biocompatibility are desirable to obtain multifunctional nanoscale diagnostic agents that will facilitate tumor screening and diagnosis after employing the multiplex detection modalities (Figs. 5.25 and 5.26). [150, 151] For the required functions and specificity to cancer diagnostics, integrated-nanoprobe diagnostic systems could include metals, oxides, polymers, enzymes, and other components in different combinations, versatile structures, and novel compositions.

Fig. 5.23

In-vitro T2∗ weighted MRI of QD-FVIOs in 2% agarose and commercial ferucarbotran in water. [149]

A single nanoparticle probe at molecular level can be used to produce images of cancer and clinically useful measurements both in-vitro and in-vivo. In the recent past, many studies have been conducted that emphasize the combination of QDs and iron oxide NPs,[152−156] because in cancer diagnostics, this combination could give MRI along with fluorescence data, a pairing that is direly needed for multimodal analysis and accurate diagnosis. Concurrent MRI and fluorescence imaging, both in-vitro and in-vivo, using the hybrid nanostructures containing MNPs and QDs has been reported recently [157] and found to be capable of more accurate and effective

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early detection of cancer. Another heterodimer comprising Fe3 O4 –CdSe NPs has been used very successfully in manipulating and probing NPs within cells, [158] as they straightforwardly deliver the specific ligands to the target moieties on one hand and at the same time enable monitoring of the NP’s location inside the cells. To realize the fundamental cellular processes and functions, and to differentiate normal and abnormal cells/tissues, this dual-mode technology can be considered to be a useful tool.

Fig. 5.24

Representative two-photon fluorescence images (756 nm excitation) of the

stained MGH bladder cancer cells with (a) yellow- and (b) red-colored internalized QD-FVIOs. [149]

The inherent properties and functions of metallic NPs hold their importance as optical contrast agents and probes. Metallic NPs are mostly used in florescence imaging and also for drug delivery, but the combination of these with MNPs has not been studied extensively, mainly because of some characteristic differences between metals and today’s MNPs. But it is likely that in future this combination will prove to be one of the best. The Fe3 O4 –Au heterodimer has been reported as a nanostructure that presents the particles with two distinct surfaces, making it possible to employ different kinds of functional molecules getting attached covalently in addition to their own dissimilar functionalities, Fe3 O4 –Au multifunctional heterodimers can bind with specific receptors and respond to external magnetic fields for specific target imaging, and may turn out to exhibit enhanced resonance absorption and dispersion. In breast cancer diagnosis, the dual functionality of EGFRA-conjugated Fe3 O4 –Au heterodimer NPs has been verified. [159]

5.4

Multifunctional MNPs for multimodal probing

Fig. 5.25

Fig. 5.26

A multi-modality nanoprobe model with its various modalities. [150]

Nanoparticle size effects on magnetism and MR contrast enhancement:

(a) canted surface atoms surrounding core magnetic atoms; (b) surface to volume ratio vs size, canted surface spins, net magnetic moment, and T2 contrast effect; (c) MRI-optical dual-mode probes consisting of 12 nm MEIO NPs and FITC fluorescent dye molecules with a dark MRI contrast effect and optical signal. [150]

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Scanning confocal microscopy is able to image A431 cells labeled with Fe3 O4 – Au heterodimers. In addition, the heterodimer exhibits a strong MR contrast enhancement under an external magnetic field, and thus could be termed as successful nanoscale multi-modal performance of a heterodimer. Various studies have proved that such heterodimers in different combinations show great potential in multiplexed probing and multimodality molecular imaging,[160−162] but some issues, like surface modification, bio-conjugation, and reproducibility, must be resolved before these dimers can realistically be considered for use as a component in in-vitro diagnostic applications. MNPs specifically targeted to the surface of MDA-435 cells in-vitro were intravenously administered to rats with glioma. They were internalized, conferring photosensitivity to the cells, and they showed significant MRI contrast enhancement. The pharmacokinetics and distribution of NPs within the tumor were analyzed by serial magnetic resonance imaging. Glioma-bearing rats treated with targeted NPs in combination with photodynamic therapy (PDT) showed a significantly better survival rate than animals that received PDT after the administration of non-targeted NPs. Furthermore, compounds that were found to be excellent photosensitizers but were limited by inherent systemic toxicity could be reevaluated in the context of polymeric nanoparticle encapsulated delivery, as the nanoparticle matrix removes the therapeutic molecule from direct interaction with the physiological milieu (see Fig. 5.27).[163,164] Commercially available SPIOs accumulate in normal lymph tissues after injection at a tumor site, whereas less or no accumulation takes place in metastatic nodes, thus enabling lymphatic staging using MRI. After comparing the findings using histology and vibrating sample magnetometry, the potential of SPIOs like EndoremW (Iron oxide NPs) as novel photoacoustic (PA) contrast agents in biological tissue has been reported using 14 T MR-imaging. The PA setup was able to detect the iron oxide accumulations in all the nodes containing the NPs. The distribution of the PA signal inside the nodes corresponded with both MRI and histological findings. Nodes without SPIO enhancement did not show up in any of the PA scans. EndoremW can be used as a PA contrast agent for lymph node analysis, and a distinction can be made between nodes with the agent and nodes without. This opens up possibilities for intra-operative nodal staging for patients undergoing nodal resections for metastatic malignancies. [164] By integrating anatomical and molecular based imaging capabilities, multimodal NP based probes are very attractive in the paradigm shift to new imaging technologies, not only at the molecular and cellular levels but also for false-free theranostics

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that in turn will lead to a better tolerance of fundamental biological developments. Such multimodal probes can be easily extended to therapeutic applications by simply adding drug molecules into the probes or by using the magnetic component as a heat generator for hyperthermia or as a guiding vector to the targeted area. A current flood of attention in nanotechnology has further boosted up the breadth and intensity of the NP research area. Although still in its early stages with only a handful of successful demonstration cases, the continued development of such multimodal probes is increasingly important for advancing this exciting and rapidly changing research field.[13,150,165−170] Magnetic immunoassay (MIA) is a kind of diagnostic immunoassay exploiting magnetic beads as labels in lieu of the conventional enzymes, radioisotopes, or fluorescent moieties. It engages the specific antibody binding to its antigen, and a magnetic tag is attached to either component of the duo. A

Fig. 5.27

Photoacoustic and MR image comparison of resected lymph nodes with con-

trast injection. As shown in lymph node 1 (white dotted line), the PA response pattern is comparable with the location of decreased MRI signal. Some nodes show a continuous contrast band throughout their periphery (1,5), while others show some small irregularities (4,6). [164]

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magnetometer measures the magnetic field change induced by the beads, leading to the detection of the target molecule. The signal measured by the magnetometer is proportional to the quantity of the analyte (virus, toxin, bacteria, cardiac marker, etc.) in the initial sample.

5.5

Conclusion and future prospects

Here we have tried to review and summarize recent developments in cancer detection methods with an emphasis on magnetism and nanotechnology. Magnetism has been one of the hottest topics in cancer care and diagnosis in the recent past, and still much is being invested, both in the scientific community and by commercial players. On one hand, nanomaterials have uniquely attractive characteristics for bio-sensing, while on the other hand various magnetism-based materials and nanotechnology have facilitated precise, specific, and sensitive screening based on cancer biomarkers. Early detection and accurate prognosis of cancers has long been awaited, especially for newly developed cancers that go unchecked because of being asymptomatic. In this respect, the role played by the detection limit is crucial, and nanotechnology can contribute immensely to successfully exploit this property before it is too late. It is not so important to develop new methods for diagnosing cancer after symptoms start appearing, but it is really vital to isolate and detect the smallest presence of cancerous cells, as it maximizes the treatment options and increases the chances of survival, nipping evil in the bud. Sensing mechanisms are the key to developing such nanoscale high speed vehicles that will push the detection limit down as low as possible. Biomarker discovery is another door that leads to more specific and more sensitive diagnosis and can work precisely with such nanotools. Nanotechnology together with magnetism and biology will undoubtedly help to screen, detect, and diagnose cancer at very early stages, keeping an ever more meticulous eye on the disease. But one has to keep in mind that these new technologies must be evaluated critically before we apply them clinically. Although the idea of capturing cancers at an early stage is very striking and badly needed, the patient safety and environmental quality must still be the top priority, and the journey of nanomaterials through the body and the environment should be fully charted. Diagnosis is a key factor in the treatment of any disease, including cancer, which is a vile mixture of lots of pathological cells and faulty mechanisms. The early and accurate diagnosis plays a pivotal role in various stages of the ultimate clinical outcome, like treatment options, care and management, severity of disease progression, possible side effects, and the probability of relapse. Here in this review we have

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Conclusion and future prospects

173

tried to address various magnetic materials that can prove to be helpful for the ever important diagnostic paradigms for cancer treatment. There is a whole field of molecular diagnostics that uses things called molecular probes. Again, they go after disease markers. And they have molecules that “light up” when they bind with those disease markers. But it turns out that one can add lots of different functionalities to a nanoparticle to recognize disease markers, to carry a signal to a disease marker, and to amplify the signal at really low NP concentrations. The beauty of nanostructures is that on one hand they are small enough, invisible to the naked eye, and capable of full dispersion in a solution, and on the other they are large enough to be decorated by variety of functional particles. They provide many additive capabilities and variable structures like balls, clusters, stars, cages, dimers, cubes, bricks, webs, shells, flowers, etc. that are not present in the conventional molecular systems. And after the decoration with numerous moieties, they still can be used as a catalyst to generate a lot of signals by associating different functionalities like color, pH, temperature, enzymes concentration, and so on. The chip-based assay has a lot of characteristics associated with it and in the foreseeable future, this chip can operate with just a minimal sample to diagnose cancer by increasing the sensitivity or the magnitude of the signal by flowing ordinary photographic developing solution over the chip. Nanodiagnosis is a whole new and exciting frontier that is likely to have a very big impact on humanity. But the proper learning and precise manufacturing are exceedingly desirable to use these nanostructures safely and to diagnose a variety of cancers and other pathogens. Such technologies are not just dreamed up in ivory towers or a research lab and forgotten. They are technologies that are going to rise and ultimately become available for human use at affordable prices globally. But it takes a long time. These are pretty exciting developments and will end up being used in lots of different types of disease management scenarios including cancer, which is very exciting. Regarding coating and surface functionalization of MNPs, a comprehensive approach for new insights to explore monomeric stabilizers, polymeric stabilizers, inorganic coatings, and the vectorization of MNPs for targeted imaging still demands new and novel scientific approaches. Moreover, the properties and characterization of MNP suspensions, like size, morphology, magnetometry, hydrodynamic size, photon correlation spectroscopy, NMR relaxation in the presence of SPIO nanoclusters, improved imaging methods, and improved contrast agents are some of the key areas for future research. Multifunctional masterpieces for multimodal imaging or for imaging cum therapy have been studied extensively, but still most of the published literature regarding NP-based contrast enhancement agents for MRI have not suf-

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ficiently addressed some of the most vital issues. It is therefore urged that more studies are undertaken, especially in-vitro testing or preliminary animal studies, to make the life-saving technologies commercially accessible. Several key issues like long-term stability, toxicological effects, and pharmacokinetics still have to be addressed before the commercial application of these nanostructures is considered. Multi-disciplinary joint research plans are indispensable to accomplish the crucial ambitions of employing magnetism based MRI contrast agents for active imaging at the cellular and molecular levels that can be functionalized for personalized diagnosis of cancer patients. But after all, we know that despite the evident prospects, the vast majority will be applied only in drug development, basic research, and academics. The pathway to apply them in human care is very lengthy, exhaustive, and costly. Hopefully and optimistically, convergent modeling and straightforward approaches developed by adopting a consistent R&D system may reduce the delay of clinical application.

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Chapter 6 Magnetic Microbubble: A Biomedical Platform Co-constructed from Magnetics and Acoustics∗ Fang Yanga) , Zhuxiao Gub) , Xiao Wanga) , Jian Tanga) , and Ning Gua)† a)

Jiangsu Key Laboratory for Biomaterials and Devices, State key Labo-

ratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China b)

Key Laboratory of Developmental Genes and Human Diseases, Ministry

of Education, Medical School, Southeast University, Nanjing 210009, China † Corresponding author. E-mail: [email protected] Generation of magnetic micrbubbles and their basic magnetic and acoustic mechanisms are reviewed. Ultrasound (US) and magnetic resonance (MR) dual imaging, controlled therapeutic delivery, as well as theranostic multifunctions are all introduced based on recent research results. Some on-going research is also discussed.

6.1

Introduction

Magnetic microbubbles exhibit many interesting acoustic and magnetic properties based on one microbubble con-constructed platform. The excellent ultrasonic ∗ Project supported by the National Basic Research Program of China (Grant Nos. 2011CB933503 and 2013CB733804), the National Natural Science Foundation of China (Grant No. 31000453), and the Fundamental Research Funds for Central Universities (Grant No. 2013CB733804).

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and magnetic responses are beneficial for the biomedical applications. With the development of micro- and nano-delivery carriers, a lot of research has demonstrated that both microbubbles (MBs) and magnetic nanoparticles (MNPs) can individually be regarded as effective imaging contrast agents and drug delivery carriers.[1−3] MBs are gas-filled microspheres with diameter of several micrometers due to the requirement of in vivo application. When an ultrasonic energy field is applied, MBs can oscillate and vibrate; thus they may reflect ultrasound waves to be distinguished from surrounding tissues. This strong ultrasonic scattering of MBs makes them become the most effective type of ultrasound imaging contrast agent this is a repetition of the previous phrase. [4] Besides, with a modified shell, drugs, DNA or antibodies can be loaded into the MBs, which opens up the possibility for molecular imaging, targeted drug delivery, gene therapy, thrombolysis, and focused ultrasound surgery. [5] Besides the excellent acoustic characteristic, gas-filled MBs have also been demonstrated to be useful in magnetic resonance (MR) imaging when the susceptibility of the gas differs from that of the surrounding medium. The localized perturbations created by MBs can act as susceptibility contrast to shorten T2 and T2∗ . Especially, some theoretical and experimental studies have shown that the magnetic susceptibility sensitivity of MBs can be improved by embedding magnetically active particles around the microbubbles’ shell. [6] Magnetic particles of micro- or nano-scale have been widely investigated for biomedical applications. When the size of magnetic particles is below 100 nm, the magnetic ordering at the surface will be changed. For ferromagnetic nanoparticles, a surface spin glass-like state due to magnetic frustration has been found. Among the ferromagnetic nanoparticles, the superparamagnetic iron oxide (SPIO) magnetic particles exhibit no remanence or coercivity. Superparamagnetism is necessary in drug delivery because once the external magnetic field is removed, magnetization disappears and thus agglomeration is avoided. [7, 8] Because of special superparamagnetic features of MNPs, they can be used to function at the cellular and molecular level of biological interactions. We can call these MNPs as biomedical magnetic nanoparticles (BMNPs). These BMNPs offer some attractive possibilities in clinical MR imaging contrast enhancement, molecular imaging, magnetically targeted release of therapeutic agents, hyperthermia, as well as magnetic field assisted radionuclide therapy, etc. [9] Recent advances in biomedical applications have driven the development of multifunctional nano-, or micro-multiscale delivery carriers. The integration of nanoand micro-multiscale technology has resulted in new devices in biomedical applications.[10−12] Combination of dual-phase character of MNPs and MBs, magnetic mi-

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crobubble (MMB) formulations have been developed as novel approach for delivery systems, analytical biochemistry and in vitro/vivo theranostics. In this review, we mainly discuss the fabrication and biomedical applications of MMBs. First, we will give an overview of the basic properties of MBs, MNPs, and MMBs individually, which may be most critical to biomedical applications. Second, we will explain the acoustic and magnetic interaction of the combined agents resulting from magnetic microbubble co-constructure. Finally, how these properties can be exploited to create and improve biomedical diagnostic techniques and treatments will be discussed.

6.2 6.2.1

Magnetic nanoparticles and magnetic characteristics Preparation, surface modification, assembly of magnetic nanoparticles

When the size of the MNPs is below a critical value (typically around 10 nm– 20 nm), each MNP has a large constant magnetic moment and behaves like a giant paramagnetic atom with a fast response to applied magnetic fields with negligible residual magnetism and coercivity. These features make superparamagnetic nanoparticles very attractive for a broad range of biomedical applications because the risk of agglomeration is negligible at room temperature. [13] In order to obtain reliable BMNPs, the enhanced magnetic moments and superparamagnetism must be considered, which must have optimum composition, appropriate surface charge, shape, size, and colloidal stability in a biological environment, biocompatibility, and specific targeting capability. [14, 15] Recently, techniques and procedures for producing BMNPs including Fe3 O4 , γFe2 O3 have advanced considerably. In order to obtain shape-controlled, highly stable, and monodisperse BMNPs, there are many synthetic routes to be developed. These synthetic methods can be classified into two categories. One is the MNPs produced from solution or vapor phases. The other is the MNPs produced by composites consisting of MNPs dispersed in the nano- or micro-sized organic or inorganic spherical matrices. Methods for MNPs produced from solution mainly include co-precipitation, thermal decomposition, microemulsion, hydrothermal synthesis techniques. Precipitation from solution methods allow the preparation of MNPs with rigorous control of size and shape in a simple way, and thus are very appropriate for use in biomedical applications. Uniform particles are usually prepared via homogeneous precipitation reactions, a process that involves the separation of the nucleation and growth of the nuclei. [16] In a homogeneous precipitation, a short single burst of nucleation occurs

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when the concentration of constituent species reaches critical supersaturation. Then, the nuclei obtained are allowed to grow uniformly by diffusion of solutes from the solution to their surface until the final size is attained. To achieve monodispersity, these two stages must be separated and nucleation should be avoided during the period of growth. [17] Methods for MNPs produced from vapor mainly include spray and laser pyrolysis. These two methods have been shown to be excellent techniques for the direct and continuous production of well-defined MNPs with high-production rate. The ultrafine particles are usually aggregated into larger particles by spray pyrolysis, while the ultrafine particles are less aggregated due to the shorter reaction time using laser pyrolysis. [18] When the MNPs have been prepared by one of the above-mentioned methods, another important issue is to maintain the stability of these particles without agglomeration or precipitation. Some pure materials or smaller size particles would be bound to instability because of oxidation in air. Therefore, it is necessary to develop efficient strategies to improve the chemical stability of MNPs. The most straightforward method is to protect them by surface modification or assembly of MNPs. All these protection methods make use of the naked MNPs as a core and coat them with a shell. The coating shell can roughly be divided into two major types: coating with surfactant and polymers, etc. organic shells or with silica, carbon, precious metals (such as Ag, Au) or oxides, etc. inorganic shells. All these shell materials can be modified on the surface of MNPs. Layer-by-layer (LBL) selfassembly is one of the most promising techniques to produce superparamagnetic composites. Using this strategy, the surface of MNPs can be coated with alternating layers of polyelectrolytes, nanoparticles, and proteins. Some other polymer-coated magnetite nanoparticles can be synthesized by microemulsion seed copolymerization in the presence of the magnetite nanoparticles. The particle size can be controlled by changing the monomer concentration and water/surfactant ratio. [19] All in all, the small size and the modified agents render MNPs a potential candidate for their use in in vivo applications. Their preparation mainly involves three steps. First, the inorganic magnetic core is produced. Second, a stable biocompatible layer can be coated on the surface of the MNPs. Finally, the anchoring of the targeting moiety or a drug is necessary for molecular level applications. 6.2.2

Special features of magnetic nanoparticles

For ferromagnetic materials, the key parameters to determine magnetic properties such as coercivity (Hc ) and susceptibility (χ) are composition, crystallographic

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structure, magnetic anisotropic energy, vacancies and defects. For biomedical application, the important parameters may be mainly involved in superparamagnetism and surface effect. 6.2.2.1

Size and superparamagnetism

Biomedical applications like MR imaging, magnetic cell separation or magnetorelaxometry utilize the magnetic properties of the nanoparticles in magnetic fluids. These applications mainly depend on the hydrodynamic size and magnetic features of MNPs. When the MNPs are submicron moieties (between 1 nm–100 nm), they are different from those of bulk materials of the same composition. When the size is reduced to nanoscale, the magnetic and electronic properties, and the role played by surface phenomena can make the NPs become excellent materials for biomedical applications (Fig. 6.1(a)). It is well known that the large magnetic particles have a multidomain structure. Domain wall, formed by the balance between the magnetostatic energy and the domain-wall energy separate the regions of uniform magnetization. The magnetic anisotropy energy barrier from a spin-up state to spin-down state of the magnet is proportional to the product of the magnetic anisotropy constant and the volume of the magnet. [20] At tens of nanometers size, ferromagnetic MNPs become a single magnetic domain and therefore maintain one large magnetic moment. While bulk materials have magnetic anisotropic energies that are much larger than the thermal energy (kb ), the thermal energy is sufficient to readily invert the magnetic spin direction. Such magnetic fluctuation leads to a net magnetization of zero, and this behavior is called superparamagnetism (Fig. 6.1(b)). [21] The transition temperature from ferromagnetism to superparamagnetism is referred to as the blocking temperature (Tb ) and is defined by Eq. (1): [22] Tb = Keff V /25kb ,

(1)

where Tb is the blocking temperature, Keff refers to magnetic anisotropy constant and V is the volume of the magnet. The blocking temperature depends on the effective anisotropy constant, the size of the particles, the applied magnetic field, and on the experimental measuring time. In a paramagnetic material, the thermal energy overcomes the coupling forces between neighboring atoms to cause random fluctuations in the magnetization direction, which results in a zero overall magnetic moment. However, in superparamagnetic materials, the fluctuations affect the direction of magnetization of entire crystallites. The magnetic moments of individual crystallites compensate each other and the overall magnetic moment becomes zero.

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When an external magnetic field is applied, the magnetic moment of entire crystallites spontaneously aligns in the direction of a magnetic field. Unlike ferromagnetic substances and because of their size, superparamagnetic agents have no magnetic properties outside an external magnetic field.

Fig. 6.1

Nanoscale transition of MNPs from ferromagnetism to superparamagnetism:

(a) in nanometer scale, parameters such as size, shape, composition, and magnetocrystalline anisotropy strongly affect the coercivity, mass magnetization, and remanence of nanoparticles. (b) Energy diagram of MNPs with different magnetic spin alignments, showing ferromagnetism in a large particle and superparamagnetism in a small nanoparticle. (c) and (d) Size-dependent transition of iron oxide nanoparticles from superparamagnetism to ferromagnetism showing TEM images and hysteresis loops of (b) 55-nm and (c) 12-nm sized iron oxide nanoparticles. Panels (b), (c), and (d) reproduced with permission from Ref. [21]. The unit 1 Oe = 79.5775 A·m−1 .

The threshold diameter of SPIO MNPs typically lies in the range of a few tens of nanometers and depends on the nature of material. Fe-based NPs become superparamagnetic at sizes < 25 nm. [23] γ-Fe2 O3 nanoparticles of 55 nm exhibit ferrimagnetic

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189

behavior with a coercivity of 52 Oe at 300 K, but smaller, 12-nm sized γ-Fe2 O3 nanoparticles show superparamagnetism with no hysteresis behavior (Figs. 6.1(c) and 6.1(d)). [24] The critical single-domain size of Co nanoparticles is expected to be around 8 nm–10 nm. This superparamagnetic property enables the particles to maintain their colloidal stability and avoid aggregation when the external magnetic field is removed. Furthermore, the coupling interactions within these single magnetic domains result in much higher magnetic susceptibilities than paramagnetic materials. Such size-dependent mass magnetization values directly affect their MR signal enhancement capabilities for molecular imaging of biological targets. [25] 6.2.2.2

Surface effects

Surface coatings, assembly and the composites are an integral component of all MNP platforms for retaining the stability and biocompatibility. Normally, there are four aims to the surface modification and assembly for biomedical applications. First, the biocompatibility and toxicity of MNPs are criteria to take into account for their biomedical applications. For instance, the use of gold or silica as a shell material allows for potential application of toxic materials as nanoparticle cores with strong magnetic properties. [26] Secondly, although MNPs have superparamagnetic properties, surface charges on the MNPs are not adequate to prevent aggregation due to of their high surface energy. Furthermore, upon intravenous injection, the surfaces of MNPs are subjected to adsorption of plasma protein, or opsonization. The conjugation of biocompatible polymers, such as dextran, PEG, or other protein resistant polymers, as surface coating, can prevent MNPs from aggregation and opsonization, and can thus can evade MNP uptake by the reticulo–endothelial system (RES), which increases plasma half-life in physiological solutions and blood circulation time. [27] Finally, the surface chemistry allows for the integration of functional ligands on the surface of MNPs, which enables MNPs to perform multiple functions simultaneously, such as in multimodal imaging, drug delivery, and real-time monitoring, as well as combined diagnostic and therapeutic approaches. However, when the surface has been modified by some biocompatible materials, the coating or surface modification may negatively affect the magnetization due to quenching of surface effect. This reduction has been associated with different mechanisms, such as the existence of a magnetically dead layer on the particle’s surface, the existence of canted spins, or the existence of a spin-glass-like behavior of the surface spins. [28] A clear correlation between the surface coating and the magnetic properties is not completely established. Hormes et al. discussed the influence of various coatings (e.g., Ag, Au) on the magnetic properties of cobalt

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nanoparticles, and came to the conclusion that a complex interplay between particle core and coating exists. [29] For example, a precious-metal layer around the MNPs will have a lower magnetic anisotropy than uncoated particles, whereas gold coating of iron particles enhances the anisotropy, an effect which has been attributed to alloy formation with the gold. Organic ligands, used to stabilize the MNPs, can also modify the anisotropy and magnetic moment of the metal atoms located at the surface of the particles by reducing the magnetic moment and a large anisotropy due to the quenching of the surface magnetic moments. [30] 6.2.3 6.2.3.1

Biomedical applications of magnetic nanoparticles MRI contrast agents

The penetration of magnetic fields through human tissue and the ability to externally control magnetic materials have been investigated for use in medicine for centuries. One of the significant applications of these phenomena is MR imaging. As a non-invasive imaging modality, MR imaging can provide high resolution anatomical images. In an external magnetic field, the colloids of MNPs composed of crystals measuring 4 nm to 6 nm align and create very high local magnetic field gradients to induce water proton spin dephasing and consequently reducing the T1 and T2 relaxation times of the surrounding water. MNPs can generate a magnetic field in their vicinity. Such field inhomogeneity accelerates the phase decoherence of the spins. The efficiency by which a contrast agent can accelerate the proton relaxation rate in a homogeneous medium is called relaxivity of the agent and is defined by Eq. (2): [31] 0 R1,2 = R1,2 + r1,2 C,

(2)

where R1,2 (s−1 ) is the respective T1 or T2 proton relaxation rate in the presence of 0 the contrast agent, R1,2 are the relaxation rates in the absence of contrast agent and C is the contrast agent concentration (mM). The constant of proportionality r1,2 (s−1 ·mM−1 ) is called relaxivity and is a measure of how much the proton relaxation rate is increased per unit of concentration of contrast medium. In a first approximation, relaxivity varies as the square of the magnetic field induced in the vicinity of the water proton. The dipolar interaction between surrounding water protons and the high magnetic moment of superparamagnetic particles results in high longitudinal r1 and transverse r2 relaxivity. The theory describing the magnetic interaction of superparamagnetic compounds with water protons has been described by different theoretical models derived from the classical outer sphere paramagnetic relaxation model. [32] In most situations, it is the significant capacity of superparamagnetic

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Magnetic nanoparticles and magnetic characteristics

191

nanoparticles to increase the so-called T2∗ effect that is used in MR imaging. This T2∗ effect is called “susceptibility effect” and describes an increase of T2∗ relaxation rates due to a magnetization difference between different voxels in the MR imaging. A large magnetization difference occurs as a result of the non-homogeneous distribution of superparamagnetic particles, which gives rise to local field gradients that accelerate the loss of phase coherence of the spins contributing to the MR signal. This process is much more important for superparamagnetic particles than for paramagnetic species, as the induced magnetization of a superparamagnetic particle is high due to the high susceptibility of iron oxide. The magnitude of this susceptibility effect depends on many factors, such as compartmentalization of the contrast agent, type of imaging sequence, aggregation of the contrast agent. It should be noted that any aggregation has an important impact on the T1 , T2 or T2 * efficiency of a superparamagnetic particle. At the clinical field used in MRI (1 T to 3 T), agglomeration tends to slightly decrease r1 but markedly increases r2 . [33] 6.2.3.2

Drug delivery and therapeutic functions

The regularly employed superparamagnetic nanoparticles in drug delivery consist of NPs, nanospheres, liposomes, and microspheres. In these systems, the drugs are bound to the NPs’ surface or encapsulated in magnetic liposomes and microspheres. The physical principles underlying magnetic targeting therapy are derived from the magnetic force exerted on MNPs by a magnetic field gradient, as in Eq. (3): [34] µ

Fm

¶ 1 = Vm ∆χ∇ B · H , 2

(3)

in which the magnetic force is related to the differential of the magnetostatic field energy density, (1/2)B · H. Thus, if ∆χ > 0, the magnetic force acts in the direction of steepest ascent of the energy density scalar field. According to the basis of MNPs’ properties, the biological effects can be divided into thermal and non-thermal effects. Figure 6.2 is a schematic illustration of MNPs and their composites to realize the drug delivery and therapeutic functions. For drug delivery, the effectiveness of the therapy depends on several physical parameters, including the field strength, gradient and volumetric and magnetic properties of the MNPs. As the delivery carriers are normally administered intravenously, hydrodynamic parameters such as blood flow rate, ferrofluid concentration, infusion route, and circulation time also will play a major role. [35] In terms of magnetization value, coercivity, and anisotropy, the nanoparticle’s heat induction properties have also attracted significant interest these days for

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magnetic hyperthermia therapy. [36] In this process, the internal magnetic spins of nanoparticles relax in phase and continuously upon application of an alternating magnetic field of 100 kHz–1000 kHz as a consequence of a combination of N´eel and Brown processes. While the spins relax, energy associated with transitions between the up and down spin states is emitted as heat. [37] Because magnetic fields are not significantly attenuated upon transmission through biological tissues, they can be utilized for hyperthermia therapy of deeply buried tumors. Moreover, cancer cells (temperature initiating apoptosis of cancer cells at 42 ◦ C–45 ◦ C) are usually more sensitive to heat than benign cells, which is sufficient to provide the temperature range for cancer cell apoptosis. [38] Heat induction from the MNPs is proportional to the size, magnetization value, and magnetic anisotropy of nanoparticles, concentrations in tissues, intensity, and frequency of alternating magnetic field.

Fig. 6.2

Schematic diagram of MNPs and their composites in hypothetical magnetic

drug delivery system: the magnetic field gradient can capture magnetic carriers flowing in the circulatory system. Then MNPs can release the loaded drugs into the specific tissue or organ. The aggregation of MNPs can also produce thermal effect to treat disease.

6.2.4

Ultrasonic characteristics of magnetic nanoparticles liquid

When an external magnetic field is applied to magnetic and MR fluids, some of the inner particles coagulate and form a clustering structure. Several theoretical and experimental studies have been conducted to investigate the influences of the ultrasonic propagation during the formation of clustering structures. The results show that the ultrasonic propagation velocities in magnetic and MR fluids change according to the magnetic field intensity, interval time, the temperature, and angle

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Microbubble formalism and acoustic characteristics

193

of magnetic field. Ultrasonic propagation velocity changes when the magnetic field is applied. The change in ultrasonic propagation velocity is evaluated by Eq. (4): [39, 40] ∆V /V0 =

V − V0 , V0

(4)

where V and V0 are ultrasonic propagation velocities with and without an external magnetic field, respectively. Under a uniform external magnetic field, a remarkable level of anisotropy is observed, generally proving that the clusters form along the direction of the magnetic field. After removal of the magnetic field, a few clusters still remain due to a residual magnetic field effect proportional to the strength of the magnetic field. These results seem to be related to Brownian motion, residual magnetic field, and clustering of the magnetic particles under an external magnetic field. [41, 42] From the point of biomedical applications, acoustical properties of MR fluid may be easily changed by applying magnetic fields. An active matching layer could be an interesting example or any coating whose attenuation might be changed depending on the requirements. This study is also beneficial for understanding physical properties of magnetic MBs.

6.3 6.3.1

Microbubble formalism and acoustic characteristics Design and preparation of microbubbles

Initially, the MBs that formed during the injection of dye or saline were clearly effective for ultrasound contrast enhancement. However, air bubbles dissolve very rapidly owing to the high surface tension at the gas–air interface. They are very short-lived and difficult to reproduce consistently. Some reports demonstrated that a 10-µm unencapsulated air bubble dissolves in 1.17 s and in 6.63 s in degassed and in air-saturated water solutions, respectively. [43] Therefore MBs encapsulated with a solid shell to stabilize the gas–liquid interface were introduced. The shell is made from lipid, surfactant, protein or biodegradable polymer. Simultaneously, low diffusivity gases were introduced to further increase the microbubble circulation time. These encapsulated shell of MBs can diminish surface tension and make MBs stable enough to sustain the pressures exerted within the vasculature. Nowadays, stabilized MBs are being employed for several biomedical applications, including contrast-enhanced ultrasound, drug, gene and metabolic gas delivery. In order to control the size, composition, stability, and uniformity of MBs and give MBs better diagnostic and therapeutic properties, advanced preparation techniques are required. Nowadays, these methods are mainly divided into four classes.

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One is that the flowing liquid is used to create the MBs. The second type is to blow only gas into the liquid to generate MBs. The third type is the preparetion of polymer encapsulated MBs, which includes emulsion solvent vaporization, cross linking polymerization, etc. The final type is to use much less power to produce MBs including flow focusing, microchannel, etc. Conventional processing techniques such as sonication and high shear emulsification offer high yield and low cost production, but poor control over size and uniformity. In light of the improvements in microbubble uniformity, more processing methods such as ink jet printing, electrohydrodynamic atomisation, and microfluidic processing techniques were developed. These novel processing techniques enable gas-filled MBs to be prepared in a single step with a predetermined mean diameter and narrow size distribution. After producing multi-layered coated bubbles, the nanoparticles or specific protein ligands can also be attached on the surface of MBs electrostatically or by chemical reaction. [44] Detailed information about the MBs generation can be found in Ref. [45]. Fig. 6.3 shows a simple explanation of the MBs’ structure and their biological effects.

Fig. 6.3

The schematic diagram of MBs’ structure and loading strategies of drugs,

genes, and targeting peptide. At low US intensity, the MBs oscillate in a nonlinear fashion with minimal destruction, which can be used to enhance the US imaging. As the acoustic power increase, the bubbles cannot compress and make the bubbles unstable until reaching a point of rupture, which can be viewed as the basis for therapeutic ultrasound.

6.3.2

Actions of MBs with ultrasound waves

MBs are more compressible than soft tissue. When MBs are exposed to an oscillating acoustic signal, alternate expansion and contraction occurs. However, because

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195

MBs do not remain static in the presence of an ultrasound wave, the interactions of MBs with an ultrasound beam are complex, beyond simple compressibility and density effects. 6.3.2.1

Enhancement of ultrasound imaging by means of MBs

Based on the principle of scattering and reflection exploited by ultrasound imaging, an ultrasound contrast agent material has to possess a high scattering cross section in order to provide a significant scatter enhancement compared to the surrounding tissue. The scattering cross section σ for a linear scatterer that is much smaller than the incident ultrasound pulse wavelength is given by Eq. (5): [46] µ σ=

4 2 πR (kR)4 9

¶µµ

κs − κ κ

¶2 +

µ ¶¶2 ¶ 1 3(ρs − ρ) , 3 2ρs − ρ

(5)

where R is the radius of the scatterer (¿ λ), λ is the wavelength, k = 2π/λ is the wave number, κs is the compressibility of the scatterer, κ is the compressibility of the surrounding medium, ρs is the density of the scatterer, and ρ is the density of the surrounding medium. As ultrasound imaging exploits changes in compressibility and density, it can be calculated from Eq. (5) that the use of gas MBs ensures maximum cross section. At low acoustic power (< 50 kPa), the MBs oscillate linearly, and the echo is mainly fundamental; when the acoustic pressure increases (50 kPa–200 kPa), nonlinear oscillations occur, giving rise to harmonics and subharmonics shown in Fig. 6.4 [47] Every echo component can be detected for construction and imaging. According to the different components detected by the detection procedure, the detection procedures of MBs can be classified as fundamental imaging, harmonic imaging, and subharmonic imaging. Recently, second harmonic imaging has become one of the most commonly used imaging modalityes in clinics and most of the high-end B-mode ultrasound imaging systems have the function of second harmonic imaging. [48, 49] Destruction of MBs has been observed during ultrasonic excitation at much higher power. The mechanisms of destruction include the outward diffusion of the gas during the compression phase, diffusion from large shell defects, and complete fragmentation of MBs. Microbubble destruction during high-power ultrasound exposure is an important feature for both perfusion imaging protocols and for therapeutic applications for local delivery of drug or gene payload. [50]

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Fig. 6.4

Magnetic Microbubble: A Biomedical Platform Co-constructed · · ·

Schematic plot of the acoustic properties of MBs. The microscopy images

demonstrate volumetric oscillation of a microbubble during exposure to ultrasound. Frequency versus amplitude data from MBs demonstrating returning signal both at the fundamental (f0 ) and second harmonic (2f0 ) frequencies. [46]

6.3.2.2

Ultrasound-assisted drug delivery of MBs

In recent years, therapeutic applications of ultrasound have gained new interest as a result of their exploitation for drug or gene delivery. Depending on the energy delivered by ultrasound, either thermal or non-thermal effects can be produced. Each has its own application. With each ultrasonic cycle under high ultrasound intensities, a fraction of the energy in the propagating wave is absorbed by tissue to induce local heating. The rate of absorption is tissue-dependent and increases with increasing ultrasound frequency. These thermal effects can locally ablate tissue. This property is employed in high-intensity focused ultrasound (HIFU) surgery or ultrasound-based physiotherapy. [51] With low ultrasound intensities, there is no sig-

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197

nificant biological effect due to temperature increases less than or equal to 1 ◦ C. The non-thermal effect can happen at low ultrasound intensities. Cavitation, mechanical streaming, and radiation forces are the main non-thermal effects. Especially, the cavitation-related mechanisms include radiation force, microstreaming, shock waves, free radicals, microjets, and strain. These effects can induce some benefits such as tissue healing or ultrasound-mediated delivery. Because the MBs can reduce the threshold of energy needed for cavitation, US can trigger the controlled release of a drug or gene encapsulated in MBs or in their surrounding in a non-invasive manner. [52]

6.4

Magnetic and acoustic character of magnetic microbubbles (MMBs)

6.4.1

Fabrication of magnetic microbubbles

Recently, functionalized MBs embedding nanoparticles or quantum dots in their shells have been developed for emerging applications in biological, medical, and materials sciences. [53] The encapsulation of paramagnetic MR imaging nanoparticles into the shell structure could facilitate a potential application as bimodal contrast agents for echosonography, MR imaging, and for targeted drug delivery. The MNPs can be embedded in the solid polymer shells. Softer vehicles, like lipid materials, have also been developed to contain the nanoparticle cargo, which is enclosed within a self-assembled phospholipid or polymer film for the nanoparticle loading (Fig. 6.5(a)). [54] It is interesting to understand the interaction mechanism among magnetic MBs, the magnetic field, and the ultrasonic field. It was important to investigate their echogenicity and also their ability to be magnetically retained under flow (Fig. 6.5(b)). The MNPs can be loaded in the inner or outer side of the shell MBs. There are mainly two methods to load the MNPs in the shell of MBs. One is physical, the other is chemical reaction. [55] By electrostatical methods, Soetanto et al. attached magnetic microparticles to the microbubble surface coated with charged stearates. [56] Our group also developed PLA–PVA double-layered polymeric MBs with the encapsulation of superparamagnetic iron-oxide (Fe3 O4 , SPIO) nanoparticles in the bubble shell by the multiple emulsion method. [57, 58] The SPIO γFe2 O3 nanoparticles can also be coated on the surface by means of a EDC chemical reaction. [59]

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Fig. 6.5

Magnetic Microbubble: A Biomedical Platform Co-constructed · · ·

(a) Schematic diagram of the types of the MNPs embedded in the shell of the

MBs. (b) Schematic plot of the ultrasound flow: When magnetic MB suspension is injected into the blood vessel, dual modal images are obtained using an ultrasound and MR imaging probe. At the same time, the magnetic MBs can be controlled by both ultrasonic and magnetic field.

6.4.2

Acoustic response of magnetic microbubbles

In the absence of any particles on its surface, a bubble would be expected to exhibit symmetrical radial oscillations in response to a low-intensity ultrasound field. The presence of particles on the shell of MBs, however, prevents the bubble from expanding and contracting with equal amplitude, due to the increased packing density of the particles during compression. Therefore, it must be considered that the high echogenicity characteristic of MBs can be reduced when MNPs are decorated on the surface of MBs. Stimulated by the challenging study, our group aims to study the influence of the nanoparticle embedded shell on the microbubble scattering prop-

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199

erty. Based on the bubble dynamics theory, [60, 61] the shell properties of the samples (MBs with different amount of Fe3 O4 nanoparticles in the shell with 2 µm average radius are simulated using an optimization method. Then, with a given excitation frequency of 3.5 MHz, the scattering cross sections of the samples are calculated with the estimated shell viscoelastic parameters (χ and κs ). Acoustic scattering, defined as the acoustic power scattered in all directions per unit incident intensity, is given the by scattering cross section σs (ω), which can be estimated from Eq. (6): [62] σs (ω) = 4πR02

(Ω 2

Ω4 , − 1)2 + Ω 2 δ 2

Ω=

ω . ω0

(6)

According to Eq. (6), when the bubble’s initial radius R0 and the excitation frequency are set, the scattering cross section σs (ω) is determined by the resonance frequency ω0 and the damping coefficient. The resonance frequency ω0 scales relative to the shell elasticity parameter, and the damping coefficient is relative to the shell viscosity parameter ωs . Thus, by calculating the shell viscoelastic properties, we can obtain information about the influence on acoustic scattering. Several parameters such as microbubble concentration, microbubble size, excitation frequency, and shell viscoelastic properties together determine the scattering response. Compared to magnetic MBs and MBs without MNPs, the scattering properties are all the same except for the shell properties. It is found that when the MNPs inclusion concentration increases, the scattering cross section of MMBs increases at first and then decreases (Fig. 6.6(a)). Therefore, controlling the appropriate concentration of MNPs in the shell of a microbubble is beneficial for the MMBs in the biomedical imaging applications.

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Fig. 6.6

Magnetic Microbubble: A Biomedical Platform Co-constructed · · ·

(a) The calculated scattering cross sections of the MMBs with the different

MNPs concentration. (b) The backscattered RF signals from MBs and MBs-water-particle.

Fig. 6.6(b) shows that amplitudes of second and third harmonic for the MBwater-MNPs (Fe2 O3 ) are highest. The reason may be that the deposition of nanoparticles on the surface of the microbubble alters the shell’s viscoelastic property and affects the microbubble’s behavior. The unevenly distributed nanoparticles respond with asymmetrical oscillation. All of them are responsible for the increase of the nonlinear behavior of MBs. Moreover, nanoparticles alter the vibration properties of the microbubbles and enhance the nonlinear properties of backscattering, which is potentially suitable for medical ultrasound contrast harmonic imaging. Thus the magnetic MBs with higher nonlinearity can be beneficial for improving the contrast effect of ultrasound harmonic imaging. 6.4.3

Magnetic response of magnetic microbubbles

When a microbubble is placed in a fluid with a magnetic permeability in which an external uniform magnetic field H0 is present, the field around the microbubble is disturbed. One of the ways to change the magnetic susceptibility of MBs in the medium is to change the susceptibility of the encapsulated gas. If the susceptibility of the gas filled in MBs differs from that of the surrounding medium, MBs create localized perturbations in the magnetic field, thereby acting as “susceptibility contrast agents” and shortening T2 and T2 *. The effects depend on magnetic field strength and are much greater at higher field strength. [63, 64] Some experiments showed that

6.4

Magnetic and acoustic character of magnetic microbubbles (MMBs)

201

the MBs can be used as MR susceptibility contrast agents on a 2-T and 4.7-T MR scanner. [65, 66] On the other hand, based on the principle that the rate constant for relaxation of the MR signal (R2 ) from a solution containing spheres is related to the size of the sphere, when the distensible MBs are present in a pressure-varying medium, the changes in size due to changes in pressure (P ) cause changes in signal decay rate constants 1/T2 (or R2 ) and 1/T2∗ (or R2∗ ). The susceptibility of air MBs was measured by transverse relaxation increase (R2∗ ). The time course of the transverse relaxation increase R2∗ (t) was estimated as Eq. (7): [67] R2∗ (t) = − ln(S(t)/Sf )/T E,

(7)

where Sf is the final signal intensity. The R2∗ is to be proportional to the MBs volume fraction. The volume change of the MBs resulting from the oscillation can change the transverse relaxation rate. From Fig. 6.7, it is clear that the increase of MBs’ volume is equivalent to increasing the susceptibility difference between the bubble and its environment. Based on this principle, some researches have reported that on a 4.7-T and 7-T MR scanner, MBs coated with shells of liposomes or human albumin have shown great potential for application as MR pressure sensors based on pressure-induced susceptibility change in vitro and in vivo. The in vitro and in vivo MRI experiments all show that the MBs can be fabricated to be the effective MR susceptibility contrast agents. However, although the above-mentioned studies indicated good magnetic response of MBs, all studies were performed with high-field MR systems because MBs have a relatively weak susceptibility effect. In practice, one means of enhancing the susceptibility is by coating or embedding magnetically active particles of high magnetic dipole moment on the lipid shells of gas-containing microbubbles. In order to obtain a significant increase in ∆χeff , thousands of magnetically active particles need to be embedded on the microbubble shell. [68, 69] Under this condition, a large magnetic susceptibility comes from SPIO particles. For in vitro measurement, the measured transverse relaxation rate (R2 ) of the samples may be described by Eq. (8): R2Total = R2MBs + R2MNPs .

(8)

We examine the possibility of enhancing the effective magnetic susceptibility difference by embedding the different concentrations 12-nm Fe3 O4 in the shell. The overall transverse relaxation rate R2Total is considered as the sum of that contributed by MBs, R2bubble , and that contributed by SPIO particles, R2SPIO . Generally speaking, R2SPIO À R2bubble , therefore R2SPIO contributed by SPIO Fe3 O4

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Fig. 6.7

Magnetic Microbubble: A Biomedical Platform Co-constructed · · ·

Schematic plot of the size change according to the pressures (a). (b) The in

vitro MRI images using 7-T scanner. I: de-ionized water, II: EMBs without SPIO inclusion, SPIO-inclusion EMBs with different SPIO concentrations (III–X are 5.73, 12.06, 33.14, 54.23, 86.47, 105.69, 122.85, 145.24, 180.23 mg/ml respectively). After the corresponding T2 computed from the T2 -maps were obtained. The relationship of R2 versus SPIO inclusion (mg/ml) is shown in panel (c). The linear fit was obtained between the SPIO-inclusion concentration in the MBs and the transverse relaxation rate (R2 ). From this curve, it is found that the effect of increasing total magnetic nanoparticle density in the shell is related to increasing the susceptibility effects of the MBs.

6.5

Applications of magnetic microbubbles in biomedicine

203

nanoparticles embedded in MBs is greater than that contributed by the free SPIO Fe3 O4 nanoparticles in the solution of the same concentration when volume fraction is greater than 60% (Fig. 6.7(c)). MBs can hold the nanoparticles in the shells and keep numerous of MNPs localized and concentrated per volume inside the shell, thus the number of MNPs per volume much higher than those anywhere for the free MNP. Since in this case the effect due to highly concentrated MNPs dominates, the linear relationship condition with respect to ∆χ based on the uniformly distributed MBs’ susceptibility effect is no longer valid. In fact, the effect of adding the number of SPIO per volume becomes quite nonlinear. [70] There is a strong dependence on the type of magnetically active agents, the nanoparticle radius, the magnetic saturation, the total magnetic susceptibility, and the distribution in the shell.

6.5 6.5.1

Applications of magnetic microbubbles in biomedicine Multimodal imaging of MMBs

Initially, the motivation and objectives of designing magnetic microbubbles are to combine MBs and MNPs. Therefore, the introduction of nanoparticles onto the surface of microbubble produces a useful tool for multi-mode imaging based on a multifunctional contrast agent. For example, our group engineered double-layered SPIO-encapsulated MBs which showed improved r2 relaxivity and better contrast enhancement than SPIO free MBs or SPIO-included MBs on the surface. When the MNPs are embedded in the shell of MBs, the high echogenicity, characteristic of MBs coated with a thin self-assembled film of small molecules, is not reduced by the grafting of MNPs. The in vitro MRI experiments revealed a gradient decrease of gray scale associated with a corresponding increase of the SPIO concentrations. The transverse relaxation fitted well to a linear relationship with different SPIOinclusion amounts in the MBs. Then in vitro ultrasound imaging was performed to observe a distinct “brightening” contrast enhancement in the region of interest (ROI) with a certain MMB concentration. After the injection of MMB into the liver of living rats, real-time MRI anatomical images revealed a clear negatively enhanced contrast. Later, Liu et al. also reported that poly(butyl cyanoacrylate) (PBCA) polymer encapsulated ultrasmall superparamagnetic iron-oxide (USPIO) nanoparticles exhibited strong contrast in US and an increased transversal relaxation rate in MR. [71, 72] Although these existing findings reveal a promising ultrasoundMRI dual mode imaging modality for medical applications, future efforts in this regard will focus on the coupling of antibodies or peptides to the microbubble surface, to make them useful for multi-modal molecular imaging.

204

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Magnetic Microbubble: A Biomedical Platform Co-constructed · · ·

Ultrasound assisted drug delivery of MMBs

In addition to providing contrast enhancement in ultrasound imaging, to utilize microbubble-nanoparticle hybrid vehicles for drug release and therapy is another promising strategy for medical treatment applications. The basic mechanism of MBs for vesicle delivery is mainly based on enhanced membrane transport, changes in tissue/vascular transport properties, and mechanical or thermal changes. Acoustic cavitation induces high fluid velocities, shear forces, and local temperature increase, thus producing biological effects and altered transport kinetics near the site. [73, 74] Combination of MBs with nanoparticles into one single delivery system can also facilitate the possibility of effective drug transport from extracellular microenvironment to cell membrane, and controllable release at the diseased sites. [75] In the study, we have demonstrated that it is possible to control the release of Fe3 O4 NPs from shells of embedded microbubbles into cells by ultrasonic excitation. Consequently, those Fe3 O4 -NP-labeled cells can be noninvasively tracked by MRI. The appropriate balance between generation of suitable cell porosity for drug delivery and, simultaneously, maintenance of the integrity of the plasma membrane could be achieved by adjusting the acoustic intensity of the applied US, which would provide medical professionals with an alternative way to deliver nanoparticles into targeted cells noninvasively and effectively. [76] However, the multiple-scale interactions of magnetic MBs are rather complicated and warrant further research. 6.5.3

Magnetic field-controlled drug delivery and release of MMBs

An alternative and potentially complementary strategy is to use MBs loaded with MNPs whose location can be manipulated using an externally applied magnetic field. Enhanced transfection has been demonstrated in vitro and in vivo. As mentioned above, it was hypothesized that the increased transfection rates were due to the increase in both concentration and proximity of the MBs to the target cells produced by the magnetic field. Further investigation to fully understand the mechanisms of enhancement and optimization of the delivery protocols is required. One question which was not addressed in the studies is whether the MNPs significantly affected the behavior of the MBs in the presence of an external magnetic field. In order to determine the influence of these factors on a range of microbubble characteristics, their dynamics and magnetics have been investigated in in vitro and in vivo studies. [77] A recent paper reported that magnetic MBs were used for gene delivery to Chinese hamster ovary cells. Different formulations of magnetic MBs, non-magnetic MBs, and magnetic liquid droplets were co-injected with naked plasmid DNA encoding for luciferase and the cells exposed to a magnetic field, ultrasound or both. In ad-

References

205

dition, the experiments were performed with the cells on either the upper or lower surface of the culture plate so that in the case of the former, buoyant bubbles would be in contact with the cells. The results show that they would be separated by a distance of 2 mm unless they were magnetically-responsive in which case they would be translated downwards in the presence of a magnet. It was found that the highest rates of transfection were achieved with simultaneous exposure to ultrasound and a magnetic field. [78]

6.6

Summary and perspectives

When superparamagnetic iron oxide nanoparticles are coated on the shell of MBs, the MBs are endowed with nanoparticle-carrying capacity, high magnetism, and strong and adjustable US/ MRI enhancement capability. Furthermore, such elaborately fabricated MMBs are distinctly distinguished from other type of carrier materials in that they have powerful multiple loading capability as well as specific response to the ultrasound field and magnetic force. In the field of disease-specific imaging, MR and US imagings are widely used modalities for various experimental and clinical applications. It is essential to develop a multimodal co-constructed platform for multi-functional biomedical applications. Magnetic MBs have been also developed as a new multifunctional delivery system. The bubbles with a magnetic shell can possess sufficient magnetization such that they can be controlled with conventional magnets, and their shell elasticity still allows for volume oscillations in moderate acoustic fields. Since maintaining the magnetic and acoustic characteristics, the magnetic MBs can be visualized using ultrasound imaging, magnetic resonance imaging, and can be localized by using an externally applied magnetic and ultrasonic field. Further, the MMBs exploit the combined effects of magnetofection and sonoporation for therapeutic delivery. In that respect, MMBs can be considered as a co-constructed multiscale platform of magnetics and acoustics. The mechanism should be further studied. By coupling a targeting-ligand to the surface of the MMB, such as a monoclonal antibody, it will be possible to target the MMB to specific tissues within a subject. To realize molecular imaging and accurate drug delivery will be the subject of future promising and interesting investigations. The continuous efforts in development of different types of magnetic micro-/ nano-bubbles, in-situ smart responsive acoustic drug delivery system offer an attractive possibility for more wide clinical applications.

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MMBs as physical triggering smart drug delivery system

As one type of smart drug delivery systems, physical sources such as light, ultrasound, magnetic field, electrics have offered unique abilities for spatial targeting, spatiotemporal controllability of drug release, as well as promoting clinical translation. Since the MMBs maintain both the magnetic and acoustic responsive capabilities, the MMBs show promising in enhancing the therapeutic efficacy of drug delivery. Based on the feasibility of SPIO surface modification of the MMBs, it has reported that an arginine-glycine-aspartic acid (RGD)-l-tumor necrosis factor-related apoptosis-inducing ligand (RGD-l-TRAIL) protein modified MMBs could realize the magnetic and acoustic multi-gradient continuous targeting strategy, resulting in the enhanced tumor targeting efficiency and accurate dual US/MRI guidance and released TRAIL molecules to induce cell apoptosis.[79] Since the stability of MMBs is one of the major concerns for application, the magnetic lipid/cell membrane shelled nanocarriers in-situ bubble generator has been developed. Such fabricated magnetic liposomes can be remotely controlled to the target area via external magnetic field and are imaged by MRI. Then, with the gas bubble production, the carriers can be imaged and controlled by ultrasound. Such novel magneto-acoustic approach based on SPIO-ADT-LPs can be used as intracellular bubble reactors, resulting in the improved anticancer cell efficacy.[80,81] However, the controllability of MMBs is realized upon an external physical magnetic field and acoustic field. When applied by an external magnetic stimulus, both hyperthermia and drug targeting guided by a magnetic field are two major mechanisms for MMBs controlled drug release, which depends on the property of loaded magnetic nanoparticle size, shape, and concentration. From clinical application view, the major problem is the delivery depth in the body. For static external magnets, the penetration depth to attract the magnetic drug carriers is within 5 cm under the skin.[82] Although ultrasound is generally considered to be safe at the frequencies and amplitudes used clinically, and can penetrate a wide range of tissues to a great depth (2∼10 cm), it cannot penetrate air-filled spaces.[83] Therefore, the magnetic and acoustic source and sensitivity of the MMBs to the magnetic and acoustic source are the key parameters for future clinical potential applications. 6.6.2

MMBs for gene delivery

The gene therapy has been demonstrated for the treatment of many diseases such as cancer, rheumatoid arthritis, and myocardial infarction. Although there is substantial development for gene delivery carriers, effective and safe vector delivery is still a major challenge because both nucleic acids and the cell membrane are

6.6

Summary and perspectives

207

negatively charged, resulting in their mutual repulsion. The microbubble induced sonoporation effect can increase the cell membrane permeability or trigger the transient formation of pores in the cell membrane, which enhances the uptake of the macromolecules such as nucleic acids.[84−86] Some studies have demonstrated that the combined plasmid DNA with microbubbles approach bear great promise for the microbubble-enhanced sonoporation-induced gene therapies. For example, Galina Shapiro et al reported that the combination of acoustic pressure, microbubble and DNA dosage, and treatment time parameters allows an efficient and prolonged gene expression, with no evident damage to treated tissues.[87] Based on the advantages on both microbubble sonoporation enhance gene delivery and magnetofection, the MMBs may be developed as targeted gene delivery sites. In the future, in order to achieve the maximum local therapeutic effect at the target-site while reducing unwanted effects at nontarget, all of the parameters such as the magnetic nanoparticle concentration, the MMBs size, acoustic pressure, microbubble and DNA dosage, and magneto-acoustic treatment time should be studied in detail. 6.6.3

MMBs for treating diseases of the central nervous system

The central nervous system (CNS) is among the most highly perfused and vascularized organ systems in the body.[88] As a neurovascular unit, the blood-brain barrier (BBB), composed of endothelial cells, pericytes, astrocytes, and microglia, is formed as the defective tight junction in central nervous system (CNS).[89] The BBB is a dynamic, flexible interface to provide a physical barrier between the bloodstream and neural tissue. Due to the existence of the BBB, it is a major obstacle for the drug delivery to treat the neurological disorders, mainly Alzheimer’s disease, Parkinson’s disease, brain tumors, and stroke. Until now, both biochemical and physical strategies have been developed to overcome the BBB. Among all of these approaches, the physical energy strategies such as electroporation for electric current, iontophoresis for electric potential, magnetoporation for magnetic field, sonoporation, mechanoporation and phonophoresis for ultrasound, optoporation for pulsed light and thermoporation for temperature have shown advantages to achieve the enhanced and effective drug delivery through BBB.[90−95] Magnetic nanoparticle-based drug delivery has become an appealing strategy for the brain delivery because they can be magnetized in the presence of a magnetic field to precisely deliver drugs to specific sites of action. Kong et al. reported that the MNPs permeated the BBB and accumulated in the perivascular zone of the brain parenchyma when applied an external magnetic field in a mouse model.[96] For

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ultrasound, some investigations have shown that the focused, low-intensity pulsed ultrasound have indicated as a minimally invasive technique to temporarily disrupts the BBB.[97] More importantly, assisted by microbubbles, the BBB could be further opened and the carried therapeutic drugs in the microbubbles could be enhanced to deliver into the brain areas. Chen, et al reported that the focused ultrasound technique can induce size-controllable BBB opening, allowing size-selective transBBB delivery. They found that the BBB opening size was smaller than 3 kDa (2.3 nm) at 0.31 MPa, up to 70 kDa (10.2 nm) at 0.51 MPa, and up to 2,000 kDa (54.4 nm) at 0.84 MPa. Relatively smaller opening size (up to 70 kDa) was achieved with stable cavitation only; however, inertial cavitation was associated with relatively larger BBB opening size (above 500 kDa).[98] In 2019, A. Abrahao, et al.[99] conducted a single-arm, first-in-human trial by using the transcranial magnetic resonance-guided focused ultrasound (MRgFUS) combined with intravenous ultrasound contrast (perflutren lipid microbubbles) to induce BBB opening in eloquent primary motor cortex in four volunteers with amyotrophic lateral sclerosis (ALS). The results show that the MRgFUS makes the BBB successful opening, leading to gadolinium leakage at the target site immediately after sonication. This study demonstrates that MRgFUS is safe, feasible, and reversible in ALS subjects with no serious clinical, radiologic or electroencephalographic adverse events. Inspired by this clinical study, the microbubble coupled with magnetic nanoparticles may be promising theranostic platform for the CNS disease therapy due to the excellent magnetic and acoustic capabilities of MMBs. Moreover, except as drug delivery carrier, the MMBs endowed with ultrasound and MRI imaging enable to monitor the disease response during drug delivery. In order to apply for the CNS diseases in clinic in the future, the physicochemical properties, the magnetic and acoustic energy control, as well as the toxicity of the delivered magnetic nanoparticles should be considered.

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Chapter 7 Multifunctional Magnetic Nanoparticles for Magnetic Resonance Image-guided Photothermal Therapy for Cancer∗ Xiuli Yuea) , Fang Maa) , Zhifei Daib)† a)

State Key Laboratory of Urban Water Resources and Environment,

School of Municipal and Environmental Engineering, Harbin Institute of Technology, Harbin 150001, China b)

Department of Biomedical Engineering, College of Engineering, Peking

University, Beijing 100871, China † Corresponding author. E-mail: [email protected]; Homepage: http:// bme.pku.edu. cn/daizhifei Key advances in multifunctional magnetic nanoparticles (MNPs) for magnetic resonance (MR) image-guided photothermal therapy of cancer are reviewed. We briefly outline the design and fabrication of such multifunctional MNPs. Bimodal image-guided photothermal therapies (MR/fluorescence and MR/ultrasound) are also discussed.

7.1

Introduction

Due to the ease of manipulating and controlling magnetic nanoparticles (MNPs) by an external magnetic field, they are employed in sophisticated ways such as in ∗ Project supported by the National Natural Science Foundation of China (Grant Nos. 81371580 and 21273014), the State Key Program of the National Natural Science Foundation of China (Grant No. 81230036), and the National Natural Science Foundation for Distinguished Young Scholars (Grant No. 81225011).

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magnetically targeting drug delivery, and in improving therapies’ efficacy and minimizing their side effects. Of particular note, MNPs have been used clinically as a magnetic resonance imaging (MRI) contrast agent. Image-guided photothermal therapy (PTT) has drawn extensive research interest, owing to its minimal invasiveness. Multifunctional MNPs with the combination of MRI and PTT would be of great value to obtain more comprehensive diagnostic information, particularly the dynamics of disease progression, for the accurate location of a therapeutic focusing spot in the targeted tumor tissue. So cancer PTT with near-infrared (NIR) light and photoabsorbers has attracted wide research interest due to its minimal invasiveness compared with other cancer interventions that unavoidably damage or excise healthy cells along with cancerous cells, such as chemotherapy, radiation therapy, and surgery.[1−3] Nonetheless, before PTT, it is necessary to accurately identify the location and size of tumors as well as the presence of photoabsorbers for laser irradiation.[4−6] In addition, during therapy we need to monitor the treatment procedure in real time to ensure complete eradication of microscopic tumors. Moreover, after therapy we should assess its effectiveness. All these tasks could be carried out by the integration of contrast-enhanced diagnostic imaging capability with photothermal therapy.[7−10] Image-guided therapy employed diagnostic imaging modalities for planning, targeting, monitoring, controlling and assessing treatment response during the therapeutic treatment.[11−16] As one of the most exciting and challenging strategies for cancer treatment, image-guided tumor ablation has been widely used in both biomedical research and clinical trials.[17−20] Due to the great repercussions of multifunctional nanoparticles (NPs) on clinical diagnosis and therapeutic protocol, their development for both imaging and therapy is pursued with increasing zeal. [21] The administration of multiple doses of theranostic agents commonly adds stress on the body’s blood-clearance mechanisms, and NP-based agents could avoid this. [20] Magnetic NPs have been applied in both biomedical research and clinical trials and turn out to be one of the most promising nanomaterials for both diagnostic and therapeutic agents.[22−26] Superparamagnetic iron oxide nanoparticles (SPIOs) were the first nanoparticulate MRI contrast agent to be used clinically.[27−29] Due to their ease of manipulation and control using an external magnetic field, SPIO NPs are also employed in sophisticated magnetically targeted drug-delivery systems for regulating drug release, and in improving therapies’ efficacy and minimizing their side effects.[22−26] In addition, various functional components can be attached to magnetic NPs. Such multifunctional MNPs bear therapeutic moieties, as well as complementary imaging moieties for the investigation of the particle localiza-

7.2

ICG-loaded MNPs for MR/fluorescence bimodal image-guided PTT

215

tion across a number of platforms, such as magnetic resonance, optical, or nuclear imaging.[27−29] The present review will briefly outline the design and fabrication of multifunctional MNPs for image-guided photothermal therapy of cancer.

7.2

ICG-loaded MNPs for MR/fluorescence bimodal imageguided PTT

7.2.1

Fabrication of ICG-loaded SPIO NPs

The NIR fluorescence probe allows deeper penetration of tissues than visible optical probes for in vivo imaging applications, leading to 1) high sensitivity, 2) relatively low tissue absorption, and 3) minimal autofluorescence.[30−32] But fluorescent imaging’s strong light-scattering unfortunately limits its spatial resolution in turbid media (e.g. tissues). When MRI is used, no such scattering occurs. Indocyanine green (ICG), with absorption and emission maxima in the NIR region around 740 nm and 800 nm, has been approved by the U.S. Food and Drug Administration (FDA) for human medical imaging and diagnosis in clinical applications. [33, 34] However, several major challenges remain in the use of ICG for imaging applications, such as temperature- and light-dependent optical properties, a tendency to aggregate and degrade rapidly in aqueous solution, rapid clearance from the body with a short half-life of 2 min–4 min, a tendency toward photobleaching and imprecise targeting. So the indocyanine green cannot be utilized for sensitive and prolonged imaging in vivo. [35] In order to resolve these problems, a nanotheranostic agent was developed by coating oleylamine-stabilized SPIO NPs with 1,2-distearoyl-sn-glycero3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-5000] (DSPE-PEG5000), through a dual solvent exchange method, followed by loading ICG molecules into the lipid layer on the surface of the NPs for photothermal tumor ablation under the guidance of fluorescence/MR bimodal imaging (Fig. 7.1). [36] Before and after ICG loading, the SPIO NPs were well-dispersed in water with an average hydrodynamic diameter of 29.9 nm and 27.5 nm, respectively. Introduction of the PEG layer on

Fig. 7.1

Schematic illustration of SPIO@DSPE-PEG/ICG NP preparation. [36]

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the surface of nanoparticles could greatly prolong the circulation time in vivo, thus facilitating biomedical applications of these nanoparticles. 7.2.2

In vivo MR/fluorescence bimodal imaging of ICG-loaded SPIO NPs

Both MRI and fluorescence contrast behavior of the obtained NPs were evaluated in vitro and in vivo. The magnetic resonance imaging capability of the SPIO@DSPEPEG/ICG NPs was analyzed in vivo using nude mice with grafted tumors (Fig. 7.2). Twenty four hours after the injection, the whole tumor area became much darker, suggesting that a large number of SPIO@DSPE-PEG/ICG NPs had accumulated in the tumor area, reducing the T2 -weighted MR intensity.

Fig. 7.2

T2 -weighted MR images of nude mice bearing Hela tumors at (a) 0 h, (b) 0.5 h,

(c) 4 h, and (d) 24 h after tail-vein injection of SPIO@DSPE-PEG/ICG NPs. [36]

Twenty four hours after the injection of SPIO@DSPE-PEG/ICG NPs via the tail vein, the fluorescence signals were predominantly located around the tumor, with little from the vital organs, while no intense fluorescence signals were observed throughout the mouse’s body at 0.5 h and 4 h after the injection (Fig. 7.3). In contrast, the free ICG molecules were quickly excreted from the liver within 24 h

7.2

ICG-loaded MNPs for MR/fluorescence bimodal image-guided PTT

217

of injection. [37] These observations suggest that a large number of SPIO@DSPEPEG/ICG NPs circulated in the blood and then accumulated at the tumor site, which is good evidence of the high efficiency of the tumor-targeting potential of these nanoparticles. Because of the enhanced permeation and retention (EPR) effect, SPIO@DSPE-PEG/ICG NPs of around 30-nm diameter can be passively accumulated in tumor tissue. [38] In addition, the introduction of the PEG layer on the surface of SPIO NPs inhibits macrophage recognition by the reticuloendothelial system (RES) of the liver and spleen due to the good hydration property, resulting in prolonged circulation in the blood. In vivo MR and fluorescence images indicate the high tumor targeting efficiency of SPIO@DSPE-PEG/ICG NPs. The passively targeted SPIO@DSPE-PEG/ICG NPs can also display the tumor area to guide the NIR laser irradiation for photothermal ablation of tumors without damaging the surrounding healthy tissues.

Fig. 7.3

Fluorescence images of nude mice bearing Hela tumor at (a) 0 h, (b) 0.5 h, (c)

4 h, and (d) 24 h after tail-vein injection of SPIO@DSPE-PEG/ICG NPs (left) and free ICG (right). [36]

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7.2.3

In vivo photothermal therapy with ICG-loaded SPIO NPs

The ICG loaded into SPIO NPs significantly improves photostability compared with free ICG and induces intense temperature elevation upon NIR laser irradiation. So, further in vivo photothermal therapy was investigated using SPIO@DSPEPEG/ICG NPs in nude mouse xenograft models. After intravenous injection of SPIO@DSPE-PEG/ICG NPs followed by NIR laser irradiation, the growth of the mice’s tumors was first significantly inhibited and then ceased after 14 days of irradiation, while the tumors in saline only, those in saline with laser irradiation and those with SPIO@DSPE-PEG/ICG NPs only all grew significantly over the same time period. These results indicate that neither the NPs nor laser irradiation alone had significant beneficial effect on tumor growth. Tumors were effectively ablated only with the combination of the SPIO@DSPE-PEG/ICG NP injection and NIR laser irradiation, leaving black scars at their original sites with no recurrence (Fig. 7.4).

Fig. 7.4

Representative photographs of mice after in vivo photothermal therapy with various treatments, as indicated. [36]

7.3

Gold-nanoshelled magnetic cerasomes for MRI-guided photothermal therapy

7.3.1

Cerasomes combine the advantages of both liposomes and silica nanoparticles

Liposomes have been made capable of thermally controlled release of encapsulated agents by forming gold nanoshells on the surface of the liposomes and then controlling the release by heating the gold and hence the liposome membrane above the membrane’s melting temperature (Tm ) by laser irradiation. [39] A Tm close to

7.3

Gold-nanoshelled magnetic cerasomes for MRI-guided photothermal therapy

219

body temperature results in drug leakage during circulation in the human system. In contrast, a Tm far above body temperature minimizes leakage during circulation. [40] Due to the insufficient stability of familiar liposomes, gold nanoshell-coated liposomes usually form large gold aggregates, resulting in a one-time release profile instead of multiple-release dynamics. [41] Recently, a super-stable, freestanding cerasome has been reported as a novel drug delivery system, since its atomic-thick silica-like surface layer imparts a higher morphological stability than can be found in liposomes, and its liposomal bilayer structure reduces the overall rigidity and density greatly, compared to silica nanoparticles.[42−46] Because of the introduction of the liposomal architecture, cerasomes are more biocompatible than silica nanoparticles. Cerasomes possess the advantages of both liposomes and silica nanoparticles but overcome their practical disadvantages, so cerasomes are ideal drug delivery systems. [47] Cholesteryl hemisuccinate (CS) is a cholesterol derivative. Thus, we fabricated gold-nanoshelled magnetic cerasomes (GNMCs) by loading both doxorubicin and Fe3 O4 MNPs into CS cerasomes and then forming gold nanoshells on the surface of the CS cerasomes (Fig. 7.5). [48, 49]

Fig. 7.5

Schematic illustration of gold-nanoshelled magnetic cerasome. [49]

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7.3.2

Contrast-enhanced MRI imaging using GNMCs

The T2 -enhancing capability of GNMCs with various iron concentrations was compared with that of Fe3 O4 NPs (with the same iron concentration) by T2 -weighted MRI. The signal intensity of MRI decreased with the increase of iron concentration for both GNMCs and Fe3 O4 NPs. The weighted transverse relaxivity value (r2 ) of the GNMCs was 61.5 mM Fe−1 ·s−1 , much higher than that of the Fe3 O4 NPs (8.8 mM Fe−1 ·s−1 ). The increase in the transverse relaxivity is attributed to the nanoparticles’ assembly into clusters or aggregates in cerasomes, which increases the cross-sectional area. [50, 51] This phenomenon offers us an opportunity to identify the location and size of tumors, monitor therapeutic effectiveness and address the drug accumulation in the tumor, all through contrast-enhanced MRI imaging. 7.3.3

Synergistic effect in killing cancer cells using GNMCs

Superparamagnetism is important in drug delivery. It has been found that homogenously dispersed magnetic cerasomes can be redistributed quickly by external magnetic field and can be redispersed quickly with a slight shake after removal of the magnetic field. A cellular uptake study showed that the concentration of magnetic cerasomes by means of an external magnetic field enables their rapid and efficient uptake by cancer cells, resulting in a higher kill rate for tumor cells than that of drug-loaded nonmagnetic cerasomes. [52] The magnetic field enforces a tight and sustained interaction between the cerasomes and the targeted cell surface to achieve drug delivery. The study’s results indicate the suitability of magnetic cerasomes for targeting and separation as drug carriers, and such cerasomes’ great potential in anticancer applications. GNMCs exhibit an NIR-induced temperature elevation and NIR light–triggered, stepwise release of doxorubicin, due to the surface plasmon absorbance in the NIR region and frequency-specific characteristics of CS cerasomes. When GNMCs were exposed to NIR light for 10 min five times, the cumulative amount of DOX released over the whole experimental process was about 2-fold greater than when performed without laser irradiation. Although the amount of DOX released after each irradiation decreased from the first cycle to the fifth cycle, which results from increased coverage of gold nanoshells due to the melting effect of the gold nanostructure, [53] a stepwise triggered release was successfully obtained by NIR irradiation of GNMCs. This multiple-release dynamic can be attributed to the unique characteristics of CS cerasomes — their melting temperature, mechanical stability, and heat resistance are all remarkably higher than those of familiar liposomes, which usually exhibit a one-time release instead of multiple releases. [41] Photothermal cytotoxicity and

7.4

Gold-nanoshelled magnetic nanocapsules for MR/ultrasound bimodal · · ·

221

cell viability in vitro tests indicate the feasibility of using GNMCs in photothermal treatment under near-infrared irradiation. A synergistic effect in killing cancer cells might be found by a combination of photothermal therapy, chemotherapy, and magnetic field-guided drug delivery with the aid of MRI imaging guidance.

7.4

Gold-nanoshelled magnetic nanocapsules for MR/ ultrasound bimodal image-guided photothermal therapy

7.4.1

SPIOs-embedded PFOB nanocapsules with PEGylated gold shells (PGS-SP NCs)

Compared with other diagnostic imaging modalities, ultrasound (US) imaging has the advantages of real-time, low cost, high safety, and ready availability in portable devices. [54, 55] However, the spatial and anatomical resolution of US images has been relatively poor. [56] Nevertheless, these disadvantages of US might be overcome by its integration with MRI. [57] A combination of US and MRI imaging capabilities with PTT could be achieved in a multifunctional theranostic platform. For this purpose, the SPIO-embedded PFOB nanocapsules with PEGylated gold shells were synthesized via an adapted oil-in-water (O/W) emulsion solvent evaporation process, followed by the formation of gold nanoshells using a surface seeding method and surface PEGylation with methoxy-poly(ethylene glycol)-thiol (Fig. 7.6). [58] Scanning electron micrographs show that PGS-SP NCs keep their

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Fig. 7.6

Multifunctional Magnetic Nanoparticles for Magnetic Resonance· · ·

Schematic illustration (a) and scanning electron micrograph (b) of

SPIO-embedded PFOB nanocapsules with PEGylated gold shells. [58]

spherical shape after gold shell formation but exhibit rough surface morphology, and their average diameter was about 370 nm. Such a single nanotheranostic agent with the combination of US and MR imaging would be of great value to obtain more comprehensive diagnostic information and probe the dynamics of disease progression for more accurate location of the targeted tumor tissue for more effective PTT tumor ablation. 7.4.2

Bimodal US/MRI contrast imaging capability of PGS-SP NCs

Bimodal US/MRI contrast image-guided photothermal tumor ablation was performed on nude mouse xenograft models. US imaging guidance was performed under real-time monitoring using a clinical US imaging system (Fig. 7.7(a)). The tumor was first found and shown in the conventional B-mode, and no ultrasonographic enhancement was observed before injection. Then, the imaging mode was changed to PIHI contrast mode, and in contrast the boundary and size of the tumors can be clearly detected in real-time after the agent injection, suggesting that US imaging can help ensure the complete distribution of the PGS-SP NCs to guide subsequent photoablation therapy. The PGS-SP NCs also exhibit excellent contrast enhancement, increasing along with the rise of the concentration as shown in the T2 -weighted MR images with high T2 relaxivity of 395.7±8.0 mM−1 ·s−1 , which is more than 2 times as high as that of the commercial SPIO-based MRI contrast agent Resovist (185.8±9.3 mM−1 ·s−1 ), [59]

7.4

Gold-nanoshelled magnetic nanocapsules for MR/ultrasound bimodal · · ·

223

ensuring good MRI contrast enhancement. The higher T2 relaxivity is probably due to the aggregation of SPIOs in the nanocapsules, enlarging the magnetic nanoparticles somewhat, which could increase the T2 relaxivity. [23] When the agent is injected intravenously into the tumor-bearing mice, the nanocapsules tend to accumulate in the tumor sites due to the “enhanced permeability and retention” effect of the nanometer scale and the surface PEGylation of the nanocapsules. The tumor darkened somewhat 0.5 h later, suggesting the SPIO functionalized nanocapsules had been aggregated in the tumor site to generate negative contrast in the T2 -weighted MR image (Fig. 7.7(b)). The average MR intensity in the tumor area, calculated

Fig. 7.7

(a) Contrast-enhanced ultrasonograms, before, during, and after the injection of

the PGS-SP NCs (0.2 mL, 2 m·mL−1 ) into the mice; (b) T2 -weighted MR images of the tumors at different time points after injection of the agent (0.15 mL, 2 mg·mL−1 ); (c) Photographs of representative mice of the four different groups taken pre- and post-treatment. [58]

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from the MR image, decreased rapidly by 31.6% from 76.7±11.6 to 52.4±8.9, showing significant negative enhancement due to aggregation of the nanocapsules. In images taken from 1 h and 2 h after injection, the enhancement of the tumor was still clear, consistent with the MR intensity calculation. The images at 4 h and 24 h show no obvious change in contrast compared with the image at 2 h, suggesting the nanocapsules had been gradually cleared from the tumor and indicating that the nanocapsules can accumulate and remain in the tumor sites as long as two hours to provide adequate time for subsequent therapy. The accumulated nanocapsules also can display the tumor areas to guide the NIR laser irradiation for photothermal ablation of tumors without damaging the surrounding healthy tissues. After intravenous injection of PGS-SP NCs into HT-1080 tumor-bearing nude mice followed by NIR laser irradiation, tumors decreased from 709±83.49 mm3 to 444±227 mm3 on the 9th day after treatment (34.0% smaller in tumor size). In comparison with control group (2499±230 mm3 at day 9), the tumor growth was inhibited by 82.2%, suggesting that sufficient accumulation of PGS-SP NCs could trigger a great photothermal effect locally for effective photothermal tumor ablation. Furthermore, photographs of representative mice show that excellent therapeutic effectiveness was achieved by the combination of PGS-SP NCs with NIR laser irradiation (Fig. 7.7(c)). On the contrary, tumor growth was affected by either PGS-SP NCs or NIR laser irradiation alone. Therefore, effective photothermal tumor ablation was successfully carried out under the guidance of US/MRI contrast imaging due to the accumulation of nanocapsules in tumor sites through passive targeting.

7.5

Conclusion and perspectives

Theranostic magnetic NPs can provide contrast-enhanced and real-time images to guide an NIR laser to irradiate at the right location without damage to normal tissues, allowing the identification of the target site location and target-site distribution of pharmacologically active agents, as well as the prediction of treatment responses. The most noticeable feature of the platform is that all the procedures in the whole treatment are noninvasive or minimally invasive, avoiding unnecessary risk. MRI-guided photothermal therapy using multifunctional magnetic NPs enables “tailored treatment and facilitates (pre-) clinical efficacy and toxicity analyses, contributing substantially to realizing the potential of targeted therapeutic interventions. While the field has already seen great progress, exciting developments still lie ahead. We anticipate that magnetic theranostic agents will contribute to significant advances in the treatment of many classes of diseases. All these efforts will of course require interdisciplinary collaboration of chemists, materials scientists, biologists,

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pharmacologists, and physicians.

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[23] Tong S, Hou S and Zheng Z 2010 Nano. Lett. 10 4607 [24] Laurent S, Forge D and Port M 2008 Chem. Rev. 108 2064 [25] Ghosh D, Lee Y and Thomas S 2012 Nat. Nanotechnol. 7 677 [26] Lee J H, Huh Y M and Jun Y W 2007 Nat. Med. 13 95 [27] Zou P, Yu Y and Wang Y A 2010 Mol. Pharm. 7 1974 [28] Yu Y and Sun D 2010 Expert. Rev. Clin. Pharmacol. 3 117 [29] Raynal I, Prigent P and Peyramaure S 2004 Invest. Radiol. 39 56 [30] Frangioni J V 2003 Curr. Opin. Chem. Biol. 7 626 [31] Smith B A, Gammon S T, Xiao S Z, Wang W, Chapman S, McDermott R, Suckow M A, Johnson J R, Piwnica-Worms D, Gokel G W, Smith B D and Leevy W M 2011 Mol. Pharm. 8 583 [32] Adams K E, Ke S, Kwon S, Liang F, Fan Z, Lu Y, Hirschi K, Mawad M E, Barry M A and Sevick-Muraca E M 2007 J. Biomed. Opt. 12 0240171 [33] Desmettre T, Devoisselle J M and Mordon S 2000 Surv. Ophthalmol. 45 15 [34] Maarek J M I, Holschneider D P and Harimoto J 2001 J. Photochem. Photobiol. B 65 157 [35] Rudin M 2009 Curr. Opin. Chem. Biol. 13 360 [36] Ma Y, Tong S, Bao G, Gao C and Dai Z F 2013 Biomaterials 34 7706 [37] Makino A, Kizaka-Kondoh S, Yamahara R, Hara I, Kanzaki T, Ozeki E, Hiraoka M and Kimura S 2009 Biomaterials 30 5156 [38] Rhyner M N, Smith A M, Gao X H, Mao H, Yang L L and Nie S M 2006 Nanomedicine 1 209 [39] Needham D, Anyarambhatla G, Kong G and Dewhirst M W 2000 Cancer Res. 60 1197 [40] Reimhult E, Amstad E A, Kohlbrecher E J, Muller E, Schweizer T and Textor M 2011 Nano Lett. 11 1664 [41] Gao X H and Jin Y D 2009 J. Am. Chem. Soc. 131 17774 [42] Dai Z F, Tian W J, Yue X L, Zheng Z Z, Qi J J, Tamai N and Kikuchi J 2009 Chem. Commun. 45 2032 [43] Ma Y, Dai Z F, Gao Y G, Cao Z, Zha Z B, Yue X L and Kikuchi J 2011 Nanotoxicology 5 622 [44] Jin Y S, Yue X L, Wu X Y, Cao Z and Dai Z F 2012 Acta Biomater. 8 3372 [45] Liang X L, Yue X L, Dai Z F and Kikuch J 2011 Chem. Commun. 47 4751 [46] Leung S L, Zha Z B, Teng W M, Cohn C, Dai Z F and Wu X Y 2012 Soft Matter 8 5756

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Chapter 8 Magnetic-mediated Hyperthermia for Cancer Treatment: Research Progress and Clinical Trials∗ Lu Jingsonga,b) , Liu JiaYic,d) , Ouyang WeiWeic,e) , Li DanYec,f) , Li Lic,g) , Li LiYaf) , and Tang JinTianc) , Zhao LingYuna)† a)

State Key Laboratory of New Ceramics and Fine Processing, School

of Materials Science and Engineering, Tsinghua University, Beijing 100084, China, E-mail: [email protected] b)

Research Center of Magnetic and Electronic Materials, College of Ma-

terials Science and Engineering, Zhejiang University of Technology Hangzhou 310014, China c)

Institute of Medical Physics and Engineering, Department of Engineer-

ing Physics, Key Laboratory of Particle & Radiation Imaging, Ministry of Education, Tsinghua University, Beijing 100084, China d)

Affiliated Ruikang Hospital, Guangxi University of Traditional Chinese

Medicine, Nanning 530011, China e)

The Affiliated Hospital to Guiyang Medical University, Guiyang 550004,

China f)

China-Japan Friendship Hospital, Beijing 100029, China

∗ Project supported by the National Natural Science Foundation of China (Grant Nos. 81172182, 81172120, and 81041040), the 7th Singapore–China Cooperative Research Project Call between Agency of Science, Technology and Research (A*STAR), Singapore and the Ministry of Science and Technology (MOST), China (Grant No. 20113010006), and the National Key Technology Support Program (Grant No. 2012857818).

8.1

Cancer hyperthermia g)

229

Zhongnan Hospital of Wuhan University, Wuhan 430030, China

† Corresponding author. E-mail: [email protected] ‡ Corresponding author. E-mail: [email protected] Research progress and frontiers of magnetic-mediated hyperthermia (MMH) are presented, along with clinical trials in Germany, the US, Japan, and China. Special attention is focused on MMH mediated by magnetic nanoparticles, and multifunctional magnetic devices for cancer multimodality treatment are also introduced.

8.1

Cancer hyperthermia

Magnetic-mediated hyperthermia (MMH) is expected to be a new breakthrough for cancer treatment. Based on the working mechanism that heating up ferromagnetic biomaterials administered within the tumor site under alternating magnetic field (AMF), MMH can lead to a direct killing of local tumor tissue quickly with no interference to the normal tissue nearby. To meet the needs of clinical application, various kinds of magnetic mediators or agents have been developed, including millimeter-scaled thermoseeds or metallic stents for interstitial implant hyperthermia, micrometer-scaled particles for arterial embolization hyperthermia, and magnetic nanoparticles (MNPs) for intracellular hyperthermia. Recently, intensive and extensive investigations have been carried out with MMH, and some research findings have been successfully applied in clinical oncology. Nowadays cancer has become a major public health problem and one of the leading causes of morbidity and mortality in the world. It was recently reported that one in three women and one in two men in the United States will develop cancer in his or her lifetime. In 2013, a total of 1660290 new cancer cases and 580350 cancer deaths are projected to occur in the United States. [1] Therefore, there is a need for a new approach in cancer treatment — more effective, more specific, and capable of increasing the patient’s quality of life. Hyperthermia has a long tradition in medicine as a treatment modality for various diseases. Inscriptions of the ancient Egyptians and texts from the peak of Greek civilization point out its importance. [2] Hippocrates of Kos (ca. 460 BC — ca. 370 BC), father of western medicine, also gave a famous comment on hyperthermia, in which he mentioned that “those diseases which medicines do not cure, the knife cures; those which the knife cannot cure, fire cures; and those which fire cannot cure, are to be reckoned wholly incurable.” (Quae medicamenta non sanat; ferrum

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Magnetic-mediated Hyperthermia for Cancer Treatment: Research· · ·

sanat. Quae ferrum non sanat; ignis sanat. Huae vero ignis non sanat; insanabilia reportari oportet.) Hippocrates evidently believed that some diseases could be cured by raising the patient’s body temperature. In modern medicine, the biological effectiveness of heat in treating cancer has been fully recognized although the mechanisms of heat cytotoxicity are yet unclear.[3−5] It may seem to be a relatively simple demand to heat up malignant tissues, but achieving selectively up to the desired temperature is far from a simple technical task. The potential role of hyperthermia in the management of human cancer will be difficult to assess until heating techniques and hyperthermia systems capable of delivering and monitoring safe, predictable and reproducible treatments are developed. It is generally acknowledged that the following criteria must be considered when the hyperthermia approach is developed: (i) Deepness — to achieve a deep energy delivery; (ii) Focusing — to selectively focus on the malignant area only; (iii) Reproducibility — to conduct the treatment in a reproducible way; (iv) control — to have proper control of the process by standardizing the hyperthermia prescriptions (parameters of the treatment); (v) Personalization — to tune the treatment in-situ to best fit the actual situation. [6]

8.2 8.2.1

Overview of magnetic-mediated hyperthermia (MMH) Working mechanism and brief introduction to MMH

MMH, also called magnetic induction hyperthermia, is expected to be a new breakthrough in hyperthermia for cancer treatment. For the purpose of MMH, the tumor is infused or decorated with magnetic agents. Upon exposure to an external alternating magnetic field (AMF), inductive heating is generated by the magnetic agents to form a high temperature zone (around 50 ◦ C) at the tumor foci (Fig. 8.1). This process can lead to quick direct killing of the local tumor tissue, and in the meantime, activate the immune system to attack distant tumor sites, a phenomenon known as abscopal effect in cancer treatment. The concept of MMH was first proposed in the 1950s by Gilchrist, who demonstrated that magnetic particles could be deposited selectively at a tumor site and heat tumor tissue specifically when exposed to an AMF. [7] After thirty years of exploration, the world’s first clinical trial with MMH by thermoseeds was carried out in Japan. Kida carried out clinical studies for brain cancer treatment and achieved very inspiring therapeutic success.[8−11] With the inspiration of that trial, MMH

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Overview of magnetic-mediated hyperthermia (MMH)

231

was further applied in clinical trials for prostate cancer and esophageal cancer. Results from prostate cancer treatment demonstrated that MMH by thermoseeds was feasible and could attain excellent tolerances in patients.[12−18] With the metallic stent as the magnetic agent, the results showed hyperthermia mediated by stent can improve the effectiveness of combination therapy, suppress local tumor growth, and enhance the quality of life over a long period. [19]

Fig. 8.1

Illustration of MMH: (a) schematic plot of MMH, (b) illustration of the MMH treatment process.

Currently, the explosive growth of nanotechnology has burst into challenging innovations in medicine, which is in the process of revolutionizing MMH. Nanothermotherapies, which apply magnetic nanoparticles (MNPs) as heating agents, are a completely new approach for deep tissue hyperthermia application.[20−23] A rather homogenous temperature field can be achieved by the nano-scaled magnetic fluid. Moreover, it has been demonstrated that a 10-fold higher uptake by cancerous cells than by the normal cells can be achieved through proper surface modification of the nanoparticles. Therefore “intracellular hyperthermia,” which enables shifting the targeting of cancer treatment from tissue or organ level to the cellular level can be realized. [24] Taking all of the above together, the advantages of high selectivity

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and heating homogeneity can be expected in the use of either magnetic nanoparticle hyperthermia (MNH) or magnetic fluid hyperthermia (MFH). Currently, the world’s first MNP based therapy against brain tumors, with the commercial name r NanoTherm°therapy, is now under investigation in a phase-II study. Preliminary results show evidence of local effectiveness with only minor to moderate side effects. r MFH, or NanoTherm°therapy, is one of the first applications of nanotechnology [25] in medicine. Besides the clinical trial, in vitro and animal experiments regarding MFH are widely carried out worldwide. Table 8.1 summarizes the major events associated with the development of MMH. Table 8.1

Major events associated with the research development and clinical trials of MMH.

Time

Event

1957

The concept of MMH was initially described by Gilchrist et al. [7]

1959

MMH with magnetic particles was carried out on rabbits in which inguinal lymph modes were successfully targeted with heat. [165]

1976

The earliest report of AEH by applying a dog kidney model was published by Rand et al. [166]

1979

The concept of intracellular hyperthermia was first proposed by Gondon et al. [167]

1990

Kida reported the phase I clinical trial of MMH by thermoseeds for malignant gliomas in Japan. [8]

1992

Stea et al. completed the phase I clinical trials of MMH by thermoseed for malignant gliomas in US. [10]

1993

Jordan et al. published the first fundamental work describing the real potential of magnetic fluids for hyperthermia. [100]

2004

Deger et al. reported the phase I/II clinical trials of MMH by thermoseeds for prostate cancer in Germany. [16, 17]

2003∼2005 MagForce Nanotechnology AG carried out the phase I clinical trials of MNH in Germany. [135, 136, 137] 2005

MagForce Nanotechnology AG initiated the phase II clinical trials of MNH in Germany. [138]

2006

Akiyama et al. carried out clinical trials of MSH in Japan. [19]

2008

The concept of Nanothermotherapy was first proposed by Gazeau F et al. [168]

2009

The first report of post-mortem neuropathological findings of GBM patients undergone MNH was reported. [169]

2009

Ethical discussion on MFH for brain cancer was published. [25]

2009

Phase I clinical trials of MMH by thermoseeds was carried out in China.

2011

Efficacy and safety evaluation for MNH on recurrent GBM was reported. [138]

2013

MNH received approval from German Federal Institute for drug and medical devices (BfArm) to start the post-marketing study in [170] r GBM with NanoTherm°therapy.

8.2

Overview of magnetic-mediated hyperthermia (MMH)

8.2.2

233

Categories of MMH

Compared with other traditional hyperthermia approaches, such as ultrasound, microwave, radiofrequency, etc., the unique advantage of MMH lies that it can deliver tumor-specific hyperthermia to elevate local temperature for effectively killingoff the tumor cells, while stimulating the body’s active immunity as well. Since the inductive heating zone for cancer treatment is only within the tumor site, MMH can realize rather high temperature hyperthermia, not restricted to traditional hyperthermia temperatures around 43 ◦ C, therefore greatly enhancing the therapeutic efficacy for tumors. According to the different administration pathways of the magnetic agents, MMH can be divided into four categories: arterial embolization hyperthermia (AEH), direct injection hyperthermia (DIH), intracellular hyperthermia (IH), and interstitial implant hyperthermia (IIH). [26] According to the scale of the magnetic agents, they can be divided as millimeter-scaled agents (ferromagnetic alloy thermoseed, metallic stents) micrometer-scaled agents (usually for the purpose of AEH) and magnetic nanoparticles (MNPs, or magnetic fluid). Figure 8.2 illustrates the types of agents and Table 8.2 summarizes the main features and clinical trials of MMH with magnetic agents of different scales.

Fig. 8.2

Different types of magnetic agents: (a) alloy thermoseed for interstitial

hyperthermia, (b) metallic stents for interventional hyperthermia, (c) micro-size carbonyl iron powder for AEH, (d) MNPs for intracellular hyperthermia.

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Table 8.2

Magnetic agents of MMH cataloged by scale.

Scale of therapeutic agents Technical title

Application

Components

Clinical trial

Millimeter

themoseed or

IIH or inter-

ferromagneticloy

phase I/II

stent

ventional hyperthermia

Micrometer

AEH

magnetic particles coated with polymeric shell

Nanometer

ferrofluid or

IH and AEH

Fe3 O4 or γ-Fe2 O3

phase I/II

magnetic fluid

8.3 8.3.1 8.3.1.1

Research progress of MMH IIH by thermoseeds and magnetic stent hyperthermia IIH by thermoseeds

Though numerous studies carried out with various animal models have yielded convincing evidence in favor of hyperthermia as a primary or adjunctive cancer treatment in pre-clinical conditions, clinical acceptance of hyperthermia has been slow. Several factors may account for the seeming inconsistence; e.g. the present means of mapping and measuring the administered thermal dosage is considered inadequate and is priority one for further research. MMH by thermoseeds could be one solution to this problem, essentially by utilizing a low Curie point to achieve thermal selfregulation, thereby eliminating the costly and invasive thermometry now associated with hyperthermia. Lilly et al. developed self-regulating thermoseeds for IIH treatment of tumors. [27] The synthesized thermoseeds, composed of 70.4% nickel and 29.6% copper, possess a Curie point of 50 ◦ C. An inductive heating profile indicates that the thermoseeds’ rate of heat production drops sharply at temperatures above the Curie point when exposure to an AMF (90 kHz, 50 Oe, 1 Oe = 79.5775 A·m−1 ), demonstrating self-regulation of temperature during the treatment. Later, Rehman et al. carried out an in situ study for ferromagnetic self-regulating re-heatable thermoseeds implants for tissue ablation. [28] The palladium and cobalt temperature-selfregulating thermoseeds were designed to develop a maximum temperature of 70 ◦ C. The seeds were placed in renal, hepatic, uterine, and pancreatic areas of 16 pigs. Results revealed that higher temperature (> 50 ◦ C) can be achieved in all tissues with properly aligned thermoseeds. Histological evaluation showed necrosis extended 2 mm beyond the periphery of the thermoseeds. The possible reason, as explained by

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Research progress of MMH

235

the authors, may be the technical misalignment of the thermoseeds, as the authors attempted to treat more than one organ in each pig. Still, their results well support the proposition that properly aligned thermoseeds can create well-defined areas of necrosis with no skipped areas of viable tissue within the treated area. Moreover, as the seeds can be reactivated at any time, recurrent lesions within the same site can be treated repeatedly. For the research work on the ferromagnetic thermoseeds, special attention has been paid to the thermal treatment effect on the heating characteristics, as it has been proven that treatment process plays a critical role in the inductive heating properties of the thermoseeds. Work by Ferguson revealed that recrystallization (including annealing times and temperatures) is crucial for altering the seeds’ heating characteristics. [29] It is possible to increase the maximum heating temperature (Curie point) by increasing the annealing time and cooling time. Other factors, such as alloy composition and coating treatment also affect the heating property.

8.3.1.2

Magnetic stent hyperthermia

While the interstitial implant hyperthermia can be achieved by ferromagnetic alloy thermoseeds of rod shape in particular, any metallic medical device that can generate heat when subjected to AMF can be applied as a local “heat source” for cancer therapy, for instance, cylindrical metallic stents composed of alloy wire. Shoji et al. carried out some pioneering work on the feasibility of magnetic stent hyperthermia. [30] Furthermore, they carried out an in vivo investigation in the large intestine of Sprague–Dawley rats, as the bile duct of a rat is too narrow. The stent was then subjected to a magnetic field of 157 kHz. The results indicate that magnetic stent hyperthermia is feasible, as the temperature can be raised to 45 ◦ C and the treatment is tolerable. Our group also carried out a series research efforts on MSH for esophageal cancer treatment. We have demonstrated that the medical Ni–Ti stent possesses excellent inductive heating characteristics under AMF.[31−34] In vivo safety evaluation of MSH was carried out on pigs and our observation proved that a pig esophagus can actually endure higher temperature treatment without mucous hyperemia or tissue edema, indicating that MSH is safe. However, it is impossible or inconvenient to grow a tumor in a pig’s esophagus, although humans and pigs share similar physiological indexes in many aspects. Effectiveness evaluation was performed on the rabbit esophageal tumor model and our results show that MSH can effectively inhibit tumor growth for the rabbit esophageal tumor model.

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8.3.2

Magnetic-mediated Hyperthermia for Cancer Treatment: Research· · ·

AEH for liver cancer

AEH is an experimental modality of hyperthermia that consists of selective arterial embolization of tumors with ferromagnetic particles followed by exposure to AMF to generate heating of the embolized particles and also the surrounding tissues. [35] AEH has shown promise as a method for local cancer treatment with high temperatures, especially for liver tumors. It is well established that liver tumors derive virtually all their blood supply from the hepatic arterial system, while the normal hepatic parenchyma is supplied mostly by the portal venous system. [36] 8.3.2.1

AEH by microscaled magnetic particles

Moroz et al. from the University of Western Australia has conducted a series of in vivo investigations of AEH that consisted of arterially embolizing rabbit liver VX2 tumors and pig renal artery with ferromagnetic particles.[35−41] They found that AEH can target deep-seated, vascularized tissue in a large animal (pig) with therapeutic temperatures (> 42 ◦ C), and the treatment is safe and well tolerated. They further confirmed that there is a linear relationship between heating rate and iron concentration within the liver. An in vivo study performed on the tumor model demonstrated that ferromagnetic particles can result in excellent targeting of liver tumors. For the comparison of tumor response to AEH and DIH, their findings indicate that AEH is more effective than DIH at moderately elevated temperatures. The explanation, as they suggested, may be that more widespread particle distribution can be achieved by transcatheter arterial embolization (TAE), which results in more extensive and complete treatment of the tumor. The particles applied by Moroz consisted of MNPs (γ-Fe2 O3 , 100 nm) encapsulated with a polymer matrix to form 32-µm-diameter microparticles, as it had been argued by Jones that mediator particles for AEH should be micron-sized to ensure that they are trapped in the capillary bed surrounding the tumor rather than passing through to the venous circulation. [42] Under such consideration, Li et al. carried out a series of research work on fabricating MNPs encapsulated in silica microspheres for AEH. The sol–gel process was employed with tetramethoxysilane (TMOS) in water-in-oil emulsion. By applying the protocol, α-Fe-encapsulating silica microspheres were prepared. The obtained microspheres have a saturation magnetization (Ms ) up to 21 emu·g−1 and a coercive force (Hc ) of 133 Oe. The magnetic microspheres demonstrated an ideal inductive heating property in an AMF of 300 Oe and 100 kHz. [43, 44] Recently, we evaluated the feasibility of carbonyl iron powder (CIP) as a novel

8.3

Research progress of MMH

237

r ISP Pharmaceuticals) has mediator for AEH. [45, 46] CIP (trade name, Ferronyl°, been approved by FDA as a dietary iron supplement for oral administration, due to its low toxicity and excellent bioavailability. It is elemental iron with high iron content and highly resistant to oxidation. The typical average particle size is about several microns, which enables its further application as a mediator for AEH. A cytotoxicity study demonstrated that CIP has good biocompatibility. Heating curves, both in vitro and in vivo, reveal that CIP possesses ideal inductive heating characteristics under AMF. AEH mediated by CIP/Lipiodol can effectively inhibit tumor growth on the rabbit VX2 liver tumor modal. Our findings suggest that CIP is a very promising candidate as mediator of AEH for clinical application. 8.3.2.2

AEH by MNPs

Although micro-sized magnetic particles may have advantages over the MNPs in accumulating within the tumor site, as suggested by Jones, [42] with their excellent inductive heating property and size-controllable synthesis protocols, MNPs provide extra feasibility for mediating AEH. Shigeyuki et al. reported a feasibility study of AEH by nano-sized magnetic particles (ferucarbotran) in rabbits. [47] The ferucarbotran they employed as the AEH agent was purchased from Resovist, Shering, German. It is a dextran magnetite complex which is now widely used in daily clinical practice as an MRI contrast agent. It is especially noteworthy that the permissible dose of ferucarbotran in humans had already been established. Their findings demonstrated that in the heating rates of the kidney, ferucarbotran could lead to a significant temperature increase. In the AEH group, tumors could be selectively heated. Yu et al. [48] conducted combination therapy for arterial embolization hyperthermia (AEH) with arsenic trioxide (As2 O3 ) nanoparticles (ATONs) — a novel treatment for solid malignancies. This study was performed to evaluate the feasibility and therapeutic effect of AEH with As2 O3 nanoparticles in a rabbit liver cancer model. Their results demonstrate that ATON-based AEH is a safe and effective treatment that can be targeted at liver tumors using the dual effects of hyperthermia and chemotherapy. This therapy can delay tumor growth and notably inhibit tumor angiogenesis. 8.3.3

Magnetic hyperthermia by MNPs

The rapid advances in nanotechnology have improved the ability to design and manufacture the biomaterials for the purpose of specific biomedical applications. In

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recent years, considerable efforts have been made to develop MNPs. [49, 50] Possessing appropriate physicochemistry and tailored surface properties, MNPs have been extensively investigated for various applications such as drug delivery, hyperthermia magnetic resonance imaging (MRI), tissue engineering and repair, biosensing, biochemical separations, and bioanalysis.[51−54] 8.3.3.1

Synthesis and surface coating of MNPs

In MMH, SPIONs include γ-Fe2 O3 or Fe3 O4 particles with a core size of < 10 nm and an organic or inorganic coating. The SPIONs can be controllably synthesized by various chemical routes, including classic synthesis by precipitation, hightemperature reactions, reactions in steric environments, sol–gel reactions, decomposition of organometallic precursors, polyol methods, etc. Excellent reviews can be found that address the synthesis protocols for SPIONs. [49, 50] The simplest, cheapest, and most environmentally-friendly procedure by far is based on a co-precipitation + method, which involves the simultaneous precipitation of Fe+ 2 and Fe3 in a basic aqueous media. SPIONs synthesized in this way are hydrophilic and no further phase transition is needed. Since the as-synthesized SPIONs in colloidal form (known as ferrofluid or MF) have a large surface to volume ratio, they neasyly aggregate and form large clusters. Therefore, surface coating or modification is required to improve the properties of the MF, such as stability and dispersity, to deter aggregation in either a biological medium or a magnetic field. Numerous review papers have been published addressing the surface coating of MNPs and either inorganic or organic materials can act as a stabilizer for SPIONs.[55−65] Among inorganic materials, silica,[66−68] gold[69−71] or gadolinium [72, 73] are the commonly applied coating materials. These coatings not only provide stability to the nanoparticles in solution, but also help to bind various biological ligands to the SPION surface. Numerous review papers address the surface coating of MNPs, and so far, approaches have been developed to coat SPIONs with polymeric materials, including in situ coating, [63, 64] , post synthesis coatings,[76−81] deposition methods [82, 83] as well in situ polymerization process. [84] The polymers employed in the surface coating mainly include polyethylene glycol (PEG), dextran, aminosilane, chitosan, etc.[85−90] 8.3.3.2 Research progress in MNP-mediated hyperthermia Beyond SPION synthesis and surface modification, in the last 20 years, a full spectrum of MNH-related cancer treatment research has been systematically carried

8.3

Research progress of MMH

239

out — modeling MNP distribution and heat dissipation, or evaluating nanotoxicity, in vitro cytotoxicity, in vivo antitumoral effects, etc.[21,90−99] A research group led by Jordan carried out pioneering and comprehensive work on MNH.[100−104] They compared the endocytosis of dextran- or aminosilane-coated Fe3 O4 MNPs with human malignant and normal cells in vitro. Their observation confirmed that clonogenic cell survival was 3-fold lower after MNH versus water-bath hyperthermia. By comparing the results, they also concluded that dextran-coated MNPs were not suitable for MNH approaches. One of their in vivo studies, conducted on 120 male Fisher rats bearing RG-2 glioblastoma, revealed that MNH by means of aminosilane-coated MNPs prolonged patient survival 4.5-fold over control patients, while dextran-coated particles did not show any advantage. [104] They also observed that intratumoral deposition of the silane-coated particles was very stable, so repeatable treatment without repeated MNPs infusion is guaranteed. However, research reported by Wada et al., who also employed dextran-coated MNPs demonstrated that after MNPs were injected into one side of a golden hamster’s tongue, regulating the intensity under an AMF could maintain the local tissue temperature at 43 ◦ C to 45 ◦ C. [105] Subsequently, Wada injected MNPs into DMBA-induced tongue cancer in a golden hamster. Under an AMF of 500 kHz, tongue cancer could be effectively controlled. Beyond that, work with Fe3 O4 MNPs coated with polysaccharides, oleic acid, proteins, silica, carbon, gold, chitosan, and biocompatible polymers has been reported recently.[106−113] Our research group also conducted systematic investigation on SPION-mediated hyperthermia, and simulated in vivo tests were performed on tumor models of liver cancer, malignant glioma, breast cancer, pancreatic cancer, lung cancer, malignant melanoma, and esophageal cancer.[113−121] Besides Fe3 O4 magnetite nanoparticles, maghemite nanoparticles (γ-Fe2 O3 ), another type of SPION, also have been applied in MNH as an effective mediator. [122, 123] All the observations suggest that SPION-mediated hyperthermia is an effective, safe and minimally invasive treatment. Another approach that has drawn much attention in recent years is the conjugation of monoclonal antibodies or cell-specific ligands with MNPs for the purpose of targeted hyperthermia. It has been demonstrated that nanoparticles coated with dextran modulated by anti-HER-2/neu monoclonal antibodies have a specific cellconjugating capacity and excellent temperature-raising effect on co-cultured breast cancer cells.[124−127] By conjugating the epidermal growth factor (EGF) with MNPs, the MNPs were observed to effectively target over-expressed epidermal growth factor receptor (EGFR) cells, resulting in a significant (up to 99.9%) reduction in both cell viability and clonogenic cell survival in a thermal heat dose-dependent

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manner. [128, 129] Monoclonal-antibodies or ligands, such as chimeric L6 (ChL6), folic acid, etc., were also selected for active targeting studies to modify magnetic nanoparticles[130−132] In all these instances, the capability of magnetic nanoparticles to target and conjugate to specific tissues and tumor cells was confirmed. In addition to SPIONs, much attention has been given to the synthesis of MNPs with novel structures that have a high specific adsorption rate (SAR). SAR, also called specific power loss (SLP), is widely applied to quantify the heating capacity of MNPs and can be calculated based on Eq. (1) SAR = C(∆T /∆t)(1/m),

(1)

where C represents the sample-specific heat capacity (in unit J/g−1 ·K−1 , both the nanoparticle material and the dispersion medium are considered), (∆T /∆t) is the increase in temperature with time and m is the amount of magnetic material used in the experiment. In any case, it is desirable to realize the temperature enhancement needed for any given application with as few MNPs as possible. This means that the heat power generated per particle unit mass should be as high as possible. Recently, taking advantage of the exchange coupling between a magnetically hard core and magnetically soft shell to tune the magnetic properties of the MNPs, Lee et al. demonstrated that the core-shell structured MNPs have SAR values that are an order of magnitude larger than conventional SPIONs. [132] High SAR values were also reported for cube-shaped water-soluble iron-oxide nanocubes (IONCs) prepared by Guardia in a size range between 13 nm and 40 nm. [133] Among the different sizes tested, IONCs with an average diameter of 19 ± 3 nm had significant SAR values in clinical conditions and reached SAR values up to 2452 W/gFe at 520 kHz and 29 kA·m−1 , which is one of the highest values so far reported for IONCs. In vitro trials carried out on KB cancer cells treated with IONCs of 19 nm have shown efficient hyperthermia performance, with cell mortality of about 50% recorded when an equilibrium temperature of 43 ◦ C was reached after 1 h of treatment However, though compared with the novel magnetic nanostructured devices with high SAR values, SPIONs exhibit only a medium heating efficiency with minimal control of in vivo temperature evolution during the treatment, surprisingly, both experimental and commercially available MNPs for hyperthermia normally consist of SPION cores. This is because although SAR value plays a paramount role in choosing the mediator for hyperthermia, other considerations should still be met for biomedical applications, such as biocompatibility, non-toxicity, ability to escape from the mononuclear phagocyte system, as well as low protein adsorption, etc. SPIONs can simultaneously satisfy many biomedical needs, and for this reason they

8.4

Clinical applications of MMH

241

are widely applied in MRI, drug delivery, magnetic hyperthermia, and tissue repair without any detectable cytotoxicity at the applied dosage.

8.4 8.4.1

Clinical applications of MMH Clinical trials of MMH by thermoseeds

The world’s first clinical trial of MMH by thermoseeds was carried out in Japan. Kida et al. reported the first clinical experience of interstitial hyperthermia of malignant brain tumors by ferromagnetic thermoseeds in 1990, with a Curie point of 68 ◦ C. [8, 9] Though the applicability of the results is still tentative, the overall response rate was an encouraging 34.8%. Degeneration of tumor cells, hemorrhage, vascular stasis, and thrombosis were found adjacent to the necrosis. Two years after that, Stea et al. completed a phase I study of interstitial thermoradiotherapy for high-grade supratentorial gliomas. [10, 11] The main purpose of this trial was to test the feasibility and toxicity of MMH by thermoseeds. Among the 28 patients, 22 were treated at the time of their initial diagnosis with a course of external beam radiotherapy followed by an interstitial implant with Ir-192. Six patients with recurrent tumors received only the interstitial implant. A 60-minute hyperthermia treatment was given just before and right after completion of brachytherapy via the same catheter. Hyperthermia was generally well tolerated. The preliminary survival analysis showed that 16 of the 28 patients have already died, with a median survival of 20.6 months from diagnosis. The authors concluded that interstitial hyperthermia of brain tumors with ferromagnetic implants is feasible and carries significant but acceptable morbidity, given the extremely poor prognosis of this patient population. Subsequently, they used hyperthermia therapy with radiotherapy to compare their efficacy together with that of radiotherapy alone. Results showed that for around 50% of 25 patients with primary tumors, therapy was efficacious, and that MMH was one of the factors closely correlated with the patient survival period (P < 0.05). With the inspiring results from the clinical trials for malignant brain cancer, clinical trials of MMH by thermoseeds was also carried out for the targeted treatment of prostate cancer. In 2000, Tucker et al. carried out ablation of prostate cancer by MMH with thermoseeds.[12−15] They applied thermoseeds with Curie points of 55 ◦ C, 60 ◦ C, and 70 ◦ C, respectively. They observed that arrays of 70 ◦ C seeds placed within 1 cm of each other caused consistent necrosis between the seeds. As the temperature at the edge of the array dropped off quickly, they suggested that thermoseeds can be placed within 2 mm of the capsule even posteriorly near the rectum, indicating a rather safe treatment. Based on their findings, they concluded

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that arrays of high-temperature thermoseeds (70 ◦ C) can be employed for tissue ablation, while lower-temperature arrays could be used to produce hyperthermia in order to achieve synergism with adjuvant radiation therapy. As the treatment process is easy and convenient to operate, they further proposed that the technique of MMH is applicable in an outpatient setting. The level of prostate-specific antibodies markedly increased in the subjects. Eight weeks after the treatment, antibody levels were significantly lowered as compared with pre-treatment levels. Recently, based on a variety of experimental and phase I clinical data, which together have proven the synergistic effects of MMH to radiotherapy, Deger et al., from Humboldt University in Germany, reported on a phase II trial to determine the feasibility, acute toxicity, and efficacy of thermoradiotherapy for prostate cancer. The clinical trial was conducted between 1997 and 2000 on 57 patients with localized prostate cancer. During the treatment, intraprostatic temperatures were between 42 ◦ C and 46 ◦ C with no major side effects associated. [16, 17] They carried out median follow-ups up to 36 months. The phase II clinical trial strongly suggested that MMH by means of thermoseed is feasible, well tolerated and leads to a steep decrease of PSA values. Combining MMH with conformal radiotherapy may be an exciting innovative treatment option for prostate cancer. From 2010, our research group has been pioneering the clinical trial of thermoseedbased MMH. We obtained approval from SFDA, and patients with soft tissue sarcoma received such treatment. Gold-coated nickel–copper alloy thermoseeds (Fig. 8.2) with Curie point of 80 ◦ C were applied. So far, the phase I clinical trials have been successfully finished and the phase II trial is ongoing. Results from the clinical trials strongly demonstrated that MMH by thermoseeds is effective, safe, minimally invasive, and quite tolerable. 8.4.2

Clinical trials of MSH

A clinical trial of MSH was carried out in Japan. Akiyama studied the feasibility of employing a metal esophageal stent for magnetic induction hyperthermia. [19] Eighteen T3/T4 esophageal cancer patients with dysphagia were selected for this pilot clinical trial. Stages II, III, and IV involved 1, 10, and, 7 cases respectively. Thirteen patients received MMH with adjunctive chemotherapy while 5 received MMH with adjunctive radiochemotherapy. Throughout the entire course of therapy, patients displayed excellent tolerance. During hyperthermia, patients felt only mild warmth at the physical point of therapy. No complications associated with this hyperthermia were observed. In comparison with traditional canal hyperthermia, the reticular stent increased the heat exposure area of tumors. MMH raised the temper-

8.4

Clinical applications of MMH

243

ature during tumor therapy so as to boost the curative effect. Table 8.3 summarizes the clinical trials of MMH by thermoseeds. Table 8.3

Clinical trials of MMH by thermoseeds.

Institution

Cancer type

Number of patients enrolled Ferromagnetic alloy

Nagoya University,

magligant gliomas

24

Fe–Pt

20

Co–Pd

prostate

57

Co–Pd

prostate

14

Co–Pd

School of Medicine; Komaki City Hospital, Japan [8, 9] University Iowa Hospi- prostate tal, US[12−15] Hunboldt University, Germany [16, 17] University of California, Comprehensive Cancer Center, US [18] Department of Ra-

supratenorial gliomas 28

diation Oncology, University of Arizona, US [10, 11] Nogaya University,

esophageal cancer

18

Fe–Pt metallic stent

School of Medicine, Japan [19]

8.4.3

Clinical Trials of MNH

The persistent efforts and inspiring results of MNH led to the world’s first phase I trial on 14 patients with glioblastoma multiforme (GBM) at the Charit´e–University Medicine Berlin from March 2003 to January 2005. [136, 137] Note that the quick start of the clinical studies was due to the approval of the MNPs as part of a medical device but not as a drug, thus shortening the ponderous approval process for drugs. [25] A 3D image-guided intratumoral injection of aminosilane-coated iron oxide nanoparticles was conducted under general anesthesia and distribution of MNPs throughout recurrent or nonresected primary tumors was confirmed. During the hyperthermia process, neither immobilization nor anesthesia of the patient was required and the whole treatment took only about 2 hours. The median maximum intratumoral temperature was kept around 44.6 ◦ C. The patients received six treatments (two per week). MMH was tolerated well by all patients with minor or no side effects, such as headache, nausea, vomiting, allergic reactions, or neurological deficits. No bleeding,

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swelling of the brain, or rise in intracranial pressure occurred during or after the treatment. Signs of local tumor control were observed. A median survival of 14.5 months seems promising with the trials. This phase I trial has shown the feasibility, tolerability, and efficacy of MNH. Except for GBM, the phase I clinical trials of MNH were carried out on prostate carcinomas and other entities. With the success of the phase I study, a phase II study was subsequently started in January 2005. [138] It is still in progress to evaluate the efficacy of the treatment on 65 patients suffering from recurrences of glioblastoma multiforme. Another clinical study conducted with 22 patients with nonresectable and heavily pretreated recurrences of different other tumor entities having undergone radiation therapy and/or chemotherapy. All the trials show that MNH can be applied without complications. 8.4.4

Clinical trials of AEH

Compared with clinical trials of MMH with thermoseeds or MNH, systemic clinical trials have not been initiated for AEH. Jordan et al. reported their clinical experience to prove the feasibility of selective arterial infusion of SPIONs in patients with hepatocellular carcinoma (HCC). [139] Thirteen patients with HCC who underwent modified transarterial chemoembolization (TACE) were enrolled in this study. Six received concurrent infusion of ferucarbotran (Resovist, Schering, Berlin, Germany) in tumor-feeding arteries, and another six received an infusion of SPIONs produced by MagForce Nanotechnologies, Berlin, Germany. The iron content of both dispersions was 3.92 mg. It confirmed that selective arterial infusion of both SPIONs results in a significant decrease of intratumoral signal intensity on T1weighted sequences (P < 0.0001), which was greater after MagForce infusion than after Resovist (P = 0.002). Only minimal amounts of dispersed particles were found in adjacent normal liver parenchyma. No change in intratumoral signal intensity was noted when ferromagnetic particles were omitted. Results from this clinical experience prove that TACE with a selective arterial infusion of SPIONs can be used for precise tumor targeting in patients with HCC, for which MagForce appears to be superior to Resovist.

8.5

Multifunctional magnetic devices for cancer multimodality treatment

While much research has been carried out with MMH and has also led to clinical success in clinical oncology, hyperthermia alone is probably most useful for palliative treatment. Since heat has been demonstrated experimentally to sensitize cells to

8.5

Multifunctional magnetic devices for cancer multimodality treatment

245

ionizing radiation and several chemotherapeutic agents, hyperthermia combined with either radiation or systemic chemotherapy has rapidly become a clinical reality as a form of treatment for malignant disease. 8.5.1 8.5.1.1

Multifunctional magnetic device for thermoradiotherapy Heat-induced radiosensitization

The enhancement of cellular radiosensitivity by additional heat treatment is a well-documented phenomenon. [140] In general, the maximum cytotoxic effect can be observed when radiation is applied simultaneously with heat. For several decades, evaluation of the effects of heat on radiation response has been one of the most active research areas, with the purpose of an improved understanding of the mechanisms by which heat potentiates radiation-induced cell killing. As it is conclusively recognized that for cell killing by ionizing radiation, radiation to the cell nucleus will mainly determine the extent of the treatment effect, many investigators have studied how heat will interact with radiation damage of the chromosomal level, and strong evidence has proved that heat can increase the primary DNA damage or inhibit the repair of such damage.[141−143] It has been demonstrated that heat treatment after irradiation can remarkably increase the number of chromosome aberrations or of micronuclei. These observations demonstrate that the mechanism of radiosensitization by heat must interfere with processes at the chromosomal level and enhance irreparable chromosome damage in comparison to irradiation alone. However, DNA may not be the only or the primary target of IR, and meanwhile, heat can affect all aspects of cellular metabolism. Much research output has confirmed that the mechanisms of radiosensitization are complex and not completely understood. For instance, Pawlik et al. demonstrated that hyperthermia can induce cytoskeletal alterations and mitotic catastrophe in p53-deficient H1299 lung cancer cells. [144] 8.5.1.2

Radiothermotherapy mediated by thermobrachytherapy seed

Recently, Gautam et al. developed a novel thermobrachytherapy seed with a ferromagnetic core for treatment of solid tumors. [145] The proposed seed is based on the BEST Medical, Inc., Seed Model 2301-I, [124] wherein a tungsten marker core and an air gap are replaced with ferromagnetic material. The ferromagnetic core could produce heat when subjected to AMF and effectively shut off after reaching the Curie temperature of the ferromagnetic material, thus realizing self-regulation of temperature. For the thermal characteristics, the authors studied a model con-

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sisting of 16 seeds placed in the central region of a cylindrical water phantom. The thermal modeling results show that the temperature of the thermoseed surface rises rapidly and stays constant around the Curie point of the ferromagnetic material. The amount of heat produced by the ferromagnetic core is sufficient to raise the temperature of the surrounding phantom to the therapeutic range. The phantom volume reaching the therapeutic temperature range increases with any increase in frequency or magnetic field strength. Although no in vivo investigation was carried out, the proposed combination seed model has potential for implementation of concurrent brachytherapy and hyperthermia by a single multifunctional device. 8.5.2

Multifunctional magnetic devices for thermochemotherapy

8.5.2.1

Thermochemotherapy: Thermal enhancement of drug cytotoxicity

As hyperthermia can effectively enhance the cytotoxicity of various antineoplastic agents (thermal chemosensitization), in several phase-III clinical trials, an improvement of both local control and survival rates have been demonstrated by adding local/regional hyperthermia to chemotherapy for patients with locally advanced or recurrent superficial ad pelvic tumors.[146−148] Additional application of selected chemotherapeutic drugs has been shown to enhance the inhibition of clonogenic cell growth at elevated temperatures both in vitro and in animal experiments. Thermal enhancement of drug cytotoxicity is accompanied by cellular death and necrosis without increasing its oncogenic potential. [149] It also has been recognized that mechanisms for the thermal enhancement include increased rate constants of alkylation, increased drug uptake, inhibition of repair of drug-induced lethal or sub-lethal damage, etc. Generally, as supported by a wealth of biomedical and molecular biological data, the results of clinical trials strengthen the current evidence that hyperthermia combined with chemotherapy is an effective and practical modality that should be integrated in the present cancer treatment armamentarium. [150] Recognizing that MNPs can act simultaneously as both mediators for MNH and drug carriers, it is highly feasible to design and fabricate drug-incorporating magnetic nanocomposite devices for multimodal cancer treatment of thermochemotherapy, to realize the possible thermal enhancement to drug cytotoxicity. We have conducted a series of research work in magnetic nano-thermochemotherapy. Due to the space limit, we will give only a brief introduction to the research ideas on magnetic thermochemotherapy mediated by drug-loaded magnetic nanocomposite devices. Detailed information in this topic can be found in our previous publications. [22, 114, 115, 151, 152]

8.5

Multifunctional magnetic devices for cancer multimodality treatment

8.5.2.2

247

Magnetic nano-drugs

In relation to the multimodality treatment by thermochemotherapy, the intention for the design of nanocomposite devices is to use MNPs as one single tool for the combination of hyperthermia and chemotherapy to reach an enhanced therapeutic effect. So far, a series of protocols has been developed for engineering the two moieties within a single nano-platform. “Magnetic nano-drug by surface modification” is an approach to conjugate or attach drug molecules to the surface of MNPs. A number of physical or chemical approaches have been developed for the conjugation or attachment of functional molecules on MNP surfaces, which can be categorized into covalent linkages and physical interactions, as illustrated in Fig. 8.3.

Fig. 8.3

Schematic diagram of nano-drugs. a: magnetic nano-drug by covalent linkage; b: magnetic nano-drug by electrostatic interaction.

The physical interactions mainly include electrostatic, hydrophilic/hydrophobic, and affinity interactions. For some charged drug molecules, electrostatic interactions are particularly useful in the assembly of magnetic nano-drugs, for instance, cisplatin-functionalized MNPs. [153] Cisplatin is a platinum-based chemotherapy drug used to treat various types of cancers. To fabricate a cisplatin magnetic nano-drug, the SPION cores were coated by a soluble starch derivative so that particles were negatively charged with zeta potential of −41 mV, allowing electrostatic binding of positively charged aquated cisplatin molecules. In contrast with the physical interactions, a much broader spectrum of approaches has been developed based on the covalent linkage or chemical coupling strategy. Veiseh et al. summarized that covalent linkages mainly comprise three approaches: direct nanoparticle conjugation, click chemistry, and covalent linker chemistry. [79] The unique advantages and drawbacks of each of the three approaches

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have been addressed in detail. Here, we report the fabrication and characterization of an epirubicin-immobilized magnetic nano-drug that may potentially be applied for thermochemotherapy. Epirubicin is an anthracycline drug used for chemotherapy, which acts by intercalating DNA strands. In order to immobilize the epirubicin molecules onto the surface of MNPs, a conjugation strategy by linker chemistry was adopted. Briefly, polyarylic acid (PAA) was applied as the coating material to introduce carboxyl groups onto the SPION surfaces. The amino group of epirubicin can be conjugated with SPIONs via amide bonds by applying the carbodiimides (EDC) and N-hydroxysuccinimide (NHS or sulfo-NHS) as the chemical linkers. Further characterizations showed that the as-synthesized magnetic nano-drug possessing excellent inductive heat property upon exposed under AMF and magnetic heating can facilitate the drug release from the MNPs. Assessment of the viability of gastric cancer SGC-7901 cells after various treatments showed that mono-treatment treatment by hyperthermia or epirubicin released from magnetic nano-carriers could retard proliferation of the cells. When the bi-modal treatment was applied on the cells, a significantly greater decrease in cell viability can be observed (p < 0.05), indicating an intensity effect of nanothermotherapy on epirubicin treatment. 8.5.2.3

Solar-planet structured magnetic banocomposite devices

Although surface modification chemistry provides a versatile tool for conjugating drug molecules onto the MNPs surface, there are still some restrictions for this strategy. It was suggested by Veiseh et al. that the chemistry to be employed should be chosen on the basis of the chemical properties and functional groups found on the SPION coating and ligand to be linked. [79] For most drug molecules, there are no proper functional groups nor is it convenient to introduce such a functional group onto the MNP surfaces for further conjugation. Besides, SPIONs applied in MNH are normally hydrophilic, whilst numerous drugs are not soluble in water, therefore it is very challenging to find an appropriate medium to carry out the modification chemistry. We thus designed the so-called solar-planet structured devices for the combined thermochemotherapy. In the present study, docetaxel is used as a model small molecule anticancer drug, which is a poorly water-soluble, semisynthetic taxane analog commonly used in the treatment of breast cancer, ovarian cancer, small and non-small cell lung cancer, and prostate cancer. For the purpose of fabricating the solar-planet structured devices, docetaxel-loaded polymeric nanoparticles (DNPs) composed of carboxylic-terminated poly(D,L-lactic-co-glycolic acid) (PLGA) with vitamin E TPGS as emulsifier for sustained drug release were

8.5

Multifunctional magnetic devices for cancer multimodality treatment

249

prepared by a modified solvent extraction/evaporation technique. Intensive investigations have been carried out for the DNPs and the detailed fabrication protocols of DNPs can be found in our published work. [154] The size of the DNPs fabricated by solvent evaporation methods is around 200 nm. Furthermore, the MNPs modified with amino groups could be covalently attached to the surface of carboxylic terminated DNPs to form the so-called solar (DNPs)-planet (MNPs) structured MNC by EDC/NHS crosslinking protocol as described previously. The fabrication protocol for the solar-planet structured magnetic devices is illustrated in Fig. 8.4.

Fig. 8.4

Illustration of solar-planet structured magnetic nanocomposite device. A

multifunctional nanoparticle modified with targeting ligands extended from surface with polymeric extenders, imaging reporters (optical, radio, magnetic), and potential therapeutic payloads (gene, radio, chemo).

8.5.2.4

Drug-loaded magnetic nanocomposite implant

Unlike the above-mentioned two formulations, which were in colloid or suspension form and were administered by direct intra-tumoral injection, the drug-loaded magnetic nanocomposite implant was designed for post-surgical cancer treatment, mainly for preventing local recurrence of malignant gliomas. Currently, surgical debulking of an accessible tumor in a patient’s brain is the conventional clinical treatment for glioma. However, the amount of tumor removed is often limited by proximity to critical regions for brain function, thus resulting in risk of tumor re-growth from residual tumor. It is widely acknowledged that the use of surgically implanted local release systems made of biodegradable polymers for drug delivery over extended r periods of time has good potential in glioma treatment. Gliadel°(polifeprosan 20 with carmustine implant) has been approved by the US FDA for use in post-surgical local chemotherapy against recurrent malignant glioma. [155] By co-incorporating the drug and MNPs within the polymeric matrix, the drug-loaded nanocomposite implant can realize both local drug delivery and magnetic hyperthermia simultaneously.

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Figure 8.5 is a schematic diagram of the composite implant. Such an implant can be easily prepared by a solvent evaporation method, and a typical implant is flexible, smooth, and homogeneous (as shown in Fig. 8.6). An in vivo study was performed on tumor-bearing nude mice. Xenografts of human glioma cell lines were established by subcutaneous inoculation of U251 MG cells into the hind legs of BALB/c nude mice. For animals in both placebo and experimental groups, a small incision by aseptic surgery was performed on the skin and the tumor was reached after which 3/4 of the tumor volume would be carefully excised. The implants would then be placed well onto the residual tumor bed and subsequently the wound would be closed using subcutaneous suturing. Mice were then exposed under the AMF for 30-min treatment and the temperature of the tumor site was about 46 ◦ C. The body temperature was not affected, the mice did not have symptoms of dehydration and all of them survived the whole experiment of two weeks. Tumors in the thermochemotherapy group shrunk most significantly, as compared with those of the control groups and hyperthermia treatment only.

Fig. 8.5

Illustration of drug-loaded magnetic nanocomposite implant.

Except for the above-mentioned MNC devices, drug encapsulated magnetic cationic liposome (MCL) thermoresponsive core–shell MNPs, drug-loaded magnetic polymeric nanoparticles, and drug-loaded magnetic polymersomes have been extensively investigated for the bi-modal therapy of combined hyperthermia with chemotherapy[156−160] (Shinkai 2004; Purushotham 2010). The nanocomposite devices exhibit advantageous features for facilitated drug delivery from the nanocarriers, and the magnetic-mediated heating potential is adequate for hyperthermic treatments. We thus conclude that even though further detailed investigations are still necessary, tentative use in local tumor therapies aiming at a specific chemotherapeutic release in combination with magnetic heating is promising and feasible in the long term.

8.6

Conclusions and remarks

Fig. 8.6

251

Docetaxel loaded magnetic nanocomposite implant prepared by solvent evaporation method.

8.6

Conclusions and remarks

Rapid progress has been witnessed in the research and development of MMH, and the success in clinical trials suggests MMH treatment is a well-tolerated and safe cancer therapy. It is very significant to note that fewer than 50 years passed between the 1957 proposal of the MMH concept and the 1996 completion of phase I clinical trials. The remarkable progress also leaves great space and opportunity for further improvement and optimization of this therapeutic approach. The overwhelming issue is about the SAR value of the MNPs. It was argued by Hergt, who has expanded the work of Rabin, that in order to heat a 3-mm cluster of cells, the SAR of the MNPs must be unrealistically high, certainly several orders of magnitude greater

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than is currently reported. [161, 162] Consequently, the limited SAR values must require extremely high concentrations of MNPs for a sufficient thermal enhancement. Indeed, a rather high concentration of 100 mg/mL∼120 mg/mL MNPs was applied during the clinical treatment of brain tumor. The high concentration and the difficulty of forming a homogenous MNP distribution with respect to the tumor site by direct injection leads to destruction of normal tissues surrounding the tumor. To solve the problem, much attention has been given to the synthesis of MNPs with super-high SAR values. However, as mentioned earlier in the chapter, SAR value is not the only criterion for evaluating the suitability of MMH agents. Other issues, especially biocompatibility and non-toxicity, must be fully considered. Aside from improving the SAR values of MNPs, the inductive heat can also be enhanced by increasing the strength and frequency of the AMF, but only with limited scope. The machine developed by the Jordan group for clinical application operates at 100 kHz and field intensity up to 18 kA·m−1 . [135] It was also observed that patients under MMH treatment for prostate cancer were able to tolerate up to 5 kA·m−1 for an hour or so but any increase in field intensity would result in some discomfort. Moreover, it was reported by Ito et al. that higher frequencies such as those over 400 kHz would cause non-specific heating due to eddy current. [163] In parallel with the rapid progress in fabrication of high performance magnetic agents and clinical trials, further basic studies regarding MMH should also be carried out, such as heat dissipation theory in MNH, effects of AMF exposure during hyperthermia, endocytosis of MNPs by carcinoma cells, as well as the uniqueness of the cellular or molecular basis of MMH. In a very recent research work, it was reported that cell membrane permeability induced by MNH is significantly greater than that induced by hot water hyperthermia under same temperature conditions. [164] It is therefore an exciting challenge for future endeavors to explore MMH for its potential in cancer treatment as well as in-depth basic understanding.

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[111] Mohammad F, Balaji G, Weber A, Uppa R M and Kumar C S S R 2010 J. Phys. Chem. C 114 19194 [112] Sharma M, Mantri S and Bahadur D 2010 J. Magn. Magn. Mater. 324 3975 [113] Zhao L Y, Yang B, Dai X C, Wang X W, Gao F P, Zhang X D and Tang J T 2010 J. Nanosci. Nanotech. 10 7117 [114] Zhao L Y, Yang B, Wang Y Y, Yao Z, Wang X W, Feng S S and Tang J T 2012 J. Nanosci. Nanotech. 12 1024 [115] Zhao L Y, Huo M J, Liu J Y, Yao Z, Li D Y, Zhao Z W and Tang J T 2013 J. Nanosci. Nanotech. 13 741 [116] Jin H K, Xie X X, Hu B Q, Gao F P, Zhou J M, Zhang Y Y, Du L H, Wang X W, Zhao L Y, Zhang X D and Tang J T 2013 Oncol. Rep. 29 725 [117] Gao F P, Yan Z X, Zhou J, Cai Y Y and Tang J T 2012 J. Nanoparticle Res. 14 1160 [118] Wang L F, Dong J, Ouyang W W, Wang X W and Tang J T 2012 Oncol. Rep. 27 719 [119] Hu R L, Zhang X D, Liu X, Xu B, Yang H S, Xia Q S, Li L Y, Chen C L and Tang J T 2012 Thoracic Can. 3 34 [120] Gao F P, Cai Y Y, Zhou J, Xie X X, Ouyang W W, Zhang Y H, Wang X F, Zhang X D, Wang X W, Zhao L Y and Tang J T 2010 Nano Res. 3 23 [121] Du L H, Zhou J M, Wang X W, Sheng L, Wang G H, Xie X X, Xu G Q, Zhao L Y, Liao Y P and Tang J T 2009 Prog. Nat. Sci: Mater. Int. 19 1705 [122] Hergt R, Hiergeist R, Hilger I, Kaiser W A, Lapatnikov Y, Margel S and Richeter U 2004 J. Magn. Magn. Mater. 270 345 [123] Michael L, Claire W, Jean-Michel S, Olivier H, Jean-Claude B and Florene G 2008 J. Phys: Condens. Matter. 20 204133 [124] Hilger I, Dietmar E, Linß W, Streck S and Kaise W A 2006 J. Phys: Condens. Matter 18 2951 [125] Ito A, Kuga Y, Honda H, Kikkawa H, Horiuchi A, Watanabe Y and Kobayashi T 2004 Cancer Lett. 212 167 [126] Zhang J P, Dewilde A H, Chinn P, Foreman A, Barry S, Kanne D and Braunhut S J 2011 Int. J. Hyperthermia 27 682 [127] Kikumori T, Kobayashi T, Sawaki M and Imai T 2009 Breast Cancer Res. Treatment 113 435 [128] Creixell M, Bohorquez A C, Torres-Lugo M and Rinaldi C 2011 ACS Nano 5 7124

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Chapter 9 Magnetic Nanoparticle-based Cancer Therapy∗ Jing Yua,d)† , Dongyan Huangb)† , Muhammad Zubair Yousaf a) , Yanglong Houa)‡ , and Song Gaoc) a)

Department of Materials Science and Engineering, College of Engineer-

ing, Peking University, Beijing 100871, China b)

Department of Otorhinolaryngology Head & Neck Surgery, Clinical Di-

vision of Surgery, Chinese PLA (People’s Liberation Army) General Hospital, Beijing 100853, China c)

College of Chemistry and Molecular Engineering, Peking University, Bei-

jing 100871, China d)

College of Materials Science and Engineering Zhejiang University of

Technology, Hangzhou, 310014 China † These authors contributed equally to this work. ‡ Corresponding author. E-mail: mailto:[email protected] Nanoparticles (NPs) with easily modified surfaces have been playing an important role in biomedicine. As cancer is one of the major causes of death, tremendous efforts have been devoted to advance the methods of cancer diagnosis and therapy. Recently, magnetic nanoparticles (MNPs) that are respon∗ Project supported by the National Natural Science Foundation of China (Grant Nos. 51125001, 51172005, 51602285 and 90922033), the Research Fellowship for International Young Scientists of the National Natural Science Foundation of China (Grant No. 51250110078), the Doctoral Program of the Education Ministry of China (Grant No. 20120001110078), Young Elite Scuentist Sponnsorship Program by CAST(No. 2017QNRC001) and PKU COE-Health Science Center Seed Fund.

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sive to a magnetic field have shown great promise in cancer therapy. Compared with traditional cancer therapy, magnetic field triggered therapeutic approaches can treat cancer in an unconventional but more effective and safer way. In this chapter, we will discuss the recent progress in cancer therapies based on MNPs, mainly including magnetic hyperthermia, magnetic specific targeting, magnetically controlled drug delivery, magnetofection, and magnetic switches for controlling cell fate. Some recently developed strategies such as magnetic resonance imaging (MRI) monitoring cancer therapy and magnetic tissue engineering are also addressed.

9.1

Introduction

Nanoparticles (NPs), with sizes of 1 nm–100 nm, possess unique physical and chemical properties and play an important role in different research areas nowadays ranging from electronics [1−3] to energy[4−6] and biomedicine. [7, 8] Various features of NPs like easy surface modification, attachment of bio-compatible polymers, and molecules, such as antibodies, ligands, and proteins onto their surface, make them an attractive vehicle for biomedical applications. [9, 10] Among the numerous kinds of NPs, magnetic nanoparticles (MNPs) shown great promise due to their unique properties in a magnetic field with no depth-penetration limit in the human body. [11] Various kinds of MNPs have been used, including iron oxide (e.g. Fe3 O4 ,[12−14] and M Fe2 O4 (M =Mn, Co, Zn) [15, 16] ), alloys (e.g. FePt,[17−19] PtCo, [20] and FeCo [21, 22] ), and multifunctional MNPs with core/shell, [23, 24] dumbbell [25, 26] or multicomponent hybrid structures. [27, 28] As is well known, cancer has become one of the major causes of death due to the difficulty in accurate diagnosis and treatment. For many years now, enormous efforts have been devoted to improve the sensitivity and efficacy of cancer therapies. MNPs, with their ability to respond to a magnetic field, can target a specific site, and are potentially applied in targeted drug delivery, magnetofection, and tissue engineering. Moreover, when in a magnetic field, MNPs usually can absorb magnetic energy, raising their temperature, which may eventually induce hyperthermia, immunotherapy or controlled drug/gene release. In addition, MNPs have proved to be serviceable as contrast agents for magnetic resonance imaging (MRI) that can also be utilized as a tracing technique for drug and gene delivery. Recent progress in biomedicine has demonstrated that MNPs are becoming very important in cancer diagnosis and therapy. In this chapter, we mainly focus on the MNP-based strategies for cancer ther-

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apies, like magnetic hyperthermia, magnetic specific targeting, magnetically controlled drug delivery, magnetofection, magnetic switches for controlling cell fate, and some recently developed methods (Fig. 9.1).

Fig. 9.1

9.2 9.2.1

Schematic illustration of MNP-based cancer therapies.

MNPs-based cancer therapy Magnetic hyperthermia

Hyperthermia, treatments based on the generation of heat at a tumor site, is an attractive method for tumor therapy. According to the range of increased temperature, hyperthermia treatments can be classified into three types, i.e. thermo ablation (tumor subjected to temperatures > 46 ◦ C), moderate hyperthermia (41 ◦ C < T < 46 ◦ C) and diathermia (T < 41 ◦ C). [29] The traditional hyperthermia is moderate hyperthermia, which results in activation or initiation of many intra- or extracellular degradation mechanisms that kill cancerous tissues. More interestingly, by using such methods, cancer cells can be destroyed at these temperatures, while the normal cells survive. The early applications of hyperthermia usually heated the whole body, which benefited from the different tolerance of temperature between cancerous and normal tissue. However, heating for a long time and on a large scale potentially harms a human body. Later on, hyperthermia was carried out by using external devices that transfer other energy, such as ultrasound, microwave or infrared radiation, into thermal energy. However, using these external devices still poses a serious threat to the normal tissues. With the probability of converting magnetic energy into thermal energy, the heating phenomenon of magnetic materials was first investigated by

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Gilchrist et al. in 1957. [30] Subsequently, Gordon et al. [31] applied this concept to intracellular hyperthermia by using dextran magnetite in 1979, and in 1993, the first prospective study for clinical applications in humans was reported. [32] Since then, hyperthermia using MNPs has been developing as a research hotspot, due to its unique benefits like regulation by a magnetic field, localized heating, and permeability through the blood-brain barrier. [16, 33, 34] In 2010, MNP-based hyperthermia has passed preclinical stages, and received regulatory approval as a new clinical therapy, opening a new era for magnetic hyperthermia. [35] Various kinds of mechanisms have been reported for the heat generation by MNPs under an alternating magnetic field (AMF). [36] Among them, hysteresis and relaxation behavior are the two dominant factors. Hysteresis, which originates from the internal energy of magnetic particles, is the primary mechanism for magnetic hyperthermia, especially for ferromagnetic NPs-based hyperthermia. Hysteresis loss is based on a rapid variation of magnetic moments and is basically proportional to the area of the hysteresis loop. [37] Relaxation behavior, on the other hand, which includes Brownian and N´eel relaxation pathways, is another mechanism for magnetic hyperthermia, particularly in case of superparamagnetic NPs. [38] Brownian relaxation is caused by the entire magnetic particle rotating, while N´eel relaxation is related to the magnetic moment rotating within the magnetic core (Fig. 9.2). [39, 40] The competition of these two relaxation processes is controlled by the faster one. It is worth noting that in the case of intracellular MNPs, the intracellular components usually hinder the movement of NPs, which results in the fact that heat contribution is mostly from N´eel relaxation. [29, 41]

Fig. 9.2

N´eel and Brownian relaxation processes. Reproduced with permission from Ref. [40]. Copyright 2012 American Chemical Society.

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265

According to the heat generation mechanisms, several factors have been found to influence the heating power, including the AMF and the structures and magnetic properties of NPs. For AMF, generally, the heating power is enhanced by increasing amplitude and frequency. [37] However, the impacts of NPs are somehow more complicated. Certain properties of MNPs (e.g. magneto-crystalline anisotropy, diameter, magnetization, and homogeneity of NPs) can affect the heat generation. For example, high magnetization can increase the area of the hysteresis loop which eventually leads to a temperature increase. Poly-dispersed NPs exhibit a considerably low heat generation rate, compared with mono-dispersed ones; heating power is inversely proportional to the size distribution. [42] Heat released is also strongly dependent on anisotropy (K) and diameter (D). It has been reported that in order to achieve high heat generation, K and D should be in their optimal ranges, both of which differ from one kind of MNPs to another. [43] Simply put, by tuning the structure, morphology, and size of MNPs, high heat efficiency can be achieved. [16, 44, 45] By using the thermal energy generated by MNPs, cancer can be conquered by triggering cell death directly or prompting the immune system, and cancer cell death occurs by either necrosis or apoptosis. 9.2.1.1

Magnetic hyperthermia stimulated apoptosis

Apoptosis, which retains most cell membrane functionality and does not elicit inflammation, induces cells death in a programmed and biochemically active way. This process can be identified by cell shrinkage, chromatin condensation and DNA fragmentation. [46] Remarkably, during apoptosis, several key morphological events occur, including the formation of membrane blebbing, cell rounding, and detachment of actin. [47] It has been reported that γ-Mnx Fe2−x O3 (0 6 x 6 1.3) based magnetic hyperthermia can lead to cancer cell apoptosis. [48] Compared to cells without AMF and magnetic particles, cells with γ-Mnx Fe2−x O3 exposed to AMF for 30 min and further incubated for 4 h show membrane blebbing on their surface. After 8-h incubation, the actin cytoskeleton was significantly disrupted, and 12-h incubation completely destroyed the actin cytoskeleton. The mechanisms of these apoptotic phenomena are attributed to the stimulation of “initiator” cysteinyl aspartate-specific proteases (caspases) to unfold the extrinsic or intrinsic pathway, such as activation of the tumor necrosis factor (TNF) and death receptors-4 and -5 (DR4/5). [49] Among all of the caspases, caspases 3 and 7 are known as essential proteases, playing dominant roles in triggering apoptotic processes in mammalian cells. [50] Cheon et al. [45] reported that by using chitosan oligosaccharide-stabilized ferromagnetic iron oxide nanocubes (Chito–FIONs), both caspases 3 and 7 can be stimulated by magnetically modulated cancer hyperthermia, i.e. only Chito-FION

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bound cells in the area exposed to a magnetic field significantly enhanced the activation of the caspases (Figs. 9.3(a) and 9.3(b)), and this method showed much higher apoptotic population compared with commercially available Feridex (Fig. 9.3(c)), with excellent antitumor efficacy on an animal tumor model without severe toxicity. Also, a 3-fold increase in TNF-α gene expression has been produced by magnetically induced heating, and this induces cell death at the tumor area. [51] Astonishingly, apoptosis induced by magnetic hyperthermia is more severe than that by hot water, indicating an additional effect on cell viability in magnetic hyperthermia. Although the mechanisms for the increased apoptosis are still being investigated, this highlights the potential of magnetic hyperthermia for more efficient cancer therapy. [52]

Fig. 9.3

(a) and (b) Cellular apoptotic activity of Chito–FIONs-treated A549 cells in-

side (a) and outside (b) the area exposed to a magnet and subsequent application of an AMF. Cellular apoptotic activity was detected by using a red fluorogenic substrate for caspases 3 and 7 (red), and cell nuclei were stained with DAPI. (c) Apoptosis of A549 cells induced by the localized magnetic hyperthermia with Chito–FIONs or Feridex. Statistically significant difference between two groups, ∗ p < 0.01,

∗∗

p < 0.001. Reproduced

with permission from Ref. [45]. Copyright 2012 American Chemical Society.

9.2.1.2

Magnetic hyperthermia induced necrosis

Apoptosis usually takes place at the early stage of hyperthermia. With the increase of temperature, cell apoptosis will decrease, with a concomitant increase in necrosis. [49, 53] Necrosis is a process of cell death triggered directly by destroying the cellular structure, and complete dysfunction of metabolic pathways leads to cell death. It is well known that the integrity of the plasma membrane is a key factor for cell viability, and therefore, the most commonly used method for hyperthermal necrosis is to destroy the membrane integrity by heat. It is regarded that after being engulfed in an endosome and exposed to AMF, MNPs can disrupt the endosomal

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MNPs-based cancer therapy

267

membrane by heat, and the released endosomal content may induce damage to the cell membrane. [35] It is also reported that dextran coated iron oxide can be used to induce a necrotic-like cell death, including loss of membrane structure and shrinking of the cells (Fig. 9.4). [54] Moreover, heat generated from NPs dropped on the membrane (not engulfed into cells) can also disturb the membrane structure directly. [44] Thereby, combined with magnetic hyperthermia induced apoptosis, hyperthermal necrosis may also be a promising means of cancer therapy.

Fig. 9.4

Viability from FACS for (a) non-loaded cells with magnetic field off and

(b) cells loaded with magnetic particles after application of AMF for 30 min, and (c) and (d) the corresponding SEM images of cells. Reproduced with permission from Ref. [54]. Copyright 2011 IOP Publishing.

9.2.1.3

Heat-inducible immunotherapy

Not only can hyperthermia treatment kill cancer cells directly by heating, but it is also able to activate an immune response by heat shock. This effect gives rise to the reduction of both primary tumors and metastatic lesions. [55, 56] It is

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reported that natural killer cells, such as T cells, can be activated under a temperature of about 42 ◦ C, due to the presence of heat shock proteins (HSP). Meanwhile, HSPs, which can be induced by heat stress, not only protect cells from heat-induced apoptosis, [57] but also can chaperone tumor antigens, and thus can induce an antitumor immunity. [58] Kobayashi et al. [59] observed this phenomenon in 1998, in transplanting a T-9 rat glioma tumor model into each femur of a rat. Despite the fact that only one tumor was subjected to hyperthermia with magnetite liposomes, both tumors disappeared after therapy. Moreover, the tumor can only be inhibited in immune-competent syngenic rats after hyperthermia, and cannot in nude mice, [60] suggesting that the therapy was effective through an immunity mechanism. This interesting phenomenon is attributed to the heat generation after cellular uptake of MNPs and AMF exposure. The heat released can increase the intracellular HSP, followed by formation and augmentation of HSP-peptide complexes (upper route in Fig. 9.5), [55] and induce necrotic cell death as discussed previously (lower route in Fig. 9.5). [61] Both of these routes can release HSP or their peptide complexes, activate neighboring T cells, [62] stimulate monocytes, produce proinflammatory cytokines, [63, 64] and eventually stimulate the innate immune system to treat the cancer. This hyperthermia triggered immunotherapy shows great promise for tumor therapy, especially for metastatic tumors, which are still a challenge.

Fig. 9.5

Proposed scenario for the mechanism of anticancer immune response induced

by hyperthermia. Reproduced with permission from Ref. [61]. Copyright 2005 SpringerVerlag.

9.2.2

Magnetic specific targeting

Although the potential benefits of NPs are considerable, potential toxicity has been reported. [65, 66] A lot of methods have been developed to reduce the dose of NPs in order to reduce the potential toxicity, including passive targeting based on the enhanced permeability and retention (EPR) effect and positive targeting by conjugating active tumor-specific molecules, such as folic acid, [67] anti-Her2, [68] and

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269

RGD. [69] Unlike other NPs, MNPs have their unique targeting properties allowing exploitation of their response to an external magnetic field, which is denoted as magnetic targeting. After being exposed to an external magnetic field, MNPs can be magnetized, driven magnetically, and concentrated at a specific target site (Fig. 9.6). [70] The magnetic local targeting strategy reduces systemic distribution of the NPs, consequently reducing the dosage required and eliminating associated side effects. [71] Furthermore, the magnetic targeting can fix particles at a local site when it is desired to keep them away from the reticulo-endothelial system (RES). [72] After NPs are intravenously administered and concentrated within the body, a competition forms between forces exerted on the particles by the blood vessel and magnetic forces. When the magnetic forces exceed the blood flow rates in arteries (10 cm/s) or capillaries (0.05 cm/s), the MNPs are retained at the target site and may be internalized by the endothelial cells of the targeted tissue. [73]

Fig. 9.6

A schematic illustration shows the concept of magnetically targeting in vitro

(a) and in vivo (b). Reproduced with permission from Ref. [70]. Copyright 2006 Nature Publishing Group. And reproduced with permission from Ref. [78]. Copyright 2012 Elsevier.

Magnetic targeting was first developed in 1963 when Meyers et al. [74] accumulated magnetic iron particles in the leg vein of a dog by applying a horseshoe magnet, followed by some similar work in the decades after that.[75−77] However, further progress was halted until the blooming development of MNPs that showed great magnetic susceptibility. Recently, Liu et al. [78] discovered that by placing a magnet near a tumor, MNPs can be migrated toward the tumor after intravenous injection with about 8-fold higher accumulation in the tumor than would occur without mag-

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netic targeting. This remotely and noninvasively targeting control process is unique and highly effective, and can be used as a technique of actuation for drug delivery and gene translation. 9.2.3

Magnetically controlled drug delivery

Various kinds of nanomaterials have been developed for drug delivery, including inorganic NPs, micelles, and polymers. However, the major problems of therapeutic drug delivery come essentially from the lack of specificity with high cytotoxicity, which results in high side effects. [79] To improve drug localization, magnetic force with an implanted or externally applied permanent magnet has been exploited as magnetically targeted drug delivery. This method dates back to 1978, when it was reported by Widder’s group. [80] Since then, a great deal of work has been reported aiming to achieve a high drug concentration in the diseased area with fast response time and minimum side effects, including the delivery of drugs to a cancerous lung, [17, 81] prostate, [82] brain, [83, 84] melanoma, [85] breast,[86−88] or liver. [89, 90] The pioneering work for the first ever Phase-I was carried out by L¨ ubbe et al. in 1996, [91] followed by the second clinical trial, conducted by Koda et al. in 2002, and a third in 2004.[92−95] It is worth noting that hollow MNPs, with higher absorbance areas, can achieve greater drug loading efficiency than solid ones and consequently are more effective in killing cancer cells. We found that hollow iron oxide NPs can be loaded with more of a drug than solid iron oxide NPs of the same core size using the same coating strategy. Unaffected by the drug efflux phenomenon that exists in resistant cancer cells, hollow iron oxide NPs can be taken up by multidrug resistant OVCAR8-ADR cells more effectively than free drugs (Figs. 9.7(a) and 9.7(b)), [96] suggesting the NPs’ potential as drug delivery vehicles, especially for multidrug resistant cells. MNP-based drug delivery not only transports the drugs to a specific site but also permits remote control of drug release. Drugs attached to MNPs through a heat sensitive linker enable them to be released in a controlled manner by varying the AMF, which can generate heat. [97, 98] Also, drugs can be attached to NPs through π–π interaction or hydrophobic interaction, in which the improvement of drug release can also be enhanced after magnetic heating, as the desorption of drugs has been proved to be an endothermic process. [99] Moreover, in some cases, drugs can be loaded into porous materials with valves (Fig. 9.7(c)). The magnetic heat generation can build up pressure inside the porous NPs, subsequently removing the molecular valves and triggering the drug release. [40, 100] In some other situations, drugs and MNPs can be co-embedded within temperature-sensitive polymers. By local heat-

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271

ing or mechanical force induced by magnetic particles, the polymers crack, shrink or deform, followed by the desired drug release (Fig. 9.7(d)).[101−104] Interestingly, compared to normal heating at 45 ◦ C, the drug release rate of temperature-sensitive polymer-coated iron oxide during AMF condition, is 20 times improved, due to recrystallization of NPs and shrinkage of polymers. [105] It has been demonstrated that the synergistic effect of magnetic heating, magnetic disruption, and recrystallization can initiate the drug release with high precision, and this highlights the prospect of using MNPs for controlled drug delivery and release. Recently, Zhang et al. [106] reported a new method of magnetically controlled drug release and showed that the drug release rate decreased dramatically due to the aggregation of the MNPs, and increase of the drug diffusion path. Although no magnetic nanosized drug carriers are used clinically yet, [55, 107] it is still anticipated, due to the promising results in preclinical investigations.

Fig. 9.7

(a) Schematic illustration of drug delivery system based on hollow iron oxide

NPs. (b) CLSM visualization of free drug and drug loaded iron oxide NPs uptake by resistant (OVCAR8-ADR) cells. (c) and (d) Schematics of remotely controlling drug release through (c) molecular valves, and (d) shrinkage or deformation of polymers. [40, 96, 105] Reproduced with permission from Ref. [96]. Copyright 2012 Springer-Verlag. Reproduced with permission from Ref. [40]. Copyright 2012 American Chemical Society. Reproduced with permission from Ref. [105]. Copyright 2009 John Wiley & Sons.

9.2.4

Magnetofection

Numerous methods of gene transfer, including biological, physical, and chemical approaches have already been reported. However, due to the side effects of previously developed methods (e.g. unpredictable distribution, low concentration at the target

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site, and stimulation of immune response [108] ), new strategies with high efficiency, target specificity, and considerable safety are still being explored. MNP-based transfection, often called magnetofection, is a new method, which can rapidly lead the applied vectors fully to the target cell surface within a short time. [109] It benefits from the magnetic force, which can lead both to enhanced transfection efficiency and to targeting the specific site. After attaching cells, magnetofection undergoes a similar mechanism with non-magnetic gene delivery, i.e. internalization into endosomes, escape from endosomes through a “proton sponge effect,” diffusion inside cells, and transportation along microtubules.[109−112] This concept was raised by Byrne et al. in 2000 using an adeno-associated virus linked to magnetic microspheres. [113] Since then, magnetofection has been applied by transfecting blood vessel endothelial cells, lung epithelial, osteoblasts, aminocytes, and keratinocytes. [70] Both DNA and RNA have been transfected by MNPs. The initial research was mainly focused on DNA, which was directly attached to MNPs or carriers via charge interactions. Compared with commercially available transfection agents or magnetic gene carriers without a magnetic field, magnetofection in the presence of a magnetic field can remarkably enhance the transfection efficiency in cell cultures,[114−116] as well as provide a better-tolerated and more easily controllable scenario in vivo. [117, 118] Later on, some research on magnetofection of small interfering RNA (siRNA), which can knock down gene expression, was reported. It can effectively silence gene expression, i.e., knocking down eGFP expression in HeLa cells, brain cancer cells (C6 cells, SHEP cells), breast cancer cells (MCF7), prostate cancer cells (TC2 cells), and glioblastoma cells (U251 cells).119−121] More recently, magnetic delivery of short hairpin RNA (shRNA) has also been demonstrated. [122, 123] However, so far, most of the work in magnetofection is centered on reducing the dosage required or accelerating transfection kinetics. Recently, Dobson’s group found that, similar to remote control drug delivery, oscillating magnetic arrays can further enhance the overall efficiency of magnetofection. [95] This method can increase the transfection levels up to tenfold compared with magnetofection with static magnetic fields in HEK293T cells, H292 human lung epithelia cells, mouse embryonic fibroblasts cells, and human umbilical vein endothelial cells. [70, 124, 125] Although the underlying mechanisms are not well understood, based on the fact that the mechanical stimuli affects cellular membrane traffic – both endo- and exo-cytosis – Dobson et al. [109] attribute this to the association of magnetic vectors with membranes and the transmission of mechanical forces from the lateral movement of the magnetic field to cellular membranes (shown in Fig. 9.8). Therefore magnetofection may be a promising way for gene delivery in the future.

9.2

MNPs-based cancer therapy

Fig. 9.8

273

Principle of oscillating nanomagnetic transfection. Plasmid DNA or siRNA is

attached to MNPs and incubated with cells in culture (left). An oscillating magnet array below the surface of the cell culture plate pulls the particles into contact with the cell membrane (A) and drags the particles from side to side across the cells (B), mechanically stimulating endocytosis (C). Once the particle/DNA complex is endocytosed, proton sponge effects rupture the endosome (D) releasing the DNA (E), which then transcribes the target protein (F). Reproduced with permission from Ref. [125]. Copyright 2012 Indian Academy of Sciences.

9.2.5

Magnetic switches for controlling cell fate

While being exposed to a small magnetic field, cells may experience some changes in signaling pathways, such as F-actin arrangement, cell alignment, intra-cellular ion fluctuations, and mitochondria activation.[126−128] However, the effects on cell growth under normal culture conditions with magnetic field alone are extremely small. [129, 130] By introducing magnetic materials, however, the influence of a magnetic field on cells is enhanced dramatically due to the following reasons. MNPs can produce their own magnetic field, influencing the tissue area around them through more intensive interactions or biophysical effects. [126] More importantly, MNPs can be conjugated with antibodies or some ligands, which would bind to certain receptors of interest. Then, under an external magnetic field, MNPs can move on cell surfaces or between cells generating mechanical stimulations of magnetic drag, rotation or twisting, and inducing cellular activity by influencing cell growth, differentiation or death. [131, 132] Therefore, controlling cell fate by a magnetic switch is becoming more and more popular. One of the earliest biological applications of magnetic materials is to investigate the properties of cytoplasm under an applied stress, and the first application was raised by Heilbrunn and Siefriz in 1920s. [133] From then

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on, magnetically induced cellular response has been applied to a wide range of cell types, such as endothelial cells, [134, 135] macrophages, [136] glioma cells, [137] and stem cells, [138, 139] for both magnetically controlling cell fate by activation of ion channels and regulation downstream. 9.2.5.1

Magnetically activated ion channels

The pioneering work of magnetically controlling cell fate was focused on magnetic activation of the hydro-mechanical properties of the cells or ion channels.[140−142] In 1949, Crick et al. quantified the rheological properties of cells by magnetic force, a method further exploited by Ingber and his co-workers. [134, 143] Because ion channels are essential to a cell’s fate, two activation methods have been explored to control ion channels. The first one is to regulate the mechano-sensitive ion channels, as these channels can respond to membrane or cytoskeletal deformation (Fig. 9.9(a)). [133] Dobson et al. [144] have developed an MNPs-electromagnet model which can induce stretch-activated Ca2+ flux in fibroblasts by placing collagen-coated ferric oxide beads on the plasma membrane of substrate-attached fibroblasts in 1995, and then their group developed the magnetic micro- and NP mediated activation of mechanosensitive ion channels in 2005. [145] Pommerenke et al. [146] also reported stimulation of integrin receptors by using a magnetic drag force device that induces an intracellular free calcium response.

Fig. 9.9

Schematic representation of different types of nanomagnetic actuation of ions.

(a) Mechano-sensitive ion-channel activation: magnetic particles are bound to the integrin receptors (left). Upon the application of a high-gradient magnetic field (right), the particles are pulled toward the field, deforming the cell membrane and activating adjacent mechano-sensitive ion channels. (b) Targeted ion-channel activation: MNPs are attached to an ion channel via an antibody (left). Upon activation of a high-gradient magnetic field source (right), the ion channel is forced open. Reproduced with permission from Ref. [133]. Copyright 2012 Nature Publishing Group.

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275

However, the magnetic materials used in these experiments were almost in a micrometer-scale, so they can hardly manipulate a single receptor without disturbing other parts of cells. The inaccuracy in controlling the spots being affected makes this technique need a stronger magnetic field. With the development of nanotechnology, nanoscale magnetic materials enable switching ion channels by targeting specific ion channels and cell membrane receptors, in order to accurately initiate controlled cell responses. [133] Ingber et al. [147] created magnetic switching of calcium signaling in cells by applying magnetic fields to magnetize the bound superparamagnetic nanobeads and physically induce cohesion and aggregation of nanobead-receptor complexes on the cell membrane (Fig. 9.9(b)). Dobson et al. [142] also activated K+ ion channel by using 130-nm MNPs through a member of the ‘background leak’ family of tandem pore potassium channels, TREK-1. With this magnetic triggering method, ion channels can be well controlled. 9.2.5.2

Magnetic stimulation for direct control of cell destiny

Despite the actuation of cell signal transduction by switching ion channels with a magnetic field, the direct stimulation of candidate mechano-transducers using magnetic materials can also change other cellular properties, such as cell shape, cytoplasmic viscosity, cytoskeletal organization, and even cell fate. [134, 143] To accomplish this, both a static magnetic field and an alternating magnetic field have been applied. Definitely, MNPs, especially ferromagnetic NPs, could induce strong attractive forces between the dipoles of neighboring NPs, and aggregate under a static magnetic field. This aggregation will induce the clustering of a specifically targeted protein, and finally, influence the cell fate. Although the clustering of receptors can naturally be induced by multivalent biochemical ligands, [148] MNPs, with comparable size and modified with meaningful biological molecules such as DNA or proteins, show great importance for magnetically regulation of cell fate with high flexibility. Cheon et al. [149] magnetically manipulated Tie2 receptors on 293-hTie2 cells by employing TiMo214 monoclonal antibody-conjugated Zn2+ -doped ferrite MNPs. After exerting an external magnetic field with horizontal magnetic field lines, magnetization of the NPs accelerate the aggregation, which promotes the clustering of Tie2 receptors, induces intracellular signaling processes, and finally leads to angiogenesis (Fig. 9.10). Clustering of death receptors, such as the TNF-related apoptosis inducing ligand (TRAIL) through docking of biochemical ligands is another way to activate extrinsic apoptosis signaling pathways for inducing apoptosis. [150] Based on this phenomenon, Cheon et al. [151] further developed a technique recently by using a targeting antibody conjugated with zinc-doped iron oxide NPs. The antibody can target death receptor

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4 (DR4) in DLD-1 colon cancer cells. When a magnetic field is applied, aggregated MNPs induce clustering of the DR4s in a manner similar to TRAIL, and consequently promote apoptosis signaling pathways without damaging the cell membranes.

Fig. 9.10

Targeting and magnetic manipulation of Ab-Zn-MNPs. (a) and (b)

Ab-Zn-MNPs selectively bind to the specific cell-surface Tie2 receptors. (c) In the presence of an external magnetic field, the Ab-Zn-MNPs are magnetized to form nanoparticle aggregates, and induce the clustering of receptors to trigger intracellular signaling. (d) Tie2 receptor-bound NPs before and after application of the magnetic field. Reproduced with permission from Ref. [149]. Copyright 2010 John Wiley & Sons.

Except for inducing clustering of receptors, MNPs can produce an additional magnetic field. It has been reported that a static magnetic field can induce strong and replicable alterations of cell shape and plasma membrane in various cell types for controlling cell shape, motility, division or adhesion. [152, 153] Therefore, a new approach for targeted cell therapy accomplished by controlling the cell growth has been developed recently. By conjugating cells with ferromagnetic NPs and exposing

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277

them to a magnetic field, the NPs are magnetized and form a local magnetic field. Consequently, the growth of the NP-containing cells will be significantly increased, as well as increasing the anti-apoptotic effect. [126] Apart from the static magnetic field, an alternating magnetic field can also activate the MNPs. Compared with the common magnetic hyperthermia effect, MNPs can respond to an alternating magnetic field with a lower oscillating frequency. Under a spinning magnetic field, MNPs, especially particles with separate magnetic and non-magnetic parts, can move or rotate accordingly, and the resulting mechanical forces could become an effective tool for cancer treatment. Gao et al. [154] took advantage of this interesting property, and designed a nano-composite with magnetic and optical blocks spatially separated for a special therapy, called magnetolytic therapy. Due to the asymmetry in spatial distribution of magnetic components, the particle can rotate under a spinning magnetic field after attaching to a cell, and therefore, a majority of the tumor cells are killed owing to the compromised integrity of the cell membrane and the promoted apoptosis. This magnetic control of cellular fate shows great advantages over a conventional biochemical ligand system, especially in the remote control approach, and shows tremendous promise for future applications. 9.2.6

Recently developed therapies

9.2.6.1

MRI-monitoring cancer therapy

Although various therapeutic methods have been reported in the past few decades, approaches for monitoring the bio-distribution and therapeutic efficiency of the agents still need to be established. Fortunately, magnetic resonance imaging (MRI), which is based on the response of hydrogen spin to a magnetic field, has emerged as an important diagnostic tool due to the high special resolution, and it can monitor therapeutic effects effectively. [155] MNPs have been widely used as MRI contrast agents, and among them, superparamagnetic NPs are commonly applied as T2 contrast agents, while paramagnetic NPs are usually used for T1 contrast agents. Consequently, MNPs can also be applied in MRI-traced cancer therapy. The most useful application of this strategy is MRI-tracked drug delivery, in which the position, the dose, and the metabolization of drugs can be traced.[156−158] Remarkably, T1 contrast agents are preferred due to positive signal enhancement, and therefore, paramagnetic manganese oxide or manganese phosphate NPs, with five unpaired electrons, are of great research interest recently. We developed a hollow manganese phosphate NP-based drug delivery system, which is sensitive to pH value and enables tracing drug delivery by MRI. With great cellular uptake by a folic acid-mediated

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method, folic acid positive cells show high drug release as well as a bright T1 MRI signal, compared with low drug delivery and dark MRI signal from folic acid negative cells (Fig. 9.11(a)). [159] Further, we discovered that the MRI signal can be improved by increasing the number of siRNA-loaded MnO transfected cells (Fig. 9.11(b)), [160] proving this approach can also be used for supervising gene therapy. This promising technique can also monitor changes of tumor size and its microenvironment, as well as atherosclerosis, [161, 162] opening a new era for the efficient management of therapy, in which the mechanism and effect of therapy is “visible.”

Fig. 9.11

(a) Schematic illustration of the concept for MRI-monitored drug delivery by

DOX-loaded hollow manganese phosphate NPs. (b) Relative MRI T1 signal intensity at different cell amounts after transfected by siRNA-loaded MnO. Reproduced with permission from Ref. [159]. Copyright 2012 Springer-Verlag. And reproduced with permission from Ref. [160]. Copyright 2011 Royal Society of Chemistry.

9.2

MNPs-based cancer therapy

9.2.6.2

279

Magnetic force-based tissue engineering

Since cells labeled with MNPs can be manipulated by magnets, Ito et al. [163] developed a new tissue engineering method based on magnetic force. Compared to conventional tissue engineering, which relies on substrate chemistry or physical modifications, magnetic force-based tissue engineering achieves the organization of cells on substrate by controlling the magnetic field, and can create a 3D multicellular configuration with a flexible pattern. [164] This method has proved to be very promising for applications in manufacturing thick tissue sheets,[165 − 167] cellular clusters of controlled size, [168, 169] and specific shapes or constructs, [170, 171] by varying the magnetic field and number of cells (Fig. 9.12). Furthermore, an ideal

Fig. 9.12

(a) Magnetically labeled cells are attracted by the magnetized tip and pile up

to form a 3D multicellular assembly of controlled dimensions. (b) The same cell suspension spreads over the substrate when no magnetic force is applied. (c) and (d) Photographs of cells after 24-h magnetic deposition, with high (c) and low (d) cell count. Reproduced with permission from Ref. [168]. Copyright 2009 American Chemical Society.

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tissue engineering strategy should possess a high cell density for cell fusion and a highly unidirectional orientation for facilitating large forces. [169] Magnetic force can be regulated by the magnetic field to control the optical cell density, as well as the orientation. This technology is applied in various kinds of tissue engineering now, including stem cell research,[172−174] skeletal muscle tissues,[169,174−176] stented pericardia, [177] bones, [178] and orthopedic research. [179] Nowadays, magnetic forcebased tissue engineering attracts much attention and is becoming a promising strategy in tissue engineering.

9.3

Conclusions and perspectives

Cancer represents one of the biggest problems for modern societies. It is estimated that by 2020, cancer deaths worldwide could reach 10 million. An important goal of cancer research is to improve anti-cancer treatment options to alleviate cancer-related morbidity and mortality. Therefore, MNP-based cancer therapy, for its irreplaceable advantages, is becoming one of the leading topics. A variety of methods of cancer therapies based on MNPs have been reported, and they show promise in inhibiting and curing tumors. In this chapter, the applications of MNPs for magnetically modulated hyperthermia therapy, drug/gene delivery, and controlling cell fate are discussed. These applications may open new routes for treating cancer. The toxicity of MNPs is under intense investigation before they are applied clinically. Although iron is an innate metal that is essential for life, most of us attribute the potential toxic effects of MNPs to excess iron released, because of its ability to accept and donate electrons by switching between ferrous (Fe2+ ) and ferric (Fe3+ ) ions. [65] This reduction–oxidation reaction may cause an imbalance in body homeostasis and lead to aberrant cellular responses, such as DNA damage, oxidative stress, and inflammatory processes. [180] Efforts need to be made to decorate the MNPs in a fabricated manner that leads to a minimum of free iron being released and performs higher biocompatibility even active targeting property. The size of MNPs seems to be another consideration for their toxicity. MNPs with different sizes have different metabolization mechanisms, i.e. small MNPs (d < 30 nm) are metabolized through the kidneys, while large MNPs (d > 200 nm) are metabolized through the liver. Medium-sized MNPs can linger in the body for a long time, and therefore, detailed pharmacokinetic phenomena such as drug and MNP elimination and accumulation within the body are required to determine their biocompatibility, both in vitro and in vivo. Another hurdle in the treatment of cancer is the emergence of resistant malig-

9.3

Conclusions and perspectives

281

nant cells. The drug concentration may affect the birth and death rates of both the sensitive and resistant cell populations in continuous time. However, free drugs can be pumped out after cellular uptake in resistant cells, resulting in a low drug concentration within cells. Fortunately, we have primarily prove that the application of MNPs-based drug delivery models can dramatically improve the therapeutic effect in multidrug resistant cells, but still, relevant reports are few, and it needs to be further studied, especially by in vivo and clinical studies. The inherent mechanisms of magnetic therapy are not well understood. For example, the reasons why magnetic hyperthermia cures cancer more effectively than traditional hyperthermia are still being explored. In addition, the real downstream, which can be activated by magnetic force for controlling cell fate, are also unknown. Only when the intrinsic reasons are clearly known, can we design and develop therapies accordingly. Therefore, assisted by mathematical modeling, the scientific community still needs to study the detailed therapeutic mechanisms involved in MNPbase treatments. To make full use of magnetically responsive NPs, the magnetic properties of NPs should be improved to increase the efficiency of magnetic hyperthermia and maximize the sensitivity of magnetic response. Therefore, there is also a need to find novel materials to be screened for maximum absorption of magnetic field lines. Heavy metal-doped MNPs seem to be a new target for this purpose, but still, little work has been done to systematically explore the influence of doping in thermomagnetic approaches. Moreover, heavy metals seem to be more toxic than iron, and their biocompatibility is another criterion for further applications. In addition, construction of a heterogeneous MNP with hard and soft magnetism is a feasible strategy to achieve high heat-generation ability. Developing novel magnetic-responsive cancer therapies may be another way for their further applications. Inspired by the striking changes in tissue during exposure in outer space, Wang et al. [181] proposed a novel method for tumor treatment recently. As MNPs will be in a weightless environment, after being accumulated into target cells, the MNPs will lead the cells to an environment of “microgravity.” This special cell state will affect cell growth, and eventually, inhibit tumor growth. Developing accurate multi-modal MNPs with little or no toxic effects is also urgently needed. The ways cancer is cured in different therapies are different, and there may be some synergistic effects. The collaborations of different therapeutic strategies may further reduce the dose needed. Lastly, significant advancements have been emerged in MNPs-based immunotherapy, nanocatalytic therapy for the efficient treatment of cancer. The protocols for synthesis of MNPs and their functionalization with nucleic

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acids, drugs, and targeting moieties still need to be standardized along with optimization of magnetic field parameters. The field will open for broader and in depth investigations that may bring MNPs into clinical trials in the near future, with interdisciplinary collaborations from physics, chemistry, biology, pharmacy, and clinical medicine.

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Chapter 10 Composite Magnetic Nanoparticles: Synthesis and Cancer-related Applications∗ Ping Caia)b)† , Hongmin Chena) , Zhengwei Caoa) and Jin Xiea)‡ a)

Department of Chemistry, University of Georgia, Athens, GA 30602,

USA b)

College of Chemistry and Molecular Sciences, Wuhan University, Wuhan

430072, China c)

College of Chemistry and Molecular Engineering, Peking University, Bei-

jing 100871, China † Corresponding author. E-mail: [email protected] ‡ Corresponding author. E-mail: [email protected] Recent advances in the preparation and applications of composite magnetic nanoparticles are reviewed and summarized, with a focus on cancer-related applications.

10.1

Introduction

Magnetic nanoparticles (MNPs) have emerged as important nanomaterials. A myriad of highly magnetic materials, including Fe3 O4 , Fe2 O3 , MnO, FePt, Fe, Co, etc., have been prepared as nanoscale particles, and their applications in catalysis,[1-3] biomedicine,[4−7] imaging,[8−11] data storage, [12] environmental remediation, [13, 14] ∗ Project supported by the National Institutes of Health (Grant No. 5R00CA153772) and China Scholarship (Grant No. 201306275009).

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nanofluids, [15, 16] optical filters, [17] defect sensors, [18] and cation sensors [19, 20] have been investigated. On the basis of these advances, there is an interest in preparing magnetic composite nanoparticles, which comprise multiple nanocomponents. Here we consider the particles with at least one magnetic component. Composite nanoparticles of different shapes, such as dumbbell-, core/shell-, and core/satellitelike architectures, have been prepared. Accompanying the developments in synthesis, a new wave of research seeks to harness the unique physical or surface properties of these composite materials for novel applications, especially in bio-related areas. Manifold benefits are found in multi-component nanosystems. First, the integration means combined physical properties, which often make possible multiple functions. For instance, it is now possible to synthesize nanoparticles consisting of one iron oxide component and one semiconductor component.[21−26] The resulting nanoparticles, boasting both magnetic and optical properties, have a great potential as probes for fluorescence and MRI dual modality imaging. [27] Second, an additional component may function as a protection shell to improve the colloidal or magnetic stability of the core. This is important because many types of high-magnetism nanoparticles easily oxidize in air, diminishing their magnetism. [28, 29] A protective layer that resists oxidation can significantly improve the applicability of these materials. Lastly, composite nanoparticles usually possess more than one type of surface, enabling them to be tethered easily, with multiple functionalities and minimal crossspecies interference. For instance, it has been shown by us and others that ligands or therapeutics can be selectively conjugated onto the Au and Fe surface of the Au–Fe3 O4 nanoparticles to achieve multifunctional nanoplatforms.[30−33] Extensive effort has been applied to exploiting the novel bio-applications of these advanced nanostructures. For such applications, delicate control of the size, composition, and architecture is often critical for the physical, physiochemical, and surface features of the nanosystems. This status spurs widespread efforts to improve the synthesis and surface engineering techniques for composite nanoparticles. These advances, in turn, fuel further developments in composite nanoparticle-based diagnosis and therapy. This review summarizes recent progresses in these areas, focusing on cancer-related applications.

10.2 10.2.1

Controlled synthesis of composite nanoparticles Dumbbell-like nanoparticles

Dumbbell-like nanoparticles (NPs) are composites of two nanocomponents that are arranged head-to-head. One example is Au–Fe3 O4 nanoparticles, which were first

10.2

Controlled synthesis of composite nanoparticles

293

reported by Yu et al., who prepared them using a seed-mediated growth method. [34] Briefly, Au nanoparticle seeds were made and then mixed with Fe(CO)5 in 1octadecene along with oleic acid and oleylamine. The mixture was heated to reflux (∼ 300 ◦ C) to allow Fe3 O4 to grow on the top of the Au seeds. The size of the Au component could be tuned from 2 nm to 8 nm, and that of the Fe3 O4 component could be tuned from 4 nm to 20 nm. This synthesis approach has been extended to prepare other types of dumbbell-like nanoparticles, such as PtFe3 O4 , [35] Pd–Fe3 O4 , [36, 37] Au–CoO, [37] and Pt–CoO [37] nanoparticles. Later, the Doong group reported a one-step synthesis of dumbbell-like Au–Fe3 O4 nanoparticles using iron–oleate as the iron precursor, achieving a good size control. [38] For instance, 5 nm/14 nm Au–Fe3 O4 nanoparticles can be prepared by dissolving 0.5 mmol oleic acid, 0.5 mmol oleylamine, 1 mmol iron–oleate complex Fe(OL)3 , and 0.1 mmol Au seeds in 5 mL of 1-octadecene, and heating the mixture to reflux. [39] It is also possible to prepare 10 nm/14 nm Au–Fe3 O4 via a similar approach, using 0.3 mmol of Au seeds as the gold precursors. [38] Instead of using metal nanoparticles as the seeds, Gu et al. used Fe3 O4 NPs as the starting nanoseeds to prepare Ag-Fe3 O4 nanoparticles. [40] In their approach, Fe3 O4 NPs were prepared and then dissolved in an organic solvent, such as dichlorobenzene, dichloromethane, hexane, and dioctyl ether. On the top of the Fe3 O4 solution, an aqueous solution of silver nitrate was added, forming a two phase mixture. The subsequent sonication of the mixture resulted in the formation of Ag–Fe3 O4 NPs at the phase interface. It is believed that, due to imperfect coverage or labile ligand-surface interactions, a few Fe(II) sites are exposed on the Fe3 O4 nanoparticle surface. They act as catalytic centers that facilitate Ag+ reduction and Ag nanoparticle formation on the Fe3 O4 surface. Metal oxide nanoparticles can also grow on the surface of Fe3 O4 to form composite nanostructures. For instance, Geun et al. reported the synthesis of MnO–Fe3 O4 NPs using Fe3 O4 NPs as the seeds. [41] Interestingly, the size of the Fe3 O4 seeds has a strong influence on the shape of the resulting composite nanoparticles. When using Fe3 O4 seeds of relatively small size (e.g., 5 nm), the synthesis yields core/shell-like nanostructures. Increasing the seed size to 11 nm yields dumbbell-like Fe3 O4 /MnO nanoparticles, and increasing further to 21 nm results in flower-like products. While the Fe3 O4 nanoparticles are commonly used as T2 contrast agents, MnO is a paramagnetic material that can efficiently shorten the T1 relaxation time. Hence, the resulting composite nanoparticles can potentially be used as MRI contrast probes for both T1 - and T2 -weighted imagings. Hao et al. discussed the growth mechanism of dumbbell nanoparticles. [42] As

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mentioned above, dumbbell NPs can be obtained by the sequential growth of a second component on pre-formed NP seeds. This process relies on promoting limited heterogeneous nucleation on the seeds while suppressing nucleation in the solution. This can be achieved by fine tuning the seed-to-precursor ratio and/or controlling the heating profiles so that the concentration of the precursor remains below the homogeneous nucleation threshold throughout the synthesis. Taking the Au–Fe3 O4 synthesis as an example, the size of the Fe3 O4 component is tuned by adjusting the Fe(CO)5 /Au ratio. Krylova et al. proposed a similar growth model that explained the formation of CoPt3 /Au, FePt/Au, and Pt/Au nanodumbbells. [43] Very recently, Liakakos et al. reported the wet chemistry synthesis of Co–Fe composite nanoparticles using a Co nanorod as a seed upon which an iron nanocomponent was grown. [44] The Fe:Co ratio could be adjusted from 1:1 to 12:1 by varying the amount of the Fe precursor (Fig. 10.1). Interestingly, the mean length of the resulting nanorods was shorter than that of the initial Co seeds, indicating either rod consumption during the Fe growth or its fusion into Fe at the interface. The reason that the growth starts from the tips of the nanorods is probably due to the fact that the termini are less covered by stabilizing ligands and are, therefore, more reactive. A similar growth pattern was also observed with Au–Co heterodimer nanostructures. [45]

Fig. 10.1

Co–Fe nanoparticles obtained by tuning the ratio between the iron precursor

and the Co nanorod seeds: (a) Fe/Co = 1, (b) Fe/Co = 2, (c) Fe/Co = 4, (d) Fe/Co = 6 (scale bar = 100 nm). [44]

10.2

Controlled synthesis of composite nanoparticles

10.2.2

295

Core@shell nanoparticles

Core@shell-like nanoparticles comprising at least one magnetic component have also been widely studied, usually with the core being magnetic. Noble metals (Au[46−51] and Pt[52−54] ), metal oxides (sulfide) (Cu2−x S [27] and TiO2 [55−57] ), SiO2 ,[58−60] carbon, [61, 62] etc. have all been investigated as shell materials that can protect the cores from either oxidation or aggregation. 10.2.2.1

Gold shell

Due to inertness and unique optical properties, gold is regarded as an excellent material to coat magnetic nanoparticles. Early on, Xu et al. reported a convenient means of synthesizing core@shell structured Fe3 O4 /Au by reducing HAuCl4 on the surface of Fe3 O4 nanoparticle seeds. [47] More recently, Song et al. developed a sequential microfluidic process for the synthesis of Co@Au core@shell NPs, where the shell thickness could be tuned by repeating the Au deposition process (Fig. 10.2). [63] However, despite the successes, it remains difficult to directly impart one gold shell onto a magnetic nanoparticle.

Fig. 10.2

Co@Au NPs made by a displacement method, where the shell thickness can be tuned by repeating the reduction–deposition process. [63]

Recently, the Gao group reported a different, multi-step approach to achieve gold coating. Before adding gold precursors, they first imparted a layer of dielectric polymer, such as phospholipid-polyethylene glycol terminated with carboxylic acid (PL-PEG-COOH) and poly-L-histidine (PLH), onto Fe3 O4 NPs (Fig. 10.3). [64] The polymer layer promoted the adsorption of gold precursors onto the particle’s surface, facilitating the formation of a gold shell. A similar approach has been used to coat silica onto magnetic nanoparticles prior to gold coating. [65] In that method, the

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coagulation of tetraethyl orthosilicate (TEOS) at an early stage imparted a silica shell onto Co nanoparticles. This was followed by the adsorption of ∼ 2–3 nm gold nanoparticles onto the silica shell. The subsequent reduction of HAuCl4 filled the gaps among the gold seeds to form a relatively homogenous gold shell.

Fig. 10.3

Key steps in hybrid NP synthesis. Magnetic NPs coated with oleic acids are

first solubilized using amphiphilic PL-PEG-COOH. PLH, which is capable of chelating metal ions, is then adsorbed onto the PL-PEG-COOH layer by electrostatic interaction. After the addition of gold ions and a reducing reagent, thin gold shells form on the polypeptide template. [64]

10.2.2.2

Cu2 S shell

Photothermal nanoparticles have been shown to have potential for cancer therapy applications. While gold-based nanostructures have been the focus of research in this area, copper-containing semiconductor nanocrystals have also attracted much attention recently, given their favorable production cost, stability, nontoxicity, and photothermal conversion efficiency. Shells of these semiconductor materials have been successfully formed around magnetic nanoparticles to obtain particles with dual functions. For instance, Liu et al. reported the preparation of Fe3 O4 @Cu2−x S core@shell NPs. [27] These were obtained by first adding an excess amount of sulfur to a Fe3 O4 solution to yield Fe3 O4 @S core@shell NPs (Fig. 10.4). The sulfur-coated Fe3 O4 were subsequently treated with copper(II) acetylacetonate in a mixed solution of oleylamine and chloroform, forming Fe3 O4 @Cu2−x S core@shell nanoparticles.

10.2

Controlled synthesis of composite nanoparticles

Fig. 10.4

297

(a) Schematic diagram of the formation of Fe3 O4 @Cu2−x S core@shell

nanostructures. (b) and (c) TEM images of the as-synthesized Fe3 O4 and Fe3 O4 @Cu2−x S NPs, with corresponding high resolution images in the insets. (d) Powder X-ray diffraction patterns of Fe3 O4 and Fe3 O4 @Cu2−x S NPs. (e) STEM image of a single Fe3 O4 @Cu2−x S core@shell NP. (f) Corresponding EDX line scan profiles of the core@shell nanoparticle, showing a higher Cu concentration in the peripheral region of the crystal. [27]

10.2.2.3

Carbon shell

Non-metallic materials, such as carbon, can also be used to coat magnetic nanoparticles. For instance, Sharma et al. reported the synthesis of Co@C nanoparticles. [66]

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Li et al. reported the preparation of Ni@C core@shell nanoparticles, where a nickel core was surrounded by a 10-nm-thick nitrogen enriched carbon shell. [67] More recently, Sunny et al. obtained face centered, cubic nickel NPs with 5-nm-thick carbon layers at relatively low reaction temperatures. [68] The Dai group reported a scalable chemical vapor deposition method to synthesize FeCo@C nanocrystals. [69] Dong et al. prepared FeCo@C and FeNi@C nanocapsules by arc discharge in methane.[70−72] Gedanken et al. synthesized air-stable FeCo@C alloy NPs via a one-step thermal decomposition process. [73] Yang et al. reported the preparation of carbon-coated FeCo alloy NPs with different Co:Fe ratios using a solid-state route with melamine as the carbon source. [74] 10.2.2.4

Iron oxide shell

Iron oxides can also be coated onto various types of NPs. For instance, Sun et al. reported the synthesis of bi-magnetic core@shell Fe58 Pt42 @Fe3 O4 NPs using a thermal decomposition method. [53] Shavel et al. reported that Fe@Fe3 O4 core@shell NPs can be synthesized by simple thermal decomposition of iron oleate. [75] In a

Fig. 10.5

(a) TEM and (b) HRTEM images of Fe@Fe3 O4 nanocubes. (c) SAED and (d) XRD analyses of Fe@Fe3 O4 nanocubes. [77]

10.3

Applications

299

separate study, Fe@Fe3 O4 core@shell particles were prepared as part of a composite with graphene. [76] More recently, Mahmoud et al. reported a two-step synthesis of Fe@Fe3 O4 core@shell nanocubes (Fig. 10.5). [77] First, FeCl3 was reduced by NaBH4 in an ethylene glycol solution, with the presence of 2-mercaptopropionic acid (surfactant) and trisodium citrate (cosurfactant). Next, the surfaces of the resulting particles were oxidized with trimethylamine N-oxide, forming a core@shell structure. These nanocubes are promising contrast agents for MRI. Similar approaches have been developed to prepare other core@shell NPs. For instance, Knappett et al. reported the synthesis of Co@Fe3 O4 NPs. [78] Teng et al. prepared Pt@Fe2 O3 NPs by the sequential decomposition of Pt(acac)2 and Fe(CO)5 . [79] 10.2.3

Core/satellite- or flower-like NPs

Another type of nanostructure that is common for composite magnetic nanoparticles is the core/satellite- or flower-like shape. These particles often feature a relatively large core that is surrounded with multiple small nanosatellites. For instance, Cheon et al. fabricated core/satellite nanoparticles comprising a dye-doped silica core and multiple Fe3 O4 NP satellites. [80] These particles can be used for optical and MR dual-modality imaging. Hyeon et al. also reported SiO2 /Fe3 O4 core/satellite nanostructures which embrace multiple 7-nm Fe3 O4 decorated on the surface of a 100-nm silica sphere. [81] The same group later used mesoporous silica NPs as the core to prepare SiO2 /Fe3 O4 NPs. [82] The resulting nanoparticles, affording both high drug loading capacity (due to the mesoporous silica) and strong magnetism (due to multiple Fe3 O4 satellites), have potential as a theranostic agent for MRI and drug delivery. Zhang et al. synthesized Fe3 O4 /Au core/satellite NPs using polydopamine as a glue to link the two nanocomponents. [83] Fang et al. synthesized Fe3 O4 /SiO2 /Au nanoparticles, this time adsorbing polydopamine on the silica shell to immobilize the gold satellites. [84]

10.3

Applications

MRI is one of the most important diagnostic tools in the clinic, and magnetic NPs of different forms have been widely investigated as the contrast agents for MRI. These include NPs of high magnetism that can be used to shorten the T2 relaxation time. Also, paramagnetic NPs such as MnO can enhance signals on T1 -weighted MR maps. Composite magnetic NPs comprising both types of nanocomponents can thus perform as dual-function probes. For instance, Lee et al. reported that Fe3 O4 /MnO nanocrystals of core@shell-, dumbbell-, and flower-like structures can

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induce both hypointensities on T2 -weighted MR images and hyperintensities on T1 weighted images due to the release of Mn2+ . [41] Bae et al. developed carbon-coated iron oxide core@shell NPs, which can also be used as T1 and T2 dual functional contrast agents. [85] Meanwhile, composite NPs, comprising both magnetic and optical properties, can be used as dual-mode imaging probes. For instance, Cheon et al. prepared SiO2 /Fe3 O4 core/satellite NPs consisting of a dye-imbedded SiO2 core and multiple Fe3 O4 satellites. These NPs have proven to be effective for both MRI and fluorescence imagings (Fig. 10.6). [80] Cheng et al. reported a layer-by-layer (LBL) assembly approach to synthesize multifunctional NPs comprising an upconversion nanoparticle (UCNP) core, a layer of ultrasmall iron oxide nanoparticles (IONPs) as the intermediate shell, and a thin layer of gold as the outer shell. These nanoparticles can be used for stem cell tracking, enabling the cell movement to be regulated by an external magnetic field while being monitored by both MRI and upconversion luminescence imagings. [86] Very recently, Tian et al. reported the synthesis of NaGdF4 :Yb/Er@NaGdF4 core@shell UCNPs, which can function as tri-modality imaging probes for upconversion luminescence (UCL), MRI, and X-ray computed tomography (CT). [87]

Fig. 10.6

Dual-mode nanoparticle probes for high-performance magnetic resonance and

fluorescence imaging of a “core-satellite” hybrid nanoparticle probe. [80]

Composite NPs may also perform as theranostic agents that permit simultaneous diagnosis and therapy. For instance, gold nanoshells are highly absorptive in the near-infrared (NIR) region, a property that can be harnessed for either photoacoustic (PA) imaging or photothermal (PT) therapy. Gao et al. prepared iron oxide/gold core/shell NPs and demonstrated that the particles are promising dualmode probes for simultaneous PA and MR imagings (Fig. 10.7). [64] Similarly, Tian et al. reported that Fe3 O4 @Cu2−x S nanoparticles can serve as T2 contrast probes while also mediating the energy conversion for photothermal therapy. [27]

References

Fig. 10.7

301

(a) Schematic diagram of MNP-gold core-shell NPs’ response to a magnetic

field. The underlying red curve represents the field strength. The coupled agents move as the magnetic field is turned on and off. (b) Schematic diagram of contrast enhancement in mmPA imaging; mmPA imaging suppresses the regions not susceptible to a controlled magnetic field while identifying the regions with coupled agents responsive to a magnetic field. [64]

10.4

Summary and perspective

Overall, synthetic approaches have been developed for preparing magnetic NPs of different architectures and functions and tested for cancer imaging and therapy. Many more applications are on the horizon owing to advanced nano-engineering techniques. For instance, magnetite NPs have been tested as radiosensitizers to enhance efficacy of radiotherapy;[88] the enhancement is attributed to high-Z-element promoted generation of photoelectrons and Auger electrons.[89] Meanwhile, NPs made of metal oxides such as MnO2 may serve as an oxygen source to curb radiation induced hypoxia.[90] Moreover, iron-containing NPs such as iron oxide and iron platinum NPs have shown promise as ferroptosis inducers.[91,92] This is because ferrous (Fe2+ ) or ferric (Fe3+ ) ions released from these NPs may participate in the Fenton reaction to produce reactive oxygen spices (ROS) that cause lipid peroxidation.[93] Such NP-based ferroptosis inducers may synergize with conventional therapies for improved tumor control. Furthermore, magnetic NPs have also been tested in the context of immunotherapy. They may serve as carriers for immune modulators and improve the pharmacokinetics of the latter.[94] Magnetic NP based thermal ablation and ferroptosis are highly immunogenic processes, and may work in conjugation with immune check point inhibitors to elicit strong antitumor immunity.[95] Despite the progress, however, it is worth pointing out that the majority of these explorations are at the pre-clinical stage. Very few NPs have been tested in the clinic, let alone clinical translation. The reasons are multifold, including concerns over biosafety, manufacturing, and cost. Discrepancies in efficacy between human patients and pre-clinical models are also an issue, given that many studies are not

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conducted in models that closely recapitulate clinical situations. It is paramount that more endeavors are directed at addressing these issues in future investigations.

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Chapter 11 Formation of Multifunctional Fe3O4/Au Composite Nanoparticles for Dual-mode MR/CT Imaging Applications∗ Yong Hu, Jingchao Li, Mingwu Shen† , and Xiangyang Shi‡ College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China † Corresponding author. E-mail: [email protected] ‡ Corresponding author. E-mail: [email protected] Recent advances with iron oxide/gold (Fe3 O4 /Au) composite nanoparticles (CNPs) in dual-modality magnetic resonance (MR) and computed tomography (CT) imaging applications are reviewed. The synthesis and assembly of “dumbbell-like” and “core/shell” Fe3 O4 /Au CNPs is introduced. Potential applications of some developed Fe3 O4 /Au CNPs as contrast agents for dual-mode MR/CT imaging applications are described in detail.

11.1

Introduction

Molecular imaging is considered to be a powerful technology for disease diagnosis. Due to the fact that each imaging modality displays its inherent limits and ∗ Project supported by the National Natural Science Foundation of China (Grant Nos. 81351050, 81101150, and 21273032), the Fund of the Science and Technology Commission of Shanghai Municipality, China (Grant Nos. 11nm0506400 and 12520705500), and the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, China.

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drawbacks, [1] it is essential to perform dual- or multi-mode imaging for accurate disease detection. In this context, development of multifunctional nanoparticulate systems that are able to integrate two or more imaging contrast agents within one particulate system is necessary. Recent advances in nanotechnology have enabled the generation of various nanoparticle (NP) systems for dual-modality imaging applications, such as T1 - and T2 -weighted MR imaging,[2−5] MR/CT imaging,[1,6−8] ultrasonic/MR imaging, [9, 10] MR/PET imaging,[11−13] MR/fluorescence imaging,[14−16] and MR/optical imaging.[17−20] Among these different dual-mode combinations for molecular imaging, MR/CT imaging has attracted widespread attention. MR imaging is a powerful and noninvasive technique with high spatial resolution, tomographic capabilities, and a nonionizing type of radiation. Meanwhile, CT imaging technology is also recognized as another reliable molecular imaging mode because its spatial and density resolution are greater than those of other imaging modes. Therefore, the combination of MR and CT imaging is of great clinical significance. For MR imaging applications, superparamagnetic iron oxide (Fe3 O4 ) NPs have been widely used as negative contrast agents in recent decades due to their ability to affect the MR signal by dephasing transverse magnetization and reducing the T2 value of water protons.[21−23] Recently, some Fe3 O4 -based multifunctional composite NPs (CNPs) have been explored for multi-modal imaging applications through integration with other imaging elements, such as Gd complexes, Ag NPs, Au NPs/rods, Cu compounds, etc. [2, 6, 24, 25] On the other hand, gold (Au) NPs have been widely applied in many different fields,[26−29] especially as a kind of novel contrast agent for CT imaging, because of their higher X-ray absorption coefficient and good biocompatibility after appropriate surface modification.[30−34] Therefore, synthesis of Fe3 O4 /Au CNPs for MR/CT dual-mode imaging has received a surge of interest. Likewise, the versatility of nanotechnology has enabled the preparation of Fe3 O4 /Au “core/shell” CNPs via direct deposition of Au NPs onto the surface of Fe3 O4 NPs, [35, 36] enabled the formation of Fe3 O4 /Au “core/shell” CNPs by a sonochemical method, [37] and enabled the creation of Fe3 O4 /Au CNPs via decomposition of Fe(CO)5 on the surface of the Au NPs, followed by oxidation.[38−40] Some of these Fe3 O4 /Au CNPs have been used for dual-modality MR/CT imaging applications. This review mainly reports recent advances in the synthesis of Fe3 O4 /Au CNPs and the applications of these CNPs for MR/CT dual-mode imaging. This review will not cover all aspects of the Fe3 O4 /Au CNPs. Rather, it will introduce some key developments in the synthesis of several kinds of Fe3 O4 /Au CNPs for MR/CT imaging applications. This review starts from a brief introduction, and then discusses

11.2

Synthesis or formation of Fe3 O4 /Au CNPs

309

different approaches to preparing Fe3 O4 /Au CNPs with different structures and the uses of these CNPs for dual-mode MR/CT imaging applications. The chapter ends with a brief conclusion and a future perspective discussion.

11.2

Synthesis or formation of Fe3 O4 /Au CNPs

Fe3 O4 /Au CNPs can be categorized into “dumbbell-like” vs “core/shell” structures. In this part, we will introduce the synthesis or formation of both. 11.2.1

“Dumbbell-like” structured CNPs

The “dumbbell-like” structured Fe3 O4 /Au CNPs have generally been synthesized by one of two strategies. In the first, iron pentacarbonyl is decomposed on the surfaces of Au NPs in the presence of oleic acid and oleylamine (Fig. 11.1), followed by subsequent functionalization via a surfactant exchange process. [40] The CNPs so formed possess a unique structure: one Fe3 O4 NP is linked to one Au NP (Fig. 11.2). [38] These CNPs can be further modified through different techniques

Fig. 11.1

Schematic illustration of the preparation of “dumbbell-like” Fe3 O4 /Au CNPs. [40]

Fig. 11.2

(a) Schematic illustration of surface functionalization of the Fe3 O4 /Au CNPs.

TEM images of the 8–20 nm Fe3 O4 /Au CNPs before (b) and after (c) surface modification. [38]

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for various applications. In the second strategy, iron-oleate and gold-oleylamine are mixed in oleylamine and 1-octadecene, followed by thermal decomposition of these precursors to yield the unique “dumbbell-like” CNPs. [41, 42] The CNPs so formed may display interesting catalytic, magnetic, and optical properties. [43, 44] Fe3 O4 /Au “dumbbell-like” CNPs have been proven to be biocompatible in a certain concentration range and may be used for magnetic and optical applications in biomedicine. [45, 46] 11.2.2

“Core/shell” structured CNPs

Besides the formation of Fe3 O4 /Au “dumbbell-like” CNPs, “core/shell” type Fe3 O4 /Au CNPs have also been formed via a simple assembly process. In a recent effort, Bao et al. [47] fabricated biofunctional “core/shell” Fe3 O4 /Au CNPs by simply linking two separately prepared NPs via chemical bonds (Fig. 11.3). Compared to the Fe3 O4 NPs (4–20 nm) used for formation of “dumbbell-like” Fe3 O4 /Au CNPs, [38] the particles they used in this study were much larger. Furthermore, the

Fig. 11.3

Schematic illustration of bifunctional Fe3 O4 /Au CNP synthesis.

Amino-functionalized Fe3 O4 NPs (a, simplified as b for the convenience of illustration) were first modified by Boc-L-cysteine to have surface thiol groups (c, simplified as d). Gold NPs were then conjugated onto the surface of Fe3 O4 NPs to form the expected bifunctional Fe3 O4 /Au CNPs (f, simplified as e). [47]

11.2

Synthesis or formation of Fe3 O4 /Au CNPs

311

Fe3 O4 /Au CNPs can be easily modified with other functional molecules to realize various bio-applications. Unfortunately, this type of larger CNPs is prone to precipitate and lacks sufficient colloidal stability, which may not be suitable for in vivo biomedical applications. To improve the colloidal stability of the Fe3 O4 /Au CNPs, it is essential to select smaller sized Fe3 O4 NPs as core particles for the formation of “core/shell” structured Fe3 O4 /Au CNPs. In a recent study, Caruntu et al. reported the successful attachment of 2–3 nm Au NPs onto the surface of Fe3 O4 core NPs (10 nm) through a simple “two-step” chemically controlled procedure. [48] In this approach, Fe3 O4 NPs were synthesized from a stable colloidal methanolic solution, followed by coating with amino-terminated silane to render the particles with positive charges. Then, the Fe3 O4 NPs were treated with a colloidal solution of negatively charged Au NPs (Fig. 11.4). The transmission electron microscope (TEM) results clearly indicate the successful formation of Fe3 O4 /Au CNPs (Fig. 11.5). The colloidal Fe3 O4 /Au CNPs were highly stable against separation and exhibited magnetic properties similar to those of the parent Fe3 O4 nanocrystals, suggesting that the coating of Au NPs does not appreciably compromise the magnetic properties of the Fe3 O4 core particles.

Fig. 11.4

Schematic illustration of bifunctional Fe3 O4 /Au CNP synthesis. [48]

Another “two-step” protocol for direct coating of Au onto the Fe3 O4 core NPs was reported by Carril et al. [49] In brief, Fe3 O4 NPs (3.2 nm) were obtained by thermal decomposition of Fe(acac)3 in the presence of oleic acid and oleylamine at a high temperature. Under similar conditions, the obtained Fe3 O4 NPs were further covered with a gold layer by thermal decomposition of gold (III) acetate and protected by a coating of oleic acid to afford the formation of Fe3 O4 /Au CNPs with a size of 6.1 nm. The NPs underwent a ligand exchange step with a 1:1 mixture of carboxy-terminal ligand and glucose-terminal ligand to yield water-soluble Fe3 O4 @Au NPs.

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Fig. 11.5

Formation of Multifunctional Fe3 O4 /Au Composite Nanoparticles · · ·

Typical TEM images of the as-prepared Fe3 O4 NPs obtained from a mixture

of DEG and NMDEA (3:1, w/w) (a), the colloidal Au particles (b), the freshly prepared Fe3 O4 /Au CNPs (c), and the Fe3 O4 /Au CNPs aged for 2 (d) and 5 months (e), and sonicated for 60 min. [48]

To generate “core/shell” Fe3 O4 /Au CNPs, seed-mediated growth methods have also been developed.[50−52] In this process, preformed Ag- or Au-decorated Fe3 O4 hybrid NPs are used as seeds, and Fe3 O4 /Au CNPs with a core/shell structure can be formed by dropping the seeds into the gold growth solution. For instance, Hu et al. [50] first prepared Fe3 O4 @polyphosphazene@Au seeds with the help of NaBH4 , and then exposed the seed particles to chloroauric acid (HAuCl4 ) solution to form Au shell on the surface of the seeds via sodium citrate reduction at 100 ◦ C. In another work, [51] Ag-decorated Fe3 O4 NPs were injected into the growth solution of HAuCl4 , cetyltrimethylammonium bromide (CTAB), and silver nitrate (AgNO3 ) for subsequent formation of pin-like “core/shell” Fe3 O4 /Au CNPs using ascorbic acid as a reducing agent. The added Ag ions play an important role in the Au shell growth process because they can block the crystal growth in some direction, similar to the formation of star-shaped “core/shell” Fe3 O4 /Au CNPs reported in the literature. [52]

11.2

Synthesis or formation of Fe3 O4 /Au CNPs

313

Beyond the above-mentioned approach to synthesizing Fe3 O4 /Au CNPs, a polymer-mediated self-assembly approach can also be used to generate Fe3 O4 /Au CNPs with good water dispersibility, colloidal stability, and biocompatibility.[21,23,53−55] In a recent report, Cai et al. [6] developed a convenient approach to assembling dendrimer-entrapped Au NPs (Au DENPs) onto Fe3 O4 core NPs through a layerby-layer (LbL) self-assembly technique and dendrimer chemistry. In this work, positively charged Fe3 O4 NPs were first prepared by a controlled co-precipitation approach, and then were used as core particles for subsequent electrostatic LbL assembly of poly(γ-glutamic acid) (PGA) and poly(L-lysine) (PLL) to form PGA/PLL/ PGA multilayers, followed by assembly with Au DENPs formed using amine-terminated generation 5 (G5) poly (amidoamine) dendrimers as templates (Fig. 11.6). Similarly, Zhang et al. [56] prepared Fe3 O4 /polypyrrole (PPy)/Au core/shell NPs by coating PPy onto the preformed Fe3 O4 NPs through the chemical oxidative polymerization of pyrrole and subsequent assembly of plentiful Au NPs on the surface of Fe3 O4 /PPy.

Fig. 11.6

Schematic representation of the fabrication of Fe3 O4 /Au CNPs. [6]

Although the polymer-mediated assembly approach is powerful to generate Fe3 O4 /Au CNPs, the approach usually involves multiple assembly steps and requires preformed Fe3 O4 NPs and Au NPs. Recently, “one pot” hydrothermal route has been widely used to synthesize different NPs, such as Fe3 O4 NPs, 3-aminopropyltrimethoxysilane (APTS)-coated Fe3 O4 (Fe3 O4 /APTS) NPs, [57] and polyethyleneimine (PEI)-coated Fe3 O4 (Fe3 O4 -PEI) NPs. [54] In a recent report, Li et al. [58] developed a “one pot” hydrothermal approach to synthesizing Fe3 O4 /Au CNPs with good water dispersibility and colloidal stability. In this work, PEI partially modified with poly(ethylene glycol) monomethyl ether (mPEG-PEI.NH2 ) was used as a stabilizer to synthesize Au NPs via NaBH4 reduction chemistry to form mPEG-PEI.NH2 -Au NPs. Then, those NPs were mixed with Fe (II) salt in a basic aqueous solution and autoclaved at elevated temperature and pressure. This process led to the formation of Fe3 O4 /Au CNPs with abundant PEI surface amines. After further acetylation of the PEI amines, the final Fe3 O4 /Au CNPs were formed. The mPEG modification and the final acetylation are intended to improve the biocompatibility of these CNPs for biomedical imaging applications.

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11.3

Formation of Multifunctional Fe3 O4 /Au Composite Nanoparticles · · ·

Dual-mode MR/CT imaging applications of Fe3 O4 /Au CNPs

Fe3 O4 /Au CNPs have been used in a wide range of applications such as protein separation, [47] cell separation, [59] drug delivery and hyperthermia,[60−62] catalysis, [63] and biomedical imaging. [6, 58, 64] Herein, we will not introduce all of their applications; rather, we will discuss only their uses as contrast agents for dual-mode MR/CT imaging. Although there are many reports related to the synthesis and characterization of the “dumbbell-like” Fe3 O4 /Au CNPs, only one report up to now attempted to use them for dual-mode MR and CT imaging. [1] By coating with amphiphilic poly(DMA-r-mPEGMA-r-MA) polymer, the particles were able to be imparted with water-dispersibility and antibiofouling properties. The Fe3 O4 /Au CNPs displayed a better X-ray attenuation property than pure Au NPs at the same Au concentration, which should be attributed to the presence of Fe3 O4 NPs that also have an X-ray absorption property. Surprisingly, the T2 relaxivity (r2 ) of the Fe3 O4 /Au CNPs was measured to be 245 mM−1 ·s−1 , much higher than that of the commercial T2 contrast agent (150 mM−1 ·s−1 ). This increased r2 is likely due to the synergistic effect when more than one Fe3 O4 NP is linked to each Au NP, whereby the surrounding water molecules can be effectively influenced by the tiny multiple magnets in their vicinity. This synergistic effect in both X-ray attenuation and r2 enabled this kind of “dumbbell-like” Fe3 O4 /Au CNPs to be used as an ideal dual-mode MR/CT imaging agent. Intravenous injection of the hybrid Fe3 O4 /Au CNPs into hepatomabearing mice resulted in high contrast between the hepatoma and normal hepatic parenchyma in both MR and CT imaging modes. Different from the “dumbbell-like” Fe3 O4 /Au CNPs, the core/shell CNPs have been widely used as contrast agents for dual-mode MR and CT imaging applications. It is interesting to note that core/shell CNPs usually have a lower r2 relaxivity when compared with Fe3 O4 NPs because of the uniform surface coating of Au. In an early work, [65] biocompatible core/shell Fe3 O4 /Au CNPs contrast agents were synthesized via green chemistry for MR and CT imaging. Both bare Fe3 O4 and Fe3 O4 /Au CNPs were dispersed in agar gels with different Fe concentrations (0.06, 0.12, 0.24, 0.36, and 0.48 mM), with plain agar gel as the control. In the T2 -weighted MR phantom images, a noticeable darkening was observed with the Fe concentration for both bare Fe3 O4 and Fe3 O4 /Au CNPs (Fig. 11.7(a)). Meanwhile, they showed similarly decreased MR signal intensity with the Fe concentration (Figs. 11.7(b) and 11.7(c)). It was further observed that the relaxation rate (1/T2 ) varied linearly with Fe con-

11.3

Dual-mode MR/CT imaging applications of Fe3 O4 /Au CNPs

315

centration, and the r2 relaxivity was measured to be 161 ± 2.48 mM−1 ·s−1 for bare Fe3 O4 particles and 124.2 ± 3.02 mM−1 ·s−1 for Fe3 O4 /Au CNPs (Fig. 11.7(d)). The feasibility to use the Fe3 O4 /Au CNPs as CT contrast agents was also studied using a clinical CT scanner. To show their better imaging ability, Omnipaque (a popular iodine-based CT contrast agent currently in clinical use) was also compared. The results showed that the X-ray attenuation intensity of the Fe3 O4 /Au CNPs increased with increasing Au concentration, and was much higher than PBS, water, and bare Fe3 O4 NPs even at the lowest Au concentration of 0.2 mg/mL (Fig. 11.8(a)). Figure 11.8(b) shows that the Fe3 O4 /Au CNPs with Au concentration of 4.4 mg/mL display an X-ray attenuation intensity similar to Omnipaque at the iodine concentration of 7.2 mg/mL. The results suggest that these Fe3 O4 /Au CNPs could be used as contrast agents for dual-mode MR and CT imaging applications.

Fig. 11.7

MR imaging. (a) T2 -weighted MR phantom images of Fe3 O4 and Fe3 O4 /Au

CNPs with reference to control. (b), (c) Signal intensity versus TE plots for Fe3 O4 and Fe3 O4 /Au CNPs, respectively. (d) T2 relaxation rate (1/T2 ) versus Fe concentration. [65]

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Fig. 11.8

Formation of Multifunctional Fe3 O4 /Au Composite Nanoparticles · · ·

CT imaging of CNPs. (a) CT images of the phantoms at 100 kVp with

reference to control samples. (b) Au concentration (in CNPs) versus HU plot showing linear dependence. [65]

In a recent study, Fe3 O4 /Au CNPs prepared via LbL assembly of polymer multilayers and Au DENPs have also been used as contrast agents for dual-mode MR and CT imaging applications. In this work, the MR/CT imaging performance of different particles dispersed in an aqueous solution was evaluated. The results showed that Fe3 O4 /Au CNPs and Fe3 O4 /G5 NPs (Fe3 O4 /PGA/PLL/PGA/G5 NPs without Au NPs) also had a lower r2 relaxivity when compared with the uncoated Fe3 O4 NPs, which is due to the surface coating that limits the access of water molecules to the surface of Fe3 O4 NPs. [23] For CT imaging, Fe3 O4 /Au CNPs, Fe3 O4 /G5 NPs, and Au DENPs were all able to induce CT contrast enhancement with the Au or Fe concentration. Further, Fe3 O4 /Au CNPs displayed much stronger X-ray attenuation intensity than Au DENPs at the same Au concentration and Fe3 O4 /G5 NPs at the same Fe concentration, suggesting that the combination of both Au and Fe elements within one NP system can result in enhanced X-ray attenuation intensity for sensitive CT imaging applications. Their good MR and CT imaging performance enabled their uses as contrast agents for in vivo MR imaging of a mouse liver after intravenous injection and in vivo CT imaging of the right back of a mouse after subcutaneous injection (Fig. 11.9).

11.3

Dual-mode MR/CT imaging applications of Fe3 O4 /Au CNPs

Fig. 11.9

317

(a) T2 -weighted MR images of mouse liver before and after intravenous

injection of 0.1 mL Fe3 O4 /Au CNPs ([Fe] = 8.82 mg/mL, and [Au] = 1.57 mg/mL). In MR image, the black arrow indicates the gallbladder, while the white arrow indicates the liver. (b) CT image of a mouse subcutaneously injected with 0.5 mL Fe3 O4 /Au CNPs ([Fe] = 8.82 mg/mL, and [Au] = 1.57 mg/mL) into its back on the right at 5 min post-injection. [6]

Another successful example to use core/shell Fe3 O4 /Au CNPs for MR/CT dualmode imaging was reported by Li et al. [58] In their work, the “one pot” hydrothermally formed Fe3 O4 /Au CNPs were demonstrated to have a relatively high r2 relaxivity (146.07 mM−1 ·s−1 , quite similar to the hydrothermally synthesized Fe3 O4 -PEI NPs without Au coating [54] ) and a good X-ray attenuation property, which allowed them to be used for dual-mode MR/CT imaging applications. The non-compromised r2 relaxivity may be due to the non-uniform coating of Au shell onto the Fe3 O4 core. On one hand, the synthesized Fe3 O4 /Au CNPs were able to induce MR contrast enhancement of liver as a function of time post-injection after the particles were intravenously delivered to the mouse (Fig. 11.10). At 0.5 h post injection, the mouse liver showed a significantly reduced T2 MR signal intensity compared to the initial one before injection. Subsequently, the signal intensity gradually recovered at 1 h post-injection due to the further metabolic process. On the other hand, the Fe3 O4 /Au CNPs were able to induce a clear CT contrast enhancement of the rat aorta (Fig. 11.11(a)) as indicated by the red arrow and the rat liver (as indicated by the white star) at 20 min post-injection. Quantitative CT value measurements show that the CT values of the liver and aorta are much higher than the initial respective values before injection (Fig. 11.11(b)). In addition, the CNPs did not display any visible hemolytic effect and apparent cytoxicity in the studied concentration range. Therefore, the formed CNPs may be used as a contrast agent for dual-mode MR/CT imaging applications in vivo.

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Fig. 11.10

Formation of Multifunctional Fe3 O4 /Au Composite Nanoparticles · · ·

T2 -weighted MR images (a) and signal intensity (b) of a mouse liver before

injection and at different time points post intravenous injection of Fe3 O4 /Au CNPs (0.3 mL in PBS, [Fe] = 129.17 mM, [Au] = 68.46 mM). [58]

Fig. 11.11

CT images (a) and CT values (HU) (b) of rat liver and aorta before injection

and at different time points post intravenous injection of Fe3 O4 /Au CNPs (1.0 mL in PBS, [Fe] = 129.17 mM, [Au] = 68.46 mM). [58]

11.4

Concluding remarks and outlooks

319

In general, both “dumbbell-like” and “core/shell” Fe3 O4 /Au CNPs have more enhanced X-ray attenuation property than pure Au NPs due to the existence of Fe3 O4 NPs. Unlike the “dumbbell-like” Fe3 O4 /Au CNPs, core/shell Fe3 O4 /Au CNPs always have lowered r2 relaxivity when compared to uncoated Fe3 O4 NPs due to the uniform coating of Au shells that limits the water accessibility to the surface of Fe3 O4 NPs. To achieve a non-compromised r2 relaxivity, one strategy is to design non-uniform Au coating onto the surface of Fe3 O4 NPs. [58] The other strategy is to coat thin Au shells onto the surface of nanoclustered Fe3 O4 NPs. [61] In a recent study, Ma et al. [61] reported a facile approach to forming thin gold shells onto the surface of the nanoclusters of 70 Fe3 O4 NPs. The formed nanoclusters with a size of 30 nm possessed a higher r2 relaxivity (219 mM−1 ·s−1 ) than that of the “dumbbelllike” CNPs, which may be due to the porous structure of the nanoclusters and the thin gold coatings (3 nm) that result in short distances between Fe3 O4 surfaces and water molecules, favoring high local inhomogeneities in the magnetic field.

11.4

Concluding remarks and outlooks

In summary, this review reports the recent advances in the synthesis or assembly of Fe3 O4 /Au CNPs for dual-mode MR/CT imaging applications. Fe3 O4 /Au CNPs with a “dumbbell-like” or “core/shell” type structure can be formed via controlled thermal deposition of iron precursor onto preformed Au NPs, direct coating of Au NPs onto preformed Fe3 O4 NPs, seed-mediated growth methods, polymer-mediated assembly of Au NPs onto preformed Fe3 O4 NPs, or hydrothermal formation of Fe3 O4 NPs in the presence of preformed Au NPs. The Fe3 O4 /Au CNPs can be rendered with good biocompatibility after appropriate surface functionalization for dual-mode MR/CT imaging applications. Although much effort has been devoted to the generation of Fe3 O4 /Au CNPs for MR/CT imaging applications, the preparation and development of these NP systems still remains an open area and offers great challenges. For instance, the formed “dumbbell-like” Fe3 O4 /Au CNPs have not been widely investigated for dual-mode MR/CT imaging applications so far. The versatility of nanotechnology may make it possible to synthesize other types of Fe3 O4 /Au CNPs by tuning the diameter of Fe3 O4 NPs and shape of Au NPs. On one hand, the diameter of Fe3 O4 NPs in CNPs can be restricted to be smaller than 5 nm, allowing for T1-weighted MR imaging. On the other hand, control over the shape of Au NPs in CNPs is beneficial to optimize their inherent surface plasmon resonance absorption to the near-infrared region, thus having an excellent photothermal conversion property for photoacoustic imaging and photothermal therapy applications. Furthermore, besides the convenient sur-

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face modification strategies available for conjugation of targeting ligands onto the surface of Fe3 O4 /Au CNPs for active tumor targeting, it may also be highly possible to afford the CNPs with homologous tumor targeting specificity and immune evasion ability by coating of cancer cell membranes on their surface. Lastly, various theranostic agents incorporated with the Fe3 O4 /Au CNPs may also be developed for dual-mode CT/MR imaging-guided single-mode chemotherapy, gene therapy, immunotherapy, or radiotherapy, as well as different combinations of two-mode or multimode therapies.

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[34] Sun I C, Eun D K, Na J H, Lee S, Kim I J, Youn I C, Ko C Y, Kim H S, Lim D and Choi K 2009 Chem. Eur. J. 15 13341 [35] Cui Y L, Wang Y N, Hui W L, Zhang Z F, Xin X F and Chen C 2005 Biomed. Microdevices 7 153 [36] Chen C, Liu Y and Gu H Y 2010 Microchim. Acta 171 371 [37] Wu W, He Q G, Chen H, Tang J X and Nie L B 2007 Nanotechnology 18 145609 [38] Xu C J, Xie J, Ho D, Wang C, Kohler N, Walsh E G, Morgan J R, Chin Y E and Sun S H 2008 Angew. Chem. Int. Ed. 47 173 [39] Xu C J, Wang B D and Sun S H 2009 J. Am. Chem. Soc. 131 4216 [40] Yu H, Chen M, Rice P M, Wang S X, White R L and Sun S H 2005 Nano Lett. 5 379 [41] Choi S H, Na H B, Park Y I, An K, Kwon S G, Jang Y, Park M H, Moon J, Son J S and Song I C 2008 J. Am. Chem. Soc. 130 15573 [42] Kirui D K, Rey D A and Batt C A 2010 Nanotechnology 21 105105 [43] Wood A, Giersig M and Mulvaney P 2001 J. Phys. Chem. B 105 8810 [44] Haruta M 2004 Gold Bull. 37 27 [45] El-Sayed I H, Huang X and El-Sayed M A 2005 Nano Lett. 5 829 [46] Gupta A K, Naregalkar R R, Vaidya V D and Gupta M 2007 Nanomedicine 2 23 [47] Bao J, Chen W, Liu T T, Zhu Y L, Jin P Y, Wang L Y, Liu J F, Wei Y G and Li Y D 2007 ACS Nano 1 293 [48] Caruntu D, Cushing B L, Caruntu G and O’Connor C J 2005 Chem. Mater. 17 3398 [49] Carril M, Fern´ andez I, Rodr´ıguez J, Garc´ıa I and Penad´es S 2014 Part. Part. Syst. Charact. 31 81 [50] Hu Y, Meng L, Niu L and Lu Q 2013 ACS Appl. Mater. Interfaces 5 4586 [51] Bhana S, Rai B K, Mishra S R, Wang Y and Huang X 2012 Nanoscale 4 4939 [52] Fan Z, Senapati D, Singh A K and Ray P C 2013 Mol. Pharm. 10 857 [53] Guo R, Wang H, Peng C, Shen M W, Pan M J, Cao X Y, Zhang G X and Shi X Y 2010 J. Phys. Chem. C 114 50 [54] Cai H D, An X, Cui J, Li J C, Wen S H, Li K G, Shen M W, Zheng L F, Zhang G X and Shi X Y 2013 ACS Appl. Mater. Interfaces 5 1722 [55] Lu X Y, Niu M, Qiao R R and Gao M Y 2008 J. Phys. Chem. B 112 14390 [56] Zhang H, Zhong X, Xu J J and Chen H Y 2008 Langmuir 24 13748 [57] Shen M W, Cai H D, Wang X F, Cao X Y, Li K G, Wang S H, Guo R, Zheng L F, Zhang G X and Shi X Y 2012 Nanotechnology 23 105601

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Biocompatibility

Chapter 12 Using Magnetic Nanoparticles to Manipulate Biological Objects∗ Tianli Hu, Yi Liu, Yu Gao, Jiachen Zhang, Chenjie Xu∗† Department of Biomedical Engineering, City University of Hong Kong, Hong Kong SAR, China † Corresponding author. E-mail: [email protected] The use of magnetic nanoparticles (MNPs) for the manipulation of biological objects, including proteins, genes, cellular organelles, bacteria, cells, and organs, are reviewed. MNPs are popular candidates for controlling and probing biological objects with a magnetic force. In the past decade, progress in the synthesis and surface engineering of MNPs has further enhanced this popularity.

12.1

Introduction

Cellular-scale manipulation of biological objects is critical for both fundamental biomedical studies and the large-scale separation/purification of biological products.[1−4] For example, the ability of optical tweezers to precisely position and manipulate micro/nano objects like particles, proteins, and DNAs allows researchers to study the strength of interactions between single molecules with picoNewton accuracy. Recombination technology produces recombinant proteins with a known affinity, which can be efficiently purified from crude extracts by affinity chromatography. ∗ Project supported by the City University of Hong Kong (#9610472), General Research Fund (GRF) from University Grant Committee of Hong Kong (UGC) Research Grant Council (RGC) (#9042951 and 9043133), and NSFC/RGC Joint Research Scheme (#N CityU118/20).

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Among many technologies of manipulation at the scale of the cell and beyond, the magnetic manipulation is attractive due to its non-contact or action at a distance characteristic. [2, 5] Typically, samples containing biological objects of interest are mixed with magnetic probes that could specifically recognize and label the interested objects. Then the samples are placed in a magnetic field, which isolates the labeled objects from the rest. As such, the magnetic manipulation is time-efficient, costeffective, and easily scalable. To achieve a successful manipulation, the key is to specifically magnetize biological objects of interest with magnetic labels which are usually magnetic micro/nano particles (MNPs). Those particles should be made of biocompatible materials in the dimension range from 1 nm to 10 µm, which allows them to fully interact with the biological objects. They can be coated with either inorganic (e.g., gold, silica, hydroxyapatite) or organic (e.g., dextran, polyvinyl alcohol (PVA), polyethylene glycol (PEG)) shells to prevent the aggregation caused by hydrophobic interaction and/or magnetic attraction. In the case of in vivo manipulation, a proper surface coating will be required to make the MNPs undetected by the immune system for a prolonged circulation time. Finally, a targeting agent like an antibody has to be incorporated for the recognition and labeling of the biological objects of interest. Because of the importance of MNPs in the magnetic manipulation and other applications like the magnetic resonance imaging (MRI), which are not the focus here, the design and fabrication of MNPs have been frequently reviewed.[5−10] Instead of narrating similar stories, this review focuses on the latest progress in the magnetic manipulation of proteins, genes, bacteria, cellular organelles, cells, and organs. The goal is to provide an overview of the magnetic manipulation of biological objects (Fig. 12.1), aiming to help readers find the challenges and opportunities in this field.

Fig. 12.1

The use of magnetic nanoparticles for the manipulation of biological objects.

12.2

12.2

Protein separation

329

Protein separation

The effective and efficient purification of proteins from crude extracts without changing their properties is important for both life science research and pharmaceutical production.[11−14] Among the many methods for large-scale protein separation, magnetic separation techniques have several advantages. First, they are costeffective, with no need for expensive liquid chromatography systems, centrifuges, filters, or other equipment. The separation is also simple, which can be performed directly in crude samples. Second, the magnetic separation is gentle with a minimal potential to damage the proteins by shear forces. Finally, it concentrates the proteins without the need of ultrafiltration and/or ultracentrifugation. Magnetic beads of 1 µm or larger (e.g., Dynabeads from Invitrogen) are already commercially available from a variety of companies and widely used in laboratories. Based on the success of microsized magnetic beads, MNPs are also adapted for protein separation because of their higher surface-to-volume ratio, better interaction with proteins, and longer retention time in the solution. [2, 5, 15] An early example of manipulating proteins with MNPs was the recognition and separation of hexahistidine-tagged green fluorescent proteins (6His-GFP) from crude E. coli lysate. Specifically, sub-10 nm FePt MNPs were functionalized with nitrilotriacetic acid (NTA) with a thiol group acting as an anchor. Later, nickel ions were introduced to form the NTA–Ni2+ complex on the MNPs’ surface, which specifically chelated the hexahistidine tag of 6His-GFP. [16, 17] Then the FePt–NTA–Ni2+ complexes were mixed with crude E. coli lysate containing 6His-GFP. With ∼5 min incubation, 6His-GFP was extracted by a magnet and then detached from the MNPs using imidazole solution. Figure 12.2(a) is a schematic illustration of the binding process between 6His-GFP and the FePt–NTA–Ni2+ complex. Given the higher surface area, longer retention time in solution, and thus better interaction with proteins, those MNPs showed a higher purification yield for 6His-GFP (2–3 mg proteins/1 mg MNPs vs. 10–12 µg proteins/1 mg beads) – about 200 times higher than that of the commercial Dynabeads. The SDS polyacrylamide gel electrophoresis (SDS/PAGE) analysis of the separated proteins confirmed the presence and purity of extracted 6His-GFP (Fig. 12.2(b)). After that early work, more MNPs-based platforms have been developed for the purification of histidine-tagged proteins, such as Fe3 O4 @SiO2 @polymer-NTA–Ni2+ MNPs and Fe3 O4 @Au–NTA–Ni2+ MNPs. [18, 19] Unconventional chelating complexes were also examined. For example, MNPs with Ni exposure on the surface, namely Ni@NiO MNPs, were conjugated with imidazole for the purification of histidinetagged proteins that could be detached by means of another imidazole solution

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later. Similarly, MNPs with a NiO-decorated SiO2 shell were also suitable. [20] In addition, MNPs functionalized with the Cu2+ –terpyridine complex exhibited similar results. [21]

Fig. 12.2

Recognition and separation of hexahistidine-tagged green fluorescent proteins

(6His-GFP) from crude E. coli lysate: (a) surface-modified FePt MNPs selectively bound 6His-GFP in a cell lysate; (b) SDS/PAGE analysis of the cell lysate (lane 1), the fraction (lane 2) washed off a commercial NTA-Ni2+ column; the fraction washed off the FePt MNPs separation agent using imidazole solution (10 mM, lane 3; 80 mM, lane 4; 500 mM, lane 5); fractions washed off the reused FePt MNPs separation agent using imidazole solution (10 mM, lane 6; 20 mM, lane 7; 500 mM, lane 8). [15]

Up to now, we have focused on the manipulation of polyhistidine-tagged proteins. However, we should be aware that there are other protein tags such as glutathioneS-transferase (GST) and maltose binding protein (MBP). By modifying MNPs with the corresponding glutathione (GSH), Xu et al. separated GST-GFP from a crude extract by forming a conjugate of MNP-GSH/GST-GFP. Then GFP was eluted from MNPs upon the enzymatic cleavage of the TEV (Tobacco Etch Virus) linker between the two proteins. [22] Xing et al. developed maltose-modified MNPs for the separation, purification, and immobilization of MBP-heparinase I fusion enzyme. [23] In addition to small molecular ligands, other targeting molecules like antibodies can

12.2

Protein separation

331

be conjugated with MNPs for protein recognition and separation. For example, Matsunaga et al. developed a bacterial MNP with the protein-A coating. After being conjugated with anti-human insulin antibodies, the resulting antibody–protein-A– bacterial MNPs can bind and help identify human insulin in solutions. [24] Nichkova et al. used the antibodies to engineer luminescent MNPs with a Co:Nd:Fe2 O3 magnetic core and a luminescent Eu:Gd2 O3 shell for fluoroimmunoassay (Fig. 12.3). After the engineered MNPs captured the target proteins (e.g., human, rabbit, and mouse immunoglobulin Gs (IgGs)), the dye-labeled secondary reporter antibodies were added and formed a sandwich structure (i.e., MNP–protein–antibody) with both luminescent and fluorescent signals. The magnetic core of this system allowed the separation and purification of proteins, and the intrinsic luminescence from the shell of the MNPs served as an internal standard in the quantitative immunoassay. [25]

Fig. 12.3

Process of the multiplexed fluoroimmunoassay with magnetic luminescent

nanoparticles (MLNPs): (a) introduction of antibody-modified MLNPs; (b) binding of the protein analytes on the MLNPs surface; (c) capture of the dye-labeled secondary (reporter) antibodies; (d) magnetic extraction; (e) fluorescence detection of reporters and MLNPs. [25]

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Using Magnetic Nanoparticles to Manipulate Biological Objects

Magnetofection

Another type of magnetic manipulation is magnetic transfection or magnetofection. It is well known that the development of an efficient system for delivering genes into targeted cells is an important strategy to understand gene/protein functions and to develop therapeutics. Considering the public concern about the safety of viral transfection, non-viral gene delivery is preferred but suffers from a low transfection efficiency. [26] Magnetofection has arisen as a promising approach to address this challenge. This method uses a magnetic field to concentrate MNPs complexed with plasmids into the cells. The concentrated genes can be released onsite via enzymatic cleavage of the cross-linking molecules, charge interactions, degradation of the polymer matrix, etc. [27, 28] In magnetofection, MNPs are usually coated with positively charged molecules that allow the negatively charged plasmids to be associated with them. [28, 29] For example, MNPs for magnetofection can be made by coating an iron oxide core with a cationic copolymer, which is comprised of short chain polyethylenimine (PEI) and PEG grafted to chitosan. This system incorporates the biocompatibility of chitosan, the steric stabilization of PEG, and the positive charge of PEI so that it can bind, protect, and deliver plasmids into tumor cells both in vitro and in vivo. [30] In another example, Chari et al. compared magnetofection with other transfection methods for oligodendrocyte precursor cells (OPCs), finding that the transfection efficacies obtained using the magnetofection methods are highly competitive with or better than current widely used nonviral transfection methods (e.g., electroporation and lipofection) with the additional critical advantage of high cell viability. [31] Although MNPs are categorized as non-viral vectors, they could be incorporated with other viral or non-viral platforms to maximize the delivery efficiency. Byrne et al. conjugated virus vectors (i.e., recombinant adeno-associated virus 2, rAAV) onto MNPs (Fig. 12.4). With the MNP–virus complex, the amount of vector required was significantly reduced to 1% of the previous quantity for the same transfection efficiency. [32] Similar results have been obtained with smaller MNPs. For example, Tanaka et al. mixed 29 nm maghemite MNPs with the hemagglutinating virus of Japan envelope vector (HVJ-E) to enhance the transfection efficiency. They found that the MNPs with protamine sulfate that gives a cationic surface charge significantly enhance the transfection efficiency in vitro due to the enhanced association of HVJ-E with the cell membrane in the presence of a magnetic force. MNPs coated with heparin enhance the transfection efficiency in vivo. Thus, the surface chemistry of the MNPs needs to be tailored to meet specific demands. [33] Wenzel et al. reported the transduction of murine embryonic stem cells by an MNP-assisted lentiviral gene

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transfer. By the combined use of MNPs and lentivirus, they achieved a four-fold increase of the number of transduced cells in comparison to the lentivirus only. [34]

Fig. 12.4

Magnetic microparticle–rAAV complex (MNP–rAAV) for cell transfection: (a)

illustration of MNP–rAAV; (b) C12S cells were infected with free rAAV encoding the gene for green fluorescent protein (GFP); (c) C12S cells were infected with MNP–rAAV encoding the gene for GFP under a magnet field. [32]

12.4

Manipulation of cellular organelles

An organelle is a specialized subunit within a cell that has specific functions and is usually separately enclosed within its own lipid bilayer. The ability to manipulate and remotely control specific cellular organelles in vitro and in vivo would provide a powerful tool for investigating the cell function and signaling pathways. Recent representative examples that utilize MNPs for organelle manipulation are summarized in Table 12.1. Table 12.1

Magnetic nanoparticles for the manipulation of cellular organelles.

Nanoparticle

Size/nm

Ligand/antibody

Organelle

Reference

Zn0.4 Fe2.6 O4 MNPs

15

antibody for death

membrane

[35]

Superparamagnetic

480

guanine nucleotide

membrane

[36]

cytoskeleton

[37]

lysosome

[38]

receptor 4 NPs, Ademtech Iron oxide NPs

exchange factor 120

RanGTP protein/guanine exchange factor RCC1

Iron oxide

14

proteins recognize EGFR

Anti-mouse IgG1 microbeads

50

anti-TrkB agonist antibody endosome

Bacteria MNPs

50

cytochrome c-specific

(Fe3 O4 )

[39]

mitochondria [40]

binding aptamers

A cell’s membrane separates the interior of the cell from the extracellular components. It consists of a lipid bilayer with embedded proteins. Some proteins face

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the cell exterior and act as receptors for particular messengers. These are the terminations of signaling pathways that regulate the cell activities. By noticing this phenomenon, researchers realize that the cell signaling pathways could be manually controlled with a magnetic field if MNPs are bound to the interesting receptors. For example, Cheon et al. turned on the apoptosis cell signaling with zinc-doped iron oxide (Zn0.4 Fe2.6 O4 ) MNPs that were coated with death receptor 4 antibodies (DR4A) of DLD-1 colon cancer cells. Briefly, the researchers labeled DLD-1 colon cancer cells with MNPs–DR4A first. Then a magnetic field was applied, which aggregated the MNP-bound DR4s to trigger the apoptosis signaling pathways. In addition to cells, the apoptotic morphological changes of zebrafish were also achieved with this technology. [35] Similarly, the same group triggered tubulogenesis with MNPs that were labeled with TiMo214 antibodies for Tie2 receptors. [41] Recently, Dahan et al. reported the local remodeling of the actin cytoskeleton and morphological changes of living cells with magnetic manipulation. They functionalized MNPs with the catalytic domain of TIAM1 (TIAMDHPH , AS 1033–1406), a specific guanine nucleotide exchange factor (GEF) that activates Rac1, a Rho-GTPase known to induce morphological changes upon activation. As the TIAM–MNPs were localized to the cell membrane by a magnetic tip, they activated Rho-GTPase and created a protrusion and subsequently an actin comet (Fig. 12.5). [36]

Fig. 12.5

TIAM–MNPs were magnetically localized into an inactive area, which created a protrusion and subsequently an actin comet. Scale bar is 1 µm. [36]

A microtubule is a major component of the cytoskeleton and is important in a number of cellular processes including maintaining the cell structure. The polymerization of microtubules is controlled by cell-signaling pathways. Gueroui et al. showed that MNPs conjugated with key regulatory proteins can artificially control, in time and space, the Ran/RCC1 signaling pathway that regulates the cell cytoskeleton. In the presence of a magnetic field, MNPs coated with RanGTP proteins induce microtubule fibers to assemble into asymmetric arrays of polarized fibers in Xenopus laevis egg extracts. The orientation of the fibers is dictated by the direction of the magnetic force. When the researchers locally concentrated MNPs that were conjugated with the upstream guanine nucleotide exchange factor RCC1, the assembly of microtubule fibers could be induced over a greater range of distances

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Manipulation of cellular organelles

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than RanGTP–MNPs. [37] Another organelle that could be manipulated is lysosome. In cancer treatment, increasing the permeability of lysosomes can be an effective strategy to promote cell death. Rinaldi et al. utilized MNPs to target and induce the permeabilization of lysosomes under the action of an alternating magnetic field (AMF) (Fig. 12.6). They coated 14 nm iron oxide MNPs with carboxymethyl dextran and proteins that recognized the epidermal growth factor receptor (EGFR) overexpressed in cancer cell membranes. Functionalized MNPs rapidly concentrated inside the lysosomes upon the cell internalization. Under AMF, heat was generated around the MNPs, damaging the lysosome membrane. This observation suggests the possibility of remotely triggering lysosomal death pathways in cancer cells with MNPs. [38]

Fig. 12.6

Schematic diagram of lysosomal membrane permeabilization by MNPs with an

AMF: nontargeted MNPs were taken up by a nonspecific mechanism while targeted MNPs were taken up into endosomes and lysosomes due to receptor mediated endocytosis. When an AMF was applied, both types of MNPs dissipated heat. Targeted MNPs delivered heat specifically to endosomes/lysosomes, resulting in membrane permeabilization. [38]

Signaling endosomes are critical long-range communication links used by neurons in the central and peripheral nervous systems during development and regeneration. [42] Therefore, it is vital to study their localization and related functions in

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regulating neurite growth. To demonstrate this idea, Goldberg et al. activated tropomyosin-related kinase B (TrkB) signaling endosomes with MNP-based magnetic manipulation. [39] Specifically, they coated 50 nm MNPs with the anti-TrkB agonist antibody (fMNPs). The antibody facilitated the rapid MNP endocytosis into TrkB signaling endosomes. Purified retinal ganglion cells (RGCs), lacking neurites, were incubated overnight with either fMNPs or cMNPs (control MNPs, conjugated with IgG antibodies) and then plated on laminin-coated coverslips where they could extend new neurites (Figs. 12.7(a) and 12.7(b)). fMNPs and cMNPs were detected in

Fig. 12.7

FMNP signaling endosomes are transported into nascent RGC neurites, and a

focal magnetic force alters growth cone mobility and halts neurite growth. (a) FMNP puncta were robust in RGC somas (arrowheads) and co-localized with TrkB in most fMNP puncta (arrows); (b) cMNPs were also detected as puncta (arrowheads) in some RGC somas, but these puncta were less numerous and usually failed to co-localize with TrkB. Differential interference contrast (DIC) and fluorescent images of (c) an fMNP-loaded RGC demonstrated anterograde transport into nascent neurites (arrows) and growth cones (arrowhead); (d) a cMNP-loaded RGC did not migrate into either the neurite or growth cone. (Scale bars: 10 µm.) (e) In control RGCs, a constant 15-pN force failed to alter either growth cone motility or neurite growth rate. This growth cone extended new lamella and filopodia, and the neurite continued to grow at ∼50 µm/h throughout the recorded time period. (f) In fMNP-loaded RGCs, a 15-pN force applied for 3 min was sufficient to immobilize both lamellar and filopodial protrusions in the peripheral domain and halt neurite growth. Time in minutes (0) is indicated. The electromagnet tip is indicated by black arrows. (Scale bars: 5 µm.) [39]

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337

95% and 7% of RGC somas, and 80% and 0% of RGC neurites and growth cones, respectively (Figs. 12.7(c) and 12.7(d)). To alter the transportation of fMNP signaling endosomes, defined magnetic forces were applied to fMNP-loaded RGCs via an electromagnetic needle. A 15-pN magnetic force was applied to cMNP- or fMNPloaded RGCs. Figures 12.7(e) and 12.7(f) show that a continuous magnetic force failed to alter the growth cone motility or neurite growth in cMNP-loaded RGCs, while it was sufficient to halt the neurite growth without retraction in fMNP-loaded RGCs. So manipulating MNP-signaling endosomes by a focal magnetic field can alter the growth cone motility and halt the neurite growth in neurons of both the peripheral and central nervous systems. The last, but not the least, type of cellular organelles to be manipulated is mitochondria, which have both vital and lethal functions in several physiological and pathological processes. [43] Besides generating most of the cell’s energy, mitochondria are also involved in signaling, cellular differentiation, cell death and growth. Cha et al. labeled mitochondria with MNPs and applied an external magnetic field, which led to reduced cell viability. The MNPs were 50 nm single domain Fe3 O4 and labeled with cytochrome c-specific binding aptamers. [40]

12.5

Separation and detection of bacteria and virus

Pathogen detection (e.g., bacteria, viruses) is another exciting application of magnetic manipulation. Currently, the identification of microbial pathogens relies upon the conventional clinical microbiology monitoring approaches. The standard culture and susceptibility tests permit pathogen identification but are laborious, time-consuming, and expensive, and require labile natural products. [44] The conventional techniques also do not lend themselves well to managing large numbers of environmental or clinical samples. To quickly determine the presence of a pathogen for the benefit of society, researchers and clinicians need tools that are cheap and quick, but still reliable and accurate. One solution is to utilize MNPs for the labeling, isolation, and analysis of pathogens. This strategy is easy and cheap, and allows the enrichment of the pathogen from samples for sensitive detection at ultralow concentrations without tedious procedures. [45] One representative example is the isolation and detection of Gram-positive bacteria. It is well known that an antibiotic, vancomycin (Van), specifically binds the terminal peptide (D-Ala-D-Ala) on the cell wall of Gram-positive bacteria. [46, 47] Therefore, the combination of Van with MNPs allows the recognition and isolation of Gram-positive bacteria with magnetic separation. To achieve this, FePt MNPs were functionalized with Van molecules through the surface ligand exchange with

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bis(vancomycin) cystamide. Each as-prepared FePt–Van MNP contained 8 to 9 Van molecules. [45] Then the FePt–Van MNPs were mixed with a sample containing bacteria for about 10 min before being isolated with a magnet. As illustrated in Fig. 12.8(a), bacteria and FePt–Van MNPs formed aggregates after being separated from the solution with a magnet. The significant size difference allowed the researchers to distinguish the bacteria from the aggregates with a scanning electron microscope (SEM). As shown in Fig. 12.8(b), there was a uniform binding of FePt–Van MNPs onto the surface membranes of the Gram-positive bacteria such as E. faecium (VanA), but few particles could be found on the surfaces of Gramnegative bacteria such as E. coli. With this technology, the researchers could detect low counts of bacteria in human blood in cases where the PCR based detection could be inaccurate. Given that SEM is impractical in clinical settings, fluorescent markers could be grafted onto MNPs for the sensitive detection of pathogens with optical modalities. [48] Besides SEM and fluorescence, other analytical techniques can be coupled with biofunctional MNPs for bacteria detection. For example, Chen et al. reported combining biofunctional MNPs with matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), a useful tool for the characterization of microorganisms.[49−51]

Fig. 12.8

FePt–Van MNPs for bacteria capturing: (a) illustration of the capture of

bacteria by FePt–Van MNPs; TEM images of bacteria captured (b) E. faecium (VanA), (c) E. coli. [15, 45]

Besides the usual spheroid MNPs, core-shell MNPs are also suitable. For example, in the case of Ag@Fe2 O3 yolk-shell MNPs, the magnetic Fe2 O3 shell could be functionalized with glucose molecules as anchors for bacteria attachment. Simultaneously, the porous Fe2 O3 shell facilitates the release of Ag ions and/or Ag NPs, which act as broad-spectrum antibacterial agents. In a bacteria-elimination experiment with drinking water, Ag@Fe2 O3 -Glucose MNPs not only captured bacteria as precipitates, but also inhibited bacterial growth in both supernatant and precipitates. [52] Another example was magnetite@silica core/shell MNPs, which were

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Separation and detection of bacteria and virus

339

coated with anti-septic polyhexamethylene biguanide that bound lipid A of G+ bacteria. [53, 54] All the technologies discussed so far include similar procedures, including anchoring MNPs to the bacterial surface, magnetic separation with a magnet, and analyzing samples with imaging technologies. Although basically simpler than the traditional technologies for bacterial separation and detection, further analysis with additional imaging technologies is still needed to identify and quantify the captured bacteria. Weissleder and Lee minimized this requirement by developing a magnetoDNA probe capable of rapid and specific profiling of pathogens directly in clinical samples. As illustrated in Fig. 12.9, the magneto-DNA assay is based on a sandwich hybridization technique wherein two oligonucleotide probes are bound to each end of the target nucleic acid. First of all, the total RNA is extracted from a specimen, and then target regions within the 16S rRNA are amplified by asymmetric reverse transcription-PCR (RT-PCR) to produce a large quantity of single-strand DNA with only sense (or antisense) sequences. The resultant DNA is then captured by polymeric microspheres conjugated with probe oligonucleotides (the bead capture probe). Subsequently, the overhanging edges of the target DNA are hybridized with MNP-detection probe conjugates (the MNP–detection probe). These magnetically labeled beads shorten the transverse relaxation rate (R2 ) of a sample, which is detected by a miniaturized µNMR device. This method was proved to be robust and rapid in simultaneously diagnosing a panel of 13 bacterial species in clinical specimens within 2 h. [55] Lowery et al. also developed a nucleic acid-based bacterial detection platform. They first mechanically lysed Candida cells, and selectively amplified the released DNA by the PCR technique. MNPs with complementary “capture probes” could then bind to the amplified DNA. By then, the free MNPs

Fig. 12.9

The magneto-DNA assay for the detection of bacterial 16S rRNA: total RNA

is extracted from the specimen, and the 16S rRNA is amplified by asymmetric RT-PCR. Single-strand DNA of the amplified product is then captured by beads conjugated to capture probes, before hybridizing with MNPs to form a magnetic sandwich complex. Samples are subsequently analyzed using a µNMR system. [55]

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had clustered together and allowed the detection of bacteria with the T2 magnetic resonance platform (T2MR). With this technology, the researchers successfully identified 8 candidemic patients from 24 patients by whole-blood sample analysis. [56] Viral infections have threatened public health for a long time and have severely impacted socio-economic development. Traditional diagnostic and therapeutic methods are not enough to control the viral contagions that have been realized by numerous pandemics. MNPs have also shown their potential as active antimicrobial agents the isolation, detection, and clinical diagnosis of viral infections. By coupling MNPs with oligonucleotides or charged polymers, target nucleic acids are captured by sequence hybridization or charge interaction. Then, DNA or RNA can be separated from lysed biological mixture in an external magnetic field without centrifugation. Real time RT-PCR usually follows to detect virus nucleic acids after MNPs based isolation[57] . This can simplify the procedure and equipment for virus nucleic acids extraction and thus benefit the developing countries during infectious disease pandemics. For example, Chac´on-Torres et. al. developed a simple way to synthesize coated MNPs with the charged polymer layer for SARS-CoV-2 RNA extraction[58] . This low-cost and high-quality RNA extraction method is expected to be scalably implemented into real time RT-PCR detection, which supports developing countries to improve the detection efficiency of the SARS-CoV-2 virus. Furthermore, DNA sensors based on electrochemical reactions, optical techniques, and fluorescence signals are considered as the onsite detection method to identify viral nuclei acid[59] . Antibodies or specific binding proteins can also be used to detect nuclei acid hydroazidation between coated MNPs and viral DNA/RNA towards to viral proteins are usually conjugated to MNPs to isolate virus by specific binding. The isolated viral particles could be identified by protein electrophoresis, mass spectrometric analysis, enzyme-linked immunosorbent assay (ELISA), and electrochemical reaction[60] . Ganganboina et. al. encapsulated optically active quantum dots into hollow MNPs to prepare the dual-modality virus probe with electrochemical and fluorescent signals[61] . Antibodies were conjugated on the hollow MNPs surface to capture virus by antibody-antigen reaction, and the captured virus were separated by the magnetic force. Then, the antibody-conjugated electrode was used to detect the separated virus bound to MNPs with an electrical signal output. The unbound MNPs were further measured to visualize the fluorescence signals. In addition, physical methods including localized surface plasmon resonance and surfaceenhanced Raman spectroscopy are also used to detect the captured virus on the surface of MNPs. However, such methods are ideal to be applied for gold and silver based MNPs.

12.6

12.6

Manipulation of cells

341

Manipulation of cells

Magnetic labeling of living cells creates opportunities for numerous biomedical applications, from individual cell manipulation to MRI tracking. While non-specific labeling of various types of cells with MNPs has been reported, it is more important to achieve specific binding. [62] MNPs are versatile to be functionalized with biomolecules to selectively target specific cells such as tumor cells, progenitor cells, or stem cells. For example, the specific binding of MNPs to stem cells enables the visualization and manipulation of their biodistribution. [63] In 2000, Weissleder et al. reported in vivo tracking and recovery of progenitor cells using TAT peptide-derivative MNPs. [64] This technology was based on 5 nm MNPs stabilized by a 20 nm thick crosslinked aminated dextran coating. Asprepared 45 nm MNPs were derivatized with an average of four HIV-1 TAT peptides covalently attached to the dextran coating. In addition, the dextran coating was labeled with 111 In for concomitant nuclear imaging. The final MNPs were fluorescent, magnetic, and radioactive. The multi-functional MNPs were efficiently internalized into hematopoietic and neural progenitor cells in quantities up to 10–30 pg of iron per cell. The iron incorporation did not affect the viability, differentiation, or proliferation of the cells. After intravenous injection with immune-deficient mice, 4% of MNP-labeled cells were found by MRI to home to bone marrows. Finally, those magnetically labeled cells in the bone marrow could be recovered by magnetic separation columns. The localization and retrieval of cell populations revealed in this technology enables a detailed analysis of specific stem cell and organ interactions that is critical for advancing the therapeutic use of stem cells. Perez et al. investigated the role of MNP valency in the nondestructive magneticrelaxation-mediated detection and magnetic isolation of cells in complex media, such as tumor cells in blood and bacteria in milk. [65] They conjugated a small molecule, folic acid, at two different densities (low-folate and high-folate) on polyacrylic-acidcoated iron oxide MNPs for labeling cancer cells expressing the folate receptors. They found that the multivalent high-folate MNPs performed better than the lowfolate MNPs with higher sensitivity, faster detection kinetics, and more efficient magnetic isolation of cancer cells. The multivalent high-folate MNPs allowed the detection of a single cancer cell in a blood sample within 15 min. Besides the pre-labeling of cells with MNPs in vitro, as discussed above, cells can also be labeled in vivo. As shown in Fig. 12.10, Zharov et al. developed a method to capture circulating tumor cells (CTCs) in the bloodstream of mice by means of MNPs. [66] Specifically, MNPs (Fig. 12.(b)) were functionalized with the amino-terminal fragment of the urokinase plasminogen activator (uPA) that could

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specifically bind to receptors highly expressed on many types of cancer cells. Once systematically administered, MNPs recognized and bound CTCs, which could be concentrated in a blood vessel near the skin with a magnet. To allow the detection of the concentrated CTCs, the researchers introduced a second component, gold carbon nanotubes, as contrast agents for photoacoustic imaging (Fig. 12.10(c)). The occurrence of natural CTCs and the MNP targeting in vivo were demonstrated by intravenously injecting unlabelled CTCs followed by the injection of a cocktail containing the gold carbon nanotubes and MNPs. Flash photoacoustic signals gradually increased within 8–10 min after the injection of the MNPs (red curve in Fig. 12.10(d)), exhibiting a good match with the photoacoustic signals observed from the cells labeled in vitro (green curve in Fig. 12.10(d)).

Fig. 12.10

Capturing CTCs with MNPs and photoacoustic detection: (a) schematic

illustration of the magnetic enrichment of CTCs and the subsequent two-color photoacoustic detection; (b) structure (left) and TEM image (right) of MNPs; scale bar is 10 nm; (c) structure (left) and topographic atomic force microscopy image (right) of a gold carbon nanotube; (d) photoacoustic monitoring of CTCs in the abdominal vessel using fiber-based photoacoustic flow cytometry. The graph shows the clearance of cells labeled with the MNP cocktail in vitro before injection (green curve with filled circles) and those labeled with the MNP cocktail in vivo after sequential injections of unlabelled cells alone and then MNPs alone (red curve with open circles). [66]

Beyond the simple isolation and enrichment of interesting cells, the magnetic manipulation of cells could also help tissue engineering. An exciting example is threedimensional (3D) cell culture technology that uses magnetic forces to levitate cells

12.6

Manipulation of cells

343

while they divide and grow. [67] Compared with cell cultures grown on flat surfaces, 3D cell cultures tend to form tissues that more closely resemble those inside the body. As shown in Fig. 12.11, hydrogel encapsulating MNPs and filamentous bacteriophage is levitated in a medium by placing a coin-sized magnet atop the dish’s lid. More interestingly, through spatially controlling the magnetic field, the geometry of the cell mass can be manipulated and multicellular clustering of different cell types in co-culture can be achieved (bottom images of Fig. 12.11). [67]

Fig. 12.11

3D cell culture with magnetic levitation: (top row) stages of the general cell

levitation strategy; (bottom row) the corresponding optical micrograph of neural stem cells at each stage. Scale bar is 30 mm. [67]

Honda et al. took one step further and developed a novel tissue engineering strategy wherein a magnetic force was used to construct 3D tissue without scaffolds (Fig. 12.12). Briefly, human mesenchymal stem cells (MSCs) were labeled with magnetite cationic liposomes (MCLs) before being seeded onto an ultra-low attachment culture surface. By placing a magnet (4000 G) on the reverse side, MSCs formed multilayered sheet-like structures after a 24-h culture period. More interestingly, the sheets preserved the ability to differentiate into osteoblasts, adipocytes, or chondrocytes after a 21-day culture period using an induction medium. They proved the potential applicability of this technology by harvesting and transplanting the MSC sheets into bone defects in nude rats with successful bone regeneration. [68]

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Using Magnetic Nanoparticles to Manipulate Biological Objects

Schematic illustration of the procedure for MSC sheet construction: (a)

MCLs structure and the labeling process of MSCs with MCLs; (b) construction of MSC sheet with magnetic manipulation. [68]

12.7

Manipulation of organs

Finally, through manipulating the cellular organelles and cells, we can even control the functions of organs. Pralle et al. reported a novel approach based on radiofrequency (RF) magnetic-field heating of MNPs to remotely activate temperaturesensitive cation channels in cells, including neurons. [69] They adapted the approach to remotely trigger the behavioral responses of Caenorhabditis elegans worms. Fluorescence was used throughout their experiments as a nanometer-scale thermometer, showing that the heat was generated locally to the membrane without cytoplasmic heating. Specifically, 6 nm manganese ferrite (MnFe2 O4 ) MNPs conjugated with streptavidin were targeted to human embryonic kidney cells (HEK 293) expressing TRPV1 and TN-XL via the biotinylated AP-CEP-TM membrane protein. Within 15 s of applying the RF magnetic field (40 MHz, 8.4 G), they detected an increase of the cytosolic calcium concentration from about 100 nM to 1.6 µM. The increase was attributed to a calcium influx through TRPV1 channels which could be thermally activated at around 42 ◦ C. [70] In control experiments, cells with MNPs but without TRPV1 channels and cells with TRPV1 channels but without MNPs showed no calcium influx upon the application of the same RF magnetic field. Furthermore, using the MNP-labeled hippocampal neurons that express TRPV1, researchers demonstrated remotely stimulating neurons without cellular damage. For remotely

12.8

Magnetic micro-/nanorobots to interact with multi- scale biological objects

345

triggering a behavioral response in the Caenorhabditis elegans worms, all sensory neurons in the amphid region were targeted by the PEG-phospholipid coated MNPs. As in Fig. 12.13, while a RF magnetic field was applied, within 5 s, fluorescence indicated a local temperature of 34 ◦ C; the worms halted their forward locomotion, and soon afterwards reversed; just like encountering a heated probe.

Fig. 12.13

Remote stimulation of thermal avoidance response in C. elegans.

Fluorescence image sequence of the head region of a C. elegans worm labeled with fluorescein-PEG-coated MNPs and anaesthetized with sodium azide. [69]

12.8

Magnetic micro-/nanorobots to interact with multi- scale biological objects

In recent years, magnetic micro- and nanoparticles (MMPs and MNPs) start to be employed as micro-/nanorobots to interact with biological objects at vastly different size scales. Comparing with the aforementioned research efforts in previous sections, these robots are independent, versatile, multi-functional, and usually general purpose. Thus, they are often regarded as robots or the end-effectors of robotic systems, instead of just functional particles. The investigations of MMPs and MNPs towards this direction spurs the emergence of a new research field of small-scale magnetic robotics, which has grown to a full-fledged field of a diverse range of ongoing topics. This subsection reviews some representative studies of using MMPs or MNPs as robots for biomedical applications. One of the seminal pioneering studies was reported by Dreyfus et al. in 2005[71] . In this study, a linear chain of superparamagnetic 1-µm-diameter colloids was formed via DNA links and a red blood cell was attached to one end. An oscillating external uniform magnetic field induced a beating pattern of the chain that propelled the

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structure, mimicking the locomotion of eukaryotic cells with flagella. In 2019, Wang et al. presented a magnetic tweezer system that manipulate a 0.7-µm-diameter magnetic bead inside a single cell for intracellular physical measurement in different locations (spatial) and different time points (temporal), see Fig. 12.14(a)[72] . In the same year, Yu et al. reported the active generation and magnetic actuation of a swarm of 100-nm-diameter MNPs in bio-fluids[73] . Ex vivo experiments showed successful swarm generation and navigation in bovine eyeballs, see Fig. 12.14(b).

Fig. 12.14

Exemplar studies of micro-/nanorobot with microscopic magnetic particles to

interact with biological objects. (a) A magnetic bead was introduced into a single cell via endocytosis and moved to cell nucleus for spatial measurement of nuclear mechanics polarity[72] . (b) A swarm of MNPs was generated ex vivo in a bovine eyeball and controlled to move around under the guidance of ultrasound[73] . (c) Schematic of the dip-coating process of S. platensis in a suspension of Fe3O4 nanoparticles. The bottom row shows the magnetized S. platensis (MSP) subject to 6-/24-/72-hour dip-coating treatment[78] . (d) SEM image of macrophage interacting with a stealth microrobot[74] .

Besides being directly deployed, these tiny particles are also integrated into slightly larger robotic devices via embedding into a matrix[74,75] or surface trea-

References

347

tment[76,77] to interact with biological substances. One representative example is the family of artificial bacterial flagella (ABFs), which refer to helical micro-/nanorobots with integrated magnetic particles that convert body rotation into translational movement. Not only can ABFs navigate within human body to interact with different biological objects, but also they can carry functional components such as drugs and DNAs for targeted therapy. In 2017, Yan et al. reported a multifunctional biohybrid magnetite microrobot for imaging-guided therapy[78] . Fe3O4 nanoparticles were coated on the surface of Spirulina platensis (a microalgae subspecies that features helical shapes) to form biohybrid robots, which were selectively cytotoxic to cancer cells, see Fig. 12.14(c). In 2020, Cabanach et al. reported 3D-printed nonimmunogenic stealth microrobots with 50-nm-diameter iron oxide MNPs embedded inside their bodies[74] . Avoiding detection by macrophage cells, these robots could perform tasks inside human body for an extended period of time, see Fig. 12.14(d). Besides ABFs, other forms of small-scale magnetic robots with MMPs and MNPs have also been studied. In 2015, Breger et al. reported a thermo-magnetically responsive soft microgrippers with iron oxide nanoparticles embedded into its porous hydrogel layer. The microgripper excised fibroblast murine cells within its grasp. In 2021, Wang et al. reported a biohybrid microrobot made of a stem cell and polydopamine (PDA)-coated magnetic iron particles. This soft and resilient robot has high biocompatibility, can interface with the human body, and adapt to the complex surroundings while navigating inside the body[76] . In the same year, Nguyen et al. reported a magnetically guided self-rolled microrobot for targeted drug delivery[77] . The surface of the robot was coated using PDA to covalently link amine-functionalized MNPs. When deployed as robots, MMPs and MNPs exhibit versatility and can interact with various biological objects at multiple size-scales. Thus, this research field is quickly gaining momentum in recent years. It has also found applications in a large variety of fields besides the biomedical applications discussed here.

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[6] Xu C and Sun S 2007 Polym. Int. 56 821 [7] Zeng H and Sun S 2008 Adv. Funct. Mater. 18 391 [8] Frey N A, Peng S, Cheng K and Sun S 2009 Chem. Soc. Rev. 38 2532 [9] Hao R, Xing R, Xu Z, Hou Y, Gao S and Sun S 2010 Adv. Mater. 22 2729 [10] Ho D, Sun X and Sun S 2011 Acc. Chem. Res. 44 875 [11] Young C L, Britton Z T and Robinson A S 2012 Biotechnol. J. 7 620 [12] Franzreb M, Siemann-Herzberg M, Hobley T and Thomas O T 2006 Appl. Microbiol. Biotechnol. 70 505 [13] Milne J 2011 Protein Chromatography (New York: Humana Press) p. 73 [14] Jain P, Baker G L and Bruening M L 2009 Annu. Rev. Anal. Chem. 2 387 [15] Gu H, Xu K, Xu C and Xu B 2006 Chem. Commun. 0 941 [16] Xu C, Xu K, Gu H, Zhong X, Guo Z, Zheng R, Zhang X and Xu B 2004 J. Am. Chem. Soc. 126 3392 [17] Xu C, Xu K, Gu H, Zheng R, Liu H, Zhang X, Guo Z and Xu B 2004 J. Am. Chem. Soc. 126 9938 [18] Fang W, Chen X and Zheng N 2010 J. Mater. Chem. 20 8624 [19] Xu F, Geiger J H, Baker G L and Bruening M L 2011 Langmuir 27 3106 [20] Kim J, Piao Y, Lee N, Park Y I, Lee I H, Lee J H, Paik S R and Hyeon T 2010 Adv. Mater. 22 57 [21] Cho E J, Jung S, Lee K, Lee H J, Nam K C and Bae H J 2010 Chem. Commun. 46 6557 [22] Pan Y, Long M J C, Li X, Shi J, Hedstrom L and Xu B 2011 Chem. Sci. 2 945 [23] Zhou L, Wu J, Zhang H, Kang Y, Guo J, Zhang C, Yuan J and Xing X 2012 J. Mater. Chem. 22 6813 [24] Tanaka T and Matsunaga T 2000 Anal. Chem. 72 3518 [25] Nichkova M, Dosev D, Gee S J, Hammock B D and Kennedy I M 2007 Anal. Biochem. 369 34 [26] Al-Dosari M and Gao X 2009 The AAPS Journal 11 671 [27] Scherer F A n M, Schillinger U, Henke J, Bergemann C, Kru¨ uger A, G¨ ansbacher B and Plank C 2001 Gene. Ther. 9 102 [28] Dobson J 2006 Gene. Ther. 13 283 [29] Pan X, Guan J, Yoo J W, Epstein A J, Lee L J and Lee R J 2008 Int. J. Pharm. 358 263 [30] Kievit F M, Veiseh O, Bhattarai N, Fang C, Gunn J W, Lee D, Ellenbogen R G, Olson J M and Zhang M 2009 Adv. Funct. Mater. 19 2244

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[69] Jat, S.K., Gandhi, H.A., Bhattacharya, J. and Sharma, M.K., 2021. Magnetic nanoparticles: An emerging nano-based tool to fight against viral infections. Materials Advances, 2021, 2sa 4479-4496. [70] Ganganboina, A.B., Chowdhury, A.D., Khoris, I.M., Doong, R.A., Li, T.C., Hara, T., Abe, F., Suzuki, T. and Park, E.Y., Hollow magnetic-fluorescent nanoparticles for dual-modality virus detection. Biosensors and Bioelectronics, 2020, 170, 112680. [71] R. Dreyfus, J. Baudry, M. Roper, M. Fermigier, H. Stone, and J. Bibette, “Microscopic artificial swimmers,” Nature, vol. 437, pp. 862-865, 2005. [72] X. Wang et al., “Intracellular manipulation and measurement with multipole magnetic tweezers,” Sci. Robot., vol. 4, no. 28, 2019, doi: 10.1126/scirobotics.aav6180. [73] J. Yu, D. Jin, K. F. Chan, Q. Wang, K. Yuan, and L. Zhang, “Active generation and magnetic actuation of microrobotic swarms in bio-fluids,” Nat. Commun., vol. 10, no. 1, pp. 1-12, 2019, doi: 10.1038/s41467-019-13576-6. [74] P. Cabanach et al., “Zwitterionic 3D-Printed Non-Immunogenic Stealth Microrobots,” Adv. Mater., vol. 32, no. 42, pp. 1-11, 2020, doi: 10.1002/adma.202003013. [75] J. C. Breger et al., “Self-folding thermo-magnetically responsive soft microgrippers,” ACS Appl. Mater. Interfaces, vol. 7, no. 5, pp. 3398-3405, 2015. [76] B. Wang et al., “Endoscopy-assisted magnetic navigation of biohybrid soft microrobots with rapid endoluminal delivery and imaging,” Sci. Robot., vol. 6, no. 52, p. eabd2813, 2021, doi: 10.1126/scirobotics.abd2813. [77] K. T. Nguyen et al., “A Magnetically Guided Self-Rolled Microrobot for Targeted Drug Delivery, Real-Time X-Ray Imaging, and Microrobot Retrieval,” Adv. Healthc. Mater., vol. 10, no. 6, pp. 1-14, 2021, doi: 10.1002/adhm.202001681. [78] X. Yan et al., “Multifunctional biohybrid magnetite microrobots for imaging-guided therapy,” Sci. Robot., vol. 2, no. 12, p. eaaq1155, 2017.

Chapter 13 Toxicity of Superparamagnetic Iron Oxide Nanoparticles: Research Strategies and Implications for Nanomedicine∗ Lei Lia) , Lingling Jianga) , Yun Zengb)† , and Gang Liua)† a)

Center for Molecular Imaging and Translational Medicine, School of Pub-

lic Health, Xiamen University, Xiamen 361102, China b)

Department of pharmacology, Xiamen Medical College, Xiamen, 361008,

China. † Corresponding author. E-mail: [email protected]; zengyun163@ 163.com Superparamagnetic iron oxide nanoparticles (SPIONs) are one of the most versatile and safe nanoparticles in a wide variety of biomedical applications. In the past decades, considerable efforts have been made to investigate the potential adverse biological effects and safety issues associated with SPIONs, which is essential for the development of next-generation SPIONs and for continued progress in translational research. In this mini review, we summarize recent developments in toxicity studies on SPIONs, focusing on the relationship between the physicochemical properties of SPIONs and their induced toxic biological responses for a better toxicological understanding of SPIONs. ∗ Project supported by the Major State Basic Research Development Program of China (Grant Nos. 2017YFA0205201 and 2018YFA0107301), the National Natural Science Foundation of China (Grant Nos. 81801817, 81422023, U1705281, and U1505221), the Key Project of Chinese Ministry of Education (Grant No. 212149), and the Fundamental Research Funds for the Central Universities, China (Grant Nos. 20720160065 and 20720150141).

13.1

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Introduction

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Introduction

Nanotechnology is an emerging field with growing interest for its numerous applications ranging from information technologies to medicinal applications. [1] In 2008, the International Organization for Standardization (ISO) classified nanomaterials into three main groups, i.e., nanoparticles, nanoplates, and nanofibers. [2] A nanoparticle is defined as a material with all three external dimensions on a nanoscale (1 nm– 100 nm). The dramatic increase in the use of nanoparticles in research, industry, and medicine has raised many questions about the potential toxicity. [3] Among the most promising nanoparticles, superparamagnetic iron oxide nanoparticles (SPIONs) are the only magnetic nanoparticles that have been approved for clinical use to date. [4] SPIONs consist of magnetite (Fe3 O4 ) or maghemite (γ-Fe2 O3 ) cores coated with biocompatible organic/inorganic polymer. They show some unique properties such as superparamagnetism, high field irreversibility, high saturation field, and extra anisotropy contributions or shifted loops after field cooling. [5] Because of their versatile properties and biocompatibility, SPIONs have attracted a great deal of research interest and have been broadly used in bioscience and clinical research, including cell sorting; [6, 7] tissue repair;[8−10] targeted drug delivery;[11−14] contrast agents for magnetic resonance imaging (MRI); [15, 16] hyperthermia and magnetic field assisted radionuclide therapy.[17−21] The increasing applications of SPIONs are accompanied with many risks and concerns on their toxicological properties and long-term influence on human health,[22−24] since the nanoscale properties can potentially induce cytotoxicity by impairing the functions of mitochondria, nucleus and DNA.[3,25−27] In the past decades, considerable efforts have been made to investigate the potential adverse biological effects and safety issues associated with SPIONs.[28−33] Those nanotoxicity studies in this area lead to the required information to make responsible regulatory decisions for future nanomedicines. The aim of this minireview is to summarize the current toxicity studies on SPIONs and explore the relationship between the physicochemical properties of SPIONs and their induced toxic biological responses.

13.2

Mechanism of toxicity

To date, much attention has been paid to the biocompatibility of SPIONs in the human body. Many studies have demonstrated that at doses of 100 µg/mL or higher, SPIONs with varying physicochemical characteristics may cause low toxicity or cytotoxicity (Fig. 13.1). As is well known, excessive reactive oxygen species (ROS), including free radicals such as the superoxide anion, hydroxyl radicals and the

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non-radical hydrogen peroxide, contribute to most intracellular and in vivo toxicities from SPIONs. [3, 34, 35] Because of their unique physicochemical properties, SPIONs present a large surface area for the generation of free radicals as a result of redox cycling at the particle surface. The ROS can also be generated from the leaching of iron ions from the surface degradation by enzymatic degradation. Subsequently, the ROS are transferred to the interior of the cell where they can produce oxidative stress by activating transcription factors for pro-inflammatory mediators.[36−39]

Fig. 13.1

Mechanism of cytotoxicity induced by SPIONs.

Furthermore, ROS can react with macromolecules and damage cells by peroxidizing lipids, changing proteins, disrupting DNA, interfering with signaling functions, and modulating gene transcription and finally causing cell death either by apoptosis or necrosis. It was found that alterations of intracellular signaling and preinflammatory response induced by SPIONs are correlated with the toxicity profiles of SPIONs. For example, cytosolic calcium is a key intracellular signaling molecule that controls a variety of cellular processes, [40] where ROS and oxidative stress resulting from SPIONs can modulate intracellular calcium signaling to activate the transcription factor NFκB and production of the pro-inflammatory cytokine TNFα. [41, 42] and control inflammation. [43] Another mechanism by which SPIONs can induce toxicity is via iron overload, which has toxic implications as excessive accumulation of the SPIONs. Since SPIONs are required to be magnetically targeted to a particular tissue/organ in biomedical application, high concentration of iron would be localized in the targeted tissue/organ. [44] Subsequently, high levels of free Fe ions in the exposed tissue can

13.3

In vitro cytotoxicity

355

lead to an imbalance in its homeostasis and can cause aberrant cellular responses including cytotoxicity, oxidative stress, epigenetic events, inflammatory processes, and DNA damage,[26,45−47] which may initiate carcinogenesis or have a significant influence on future generations. [48] Furthermore, excess iron is associated with an increasing risk of cancer, particularly liver cancer. One of the important mechanisms is that iron, not only as a catalyst but also as a reactant, may contribute to free radical generation, which can promote the oxidation of proteins, peroxidation of membrane lipids, and modification of nucleic acids.[49−52] For example, Bhasin et al. [53] reported that spindle cell sarcoma and pleomorphic sarcoma were associated with iron-overload following intramuscular injections of SPIONs in rats.

13.3

In vitro cytotoxicity

The in vitro methods are extremely valuable for SPION safety assessments because they can produce specific and quantitative toxicity measurements rapidly and inexpensively without the use of animals. Nanoparticles often affect the metabolic activity of cells, membrane integrity of the cells, cell apoptosis, and proliferation. Therefore, the potential in vitro toxicity of SPIONs is initially determined as the viability of cells, cytotoxicity, oxidative stress, inflammatory reactions, and genotoxicity (Table 13.1). [54] Many assays have been widely used such as the lactate dehydrogenase (LDH) assay of cell membrane integrity, the 3-(4,5-dimethylthiazol2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for mitochondrial function, and immunochemistry biomarkers for apoptosis and necrosis (Fig. 13.2).

Fig. 13.2

In vitro nanotoxicity assays for SPIONs.

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In vitro cytotoxicity

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However, in vitro assays should be carried out with care since cells in culture do not experience the phase of pathogenic effects observed in vivo. SPIONs can also interact with the assay components, interfere with the readout and sometimes contribute to erroneous results. For examples, in the classical dye-based assays such as MTT, the results would be disturbed by SPIONs due to the absorption of dye or dye products and the effect of ROS induced by SPIONs on the activity of mitochondrial enzymes. Additionally, some inherent issues such as dose, time and interaction between cells and matrix should be considered as well while analyzing the results, since they can also contribute to invalid data. Furthermore, because of the great difference between two-dimensional (2D) cells and three-dimensional (3D) tissues, one should be careful to apply the cell culture results to 3D tissues. The 2D cell culture may not accurately reflect the actual toxicity of SPIONs in vivo as it can not adequately represent the functions of 3D tissues, which have extensive cell-to-cell and cell-to-matrix interactions and different transport conditions. The cytotoxicity of SPIONs was found to be highly dependent on a range of factors related to their physical properties, such as size, shape and surface coating. With the increase of particles’ size, the area of surface increases, which becomes more reactive toward surrounding biological components and affects the biocompatibility of nanoparticles. A shape dependent nanotoxicity has been observed in a series of studies on different nanoparticles. The observed particle shapes include spherical shape, nanoworms, rod-shape, or magnetic beads, each of which has its own contact area with the cells and thus causes the difference in biocompatibility from others. For example, rod-shape SPIONs have been found to be endocytosed more slowly than spherical SPIONs. [55] The type of surface-coating materials of SPIONs and their breakdown products are important to determine their toxicity. [56] Uncoated SPIONs have very low dispersibility that can lead to precipitation and a high rate of agglomeration under physiological conditions. Proper coating can not only stabilize SPIONs, but also prevent the dissolution and release of toxic ions. SPIONs are usually designed to be coated with an amphiphilic layer or bound to complex biological molecules such as antibodies, peptides, hormones or drugs. [57] The most common coatings are derivatives of dextran, polyethylene glycol (PEG), polyethylene oxide (PEO), poloxamers, and polyoxamines. [58] The cytotoxic potential of SPIONs with a range of surface coatings has been extensively investigated. For example, it was demonstrated that PEG-coated SPIONs produced negligible aggregation in cell culture media and reduced nonspecific uptake by macrophage cells. [21] However, Berry et al. [59] found that dextran-coated SPIONs could cause cell death and reduce proliferation simi-

13.4

In vivo toxicity of SPIONs

359

lar to that caused by uncoated SPIONs. In a further study, significant membrane disruptions were observed in cells treated with dextran-coated SPIONs, [60] which may be attributed to the interactions among albumin, membrane fatty acids and phospholipids. Cell culture medium is an important factor to influence the toxicity of SPIONs. Negatively charged uncoated SPIONs could bind to the serum proteins of cell culture medium and induce denaturation of proteins, which in turn can cause cytotoxicity. [61] Cell culture medium can also influence colloidal stability and cell interaction of SPIONs. Serum in the culture medium could induce agglomeration of the vinyl alcohol/vinyl amine copolymer-coated SPIONs and strongly inhibit cellular uptake of SPIONs. [62] Furthermore, proteins and other nutrients in cell culture medium may be adsorbed onto SPIONs and become unavailable for cellular activities, leading to the changes of cell growth and viability. Therefore, different medium recipes could influence the outcome of SPION cytotoxicity and optimal culture medium should be determined individually according to the type of SPIONs. [63, 64] The oxidation state of iron (Fe2+ or Fe3+ ) in SPIONs is an additional key factor that determines the cytotoxicity of SPIONs. [48] Fe3+ ions are much more potent in inducing DNA damage than Fe2+ . It has been demonstrated that maghemite (Fe2 O3 ) with an Fe2+ /Fe3+ ratio of 0.118 has a more significant genotoxicity than magnetite (Fe3 O4 ) with an Fe2+ /Fe3+ ratio of 0.435. Much more effort is required to design and prepare SPIONs with good chemical stability.

13.4

In vivo toxicity of SPIONs

In vitro assays to investigate the toxicity of SPIONs are simpler, faster, and more cost-effective without ethical problems. However, little correlation between in vivo and in vitro toxicity of SPIONs has been demonstrated. [65] Researchers have found that some toxic responses of cells observed for SPIONs in vitro [66] were not exactly reproduced in vivo. [67] This may be attributed to the homeostasis maintained by the liver and kidneys, which could efficiently regulate any changes in pH, ionic strength and chemical composition of the blood plasma in the body. Despite cost, time, and ethical considerations, in vivo tests in animal models are crucial for the study of SPION biological effect. In vivo assays have several priorities when studying the toxicity of SPIONs, such as determining the toxicokinetics in the body (i.e., absorption, distribution, metabolism, and elimination) and evaluating the immunological, neurological, reproductive, cardiovascular and developmental toxicities to determine the chronic systemic toxicity of SPIONs. [23]

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Therefore, in order to understand their activity and potential toxicity, it is necessary to conduct a systematic analysis of the pharmacokinetics of SPIONs, which can lead to improvements in the design of biocompatible SPIONs, a better understanding of SPION non-specificity toward tissues and cell types, and assessments of their basic distribution and clearance in the body. [68, 69] Generally, SPIONs are classified as biocompatible without severe toxic effects in vivo (Table 13.2). [70, 71] However, the toxicity of SPIONs can be considered to be dose-dependent. [72] For example, intravenously injected Ferumoxtran-10 (dextrancoated SPIONs) at a dose of 2.6 mg Fe/kg in rats produced no changes in hemodynamic parameters whereas 13 mg Fe/kg dose caused a noticeable increase in aortic blood flow, but without any treatment-related cardiovascular or respiratory toxicity. The treatment-related clinical signs were observed only at a very high single dose (e.g., 126 mg Fe/kg, a dose 45 times higher than that used in human as MRI contrast agents). Additionally, repeated intravenous injection (3 ∼ 5 times) at a dose of 17.9 mg Fe/kg in rats could lead to moderate changes in hematological parameters. Neurotoxicity study of ferumoxtran-10 showed some minor side effects on the central nervous system, including a lowered or increased spontaneous locomotor activity, rearing, exophthalmos, or mydriasis. [73] After injection of SPIONs, the serum iron level was noticeably increased. The chronic iron toxicity in humans may occur after administration of high doses of iron. It is noteworthy to mention that the biological fate of SPIONs is strongly dependent on the composition and quantity of associated proteins at the surface of SPIONs, [74] which are determined by the physicochemical properties of SPIONs including surface morphology, surface charge density, coating material, nanoparticle size, and size distribution. Additionally, tissue/cell type is another crucial factor to influence the toxic response of SPIONs. For example, Hanini et al. [70] reported that SPIONs in vivo could induce toxicity in the liver, kidneys, and lungs while the brain and heart organs remained unaffected.

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In vivo toxicity of SPIONs

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13.5

Blood compatibility

363

Blood compatibility

In terms of in vivo application of SPIONs, blood compatibility is an essential property. Should SPIONs be incompatible with bio-fluids such as blood, this could trigger coagulation and clot formation through adsorption of plasma proteins, platelet adhesion and activation of complement cascades. One of the primary screening tests on SPIONs toxicity is the haemolysis assay by using mammalian erythrocytes. The coagulation tendencies can be evaluated using widely available clinical assays including prothrombin time, activated clotting time, activated partial thromboplastin time and thrombin time, [23] which are useful in evaluating the intrinsic and extrinsic effects of SPIONs on the blood coagulation cascades. Intravenous injection (5 µM Fe/kg–40 µM Fe/kg) of Ferucarbotran, a clinically approved SPIONs coating with carboxydextran, was demonstrated to be safe except for a transient decrease in the specific clotting activity of blood coagulation Factor XI, which did not cause any clinically relevant adverse effects.

13.6

Biodistribution and elimination

The biodistribution of SPIONs used as an intravenous contrast agent for MRI is most widely studied. [58, 75] After intravenous administration, SPIONs are distributed to various organs and tissues such as colon, lungs, bone marrow, liver, spleen, and the lymphatics.[76,−78] The typical final biodistribution of SPIONs is 80%–90% in liver, 5%–8% in spleen and 1%–2% in bone marrow. [79, 80] The physicochemical characteristics of nanoparticles such as size, surface morphology and surface charge, could influence their tissue distributions. After cellular uptake, SPIONs commonly reside in endosomes/lysosomes where they decompose into free iron, which is slowly released to the cytoplasm and eventually contributes to the total cellular iron pool. The distribution of SPIONs is followed by rapid clearance from the systemic circulation, predominantly by action of the liver and spleen macrophages. [81] Generally, clearance and opsonization of SPIONs depend on their sizes and surface characteristics. [82, 83] Differential opsonization accounts for variations in clearance rates and macrophage sequestration of SPIONs. [83] For example, 55% oleic acid/ pluronic-coated SPIONs of injected dosage were accumulated in the liver of a rat. However, in the same animal model, 25% of injected dextran-coated SPIONs were eliminated via urine and feces. [84] Similarly, the distribution and elimination results obtained with ferumoxtran-10, a specific type of ultrasmall SPIONs coated with low molecular weight dextran, showed only ∼ 20% of the iron ions injected were eliminated after 2 months through urine and feces in different animal models. [85]

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More attention should be paid to the mapping of the fate, kinetics, clearance and metabolism of SPIONs with different surface coatings, which would allow the development of predictive models of nanotoxicity (Fig. 13.3). [86] SPIONs have many potential diverse applications and therefore there are a number of expected administration routes associated with the utilization of SPIONs. The distribution of SPIONs can be influenced by administration route. When being injected locally at the diseased site (e.g., tumor), SPIONs can undergo passive movement into the interstitial spaces around the administration site and gradually flow into lymphatic system. It was found that the inhaled SPIONs could cross the tight junctions/barriers such as the pulmonary epithelium, the blood-brain and blood-testis endothelium. Kwon et al. [87] reported that SPIONs administered by inhalation route to mice through the nose for 1 month, accumulated into the liver followed by testis, spleen, and brain. Intraperitoneally injected SPIONs were also distributed at high concentrations into the spleen and liver. Interestingly, SPIONs could cross the intact blood-brain barrier and were taken up by the neuronal cells. [28]

Fig. 13.3

Schematic overview of biodistribution, degradation, and clearance of PEGylated

SPIONs in the liver. The SPIONs suitable for clinical translation require the optimization of pharmacokinetic/pharmacodynamic (PK/PD) to match residence time with the imaging needs. Reproduced with permission. [86] Copyright 2012, American Chemical Society.

13.7

In silico assays for nanotoxicity

An in silico method is a kind of fast and cost efficient approach to predict the nanotoxicity through integrated computational systems accounting for multiple variables associated with the biological interactions, which can supplement or replace some expensive and time-consuming assays, especially in the early design process of new types of SPIONs. By using computer-aided simulation, Dames et al. [88]

13.8

Surface engineering for SPIONs-based nanomedicine

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observed that targeted aerosol delivery to the lung can be achieved with aerosol droplets comprising SPIONs in combination with a target-directed magnetic gradient field, which has been experienced in mice for the first time. Mathematical models were also developed by Sayes and Ivanov [89] to predict cellular membrane damage resulting from nanoparticles. Recently, Puzyn et al. [90] predicted the toxicity of 17 different metal oxide nanoparticles by using in silico assays. Such a method shows great potential for the future design of safe SPIONs. However, in silico assay requires well-defined biological, toxicological, or pharmacological endpoints observed with similar nanoparticles, while for newly engineered nanoparticles, few toxicological or pharmacological data are available. Furthermore, as far as the accuracy is concerned, the results from in silico methods cannot be expected to exceed the data used to construct the model. Therefore, it is essential to validate the results of the mathematical model by using in vivo evaluation.

13.8

Surface engineering for SPIONs-based nanomedicine

Appropriate chemical design of both the core and the shell of SPION is extremely important for medical applications since naked SPIONs are quite unstable and even form bulk aggregates in biological fluids (i.e., blood). Generally, “green chemistry” avoiding the use of toxic chemicals is strongly recommended to prepare SPIONs suitable for preclinical and clinical applications and has attracted many efforts toward this goal. Owing to the progress in synthesis and surface modification, many new or improved methods have been developed to load a wide range of functionalities onto SPION surfaces, which can enhance its biological compatibility for SPION-based nanomedicine. [21] Until now, a wide range of monomers, polymers, and inorganic biomaterials have been used for coating SPIONs, which provides a protective shell to stabilize SPION, avoid agglomeration and prevent the dissolution and release of toxic ions. The coating materials on SPIONs are required to be biocompatible and biodegradable to avoid immune response and nonspecific adsorption of serum proteins after the intravenous administration. Biodegradable polymers such as dextran and carbohydrate derivatives are traditionally used as coating biomaterials of SPIONs to accomplish multiple purposes including enhancing the colloidal stability, increasing the blood circulation time and improving the biocompatibility of nanoparticles. Taking Feridex (FDA approved SPIONs) as an example, the surface coating of dextran can angle with the growing SPIO nanocrystals, protecting them from overgrowing and aggregating. Although the marketed or clinical-trial SPIONs (i.e., Combidex, Feridex and Resovist) are all coated with dextran or its derivatives, other hydrophilic

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polymers such as polyaspartic acid were demonstrated to be able to substitute dextran for SPION surface engineering. Additionally, polyethylene glycol (PEG), one of the most important hydrophilic polymers approved by FDA, is hemocompatible, non-antigenic and non-immunogenic with less side effects, which allows its extensive application for coating SPIONs. Recently, high quality SPIO nanocrystals were synthesized in organic phase at higher temperatures for the better controlling of particle size and morphology. [91] However, these SPIO nanocrystals can be dispersed very well only in some organic solvents (i.e., chloroform, hexane, and tetrahydrofuran) with the coating of hydrophobic materials (i.e., oleic acid and oleylamine). Hence, it is quite necessary to transfer hydrophobic SPIO nanocrystals into a water phase with the help of amphiphilic biomaterials for certain biological application. To address such an issue, many surface engineering techniques have been developed, such as exchanging ligand and physical encapsulation, to increase the stability and biocompatibility of SPIONs. For example, we have tried to use ligands such as dopamine which has high affinity toward SPION surfaces. When being mixed, dopamine can cover the original coating oleic acid/oleylamine and lead to hydrophilicity. [21] Polymeric micelles have emerged as good carriers for hydrophobic SPIO nanocrystals. They can solubilize SPIO nanocrystals in their inner cores and offer attractive characteristics such as a generally nanoscale size (10 nm–100 nm) and a propensity to evade scavenging by the mononuclear phagocyte system. Recently, Alkylated polyethylenimine (PEI), a typical amphiphilic block copolymer, was demonstrated to be used to form multiple SPIO nanocrystals containing micelles in aqua phase for cell labeling and MRI. [14, 91] The polymer-encapsulated method is very flexible since it allows for the preparation of SPIONs carrying a wide variety of stabilizers. With the progress of surface engineering, there is a growing interest in developing SPIONs harboring various functions including cancer targeting, imaging, therapy, etc. Various kinds of antibodies, peptides and aptamers have been attached to SPIONs as targeting probes for specific biomarkers on target cells, providing a powerful route to the forming of multifunctional SPIONs for nanomedicine (Fig. 13.4). [21, 92] In general, a SPION surface engineered with targeting ligands has a large attractive force to bind the specific cells for targeted imaging/therapy. A typical experiment to test the SPIONs for their targeting effectiveness uses in vitro cultured cells that express unique biomarkers. Additionally, xenograft animal models are also widely used to evaluate SPIONs and explore basic pathophysiological mechanisms. However, it is noticeable that human tumors are often much more complex than the tumor xenografts in animal models, which could hinder the development of target-

13.8

Surface engineering for SPIONs-based nanomedicine

367

ing SPIONs.

Fig. 13.4

Schematic diagram of the proposed protection mechanism of SPIONs coated

with platelet endothelial cellular adhesion molecule-1antibodies (antiPECAM-1) and a targeted polymeric antioxidant (PTx). The antiPECAM-1/PTx SPIONs can bind to and internalize in endothelial cells and provide localized protection against the potential toxicity caused by SPIONs. Reproduced with permission. [92] Copyright 2013, Elsevier.

Surface charge plays a significant role in colloidal stability due to the behavior of the surface group in solution at a certain pH. Furthermore, the surface charge is one of the most important issues that affects the cell-nanoparticle interactions. [93] It can influence the cellular uptake efficiency of SPIONs, change organism/cellular responses to SPIONs and affect plasma protein binding, hence the organ distribution and clearance of SPIONs (Fig. 13.5). [33, 94] In general, surface functionalization with

Fig. 13.5

Schematic overview of biocompatibility in vitro, and long-term biodistribution

/clearance in vivo of SPIONs surface engineered with dimercaptosuccinic acid (DMSA). Negatively charged DMSA-SPIOs accumulating in liver tissues for extended periods of time could undergo a process of conversion from SPIOs to other non-SPIOs forms. The in vivo biotransformation confirms the promise of DMSA-coated SPIOs for clinical use. Reproduced with permission [94] Copyright 2013, Elsevier.

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a positively charged group could enhance the uptake of SPIONs into cells. However, cationic surfaces with excess iron cations may induce hemolysis and platelet aggregation, which may be due to the affinity of cationic SPIONs to the negative phospholipid head groups or protein domains on cellular membranes.

13.9

Conclusions and perspectives

Considering the wide preclinical and clinical applications of engineered SPIONs in the context of nanomedicine, it is crucial to understand the potential risks associated with exposure to SPIONs and the physiological effects produced by the surface coatings utilized for functionality. In this chapter, we first review the known mechanisms by which SPIONs can damage cells, including oxidative stress elicited by ROS. We provide a general discussion on the in vitro and in vivo toxicities of SPIONs while there are still a number of issues that need be clearly addressed prior to approving their clinical use. This field of nanotoxicity is important for the advancement of SPIONs in a wide range of applications. Studies in this field could lead to the required information to make responsible regulatory decisions for the development of next-generation SPIONs and for continued progress in translational research. Although SPIONs are the most preferable nanomaterials in medical sciences[95], their potential toxicity is still the major concern to prevent the adoption in clinical diagnosis and treatments. Some challenges need to be addressed including appropriate methods to assess the toxicity of novel SPIONs, such as generating gold standard and reference biomaterials for nanosafety testing, establishing ex vivo models for the specific routes of administration of nanomedicines, and developing in silico model approaches to predict the toxicological responses of SPIONs. As epigenetic changes may cause the reprogramming of gene expression long after the initial insult has been removed, epigenetic assessments should be tested early in the development of new SPIONs. Therefore, it is necessary to conduct multi-omics studies such as proteomics, genomics and metabolomics to evaluate the toxicity of SPIONs at precise levels in different cell lines and organisms[96]. More work should be done on the design of functionalized SPIONs, In recent studies, various agents have been used to functionalized by organic molecules and inorganic materials utilized in different biomedical fields [97]. More functionalized SPIONs with long-term stability should be developed, which can not only be effectively and sufficiently internalized and are appropriately magnetisable, but also meet the demands of a particular application at the expense of no cellular toxicity. As for the in vivo pharmacokinetic studies on SPIONs, detection strategies must be

REFERENCES

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capable of quantifying all of the major parts of SPIONs in tissues/organs since many multifunctional SPIONs are engineered with multiple components. Traditional radiolabeling of surface molecules coating on the SPIONs core is easily achieved, but the pharmacokinetic results might be misleading. In order to qualify the observed in vivo results, it is very important to understand how proteins interact with SPION surfaces, since this can potentially control the behavior of SPIONs in vivo. However, the studying of the toxicity aspects of SPIONs is lagged far behind their rapid development, and understanding the dynamic and complex interactions between SPIONs and biological systems is far from being complete. All of these factors give rise to conflicting results and slow down the development of this field. Recently, there are some well-established studies to present the possibilites of SPIONs in clinical practice such as MRI, drug delivery and magnetic hyperthemia[98]. However, before the full potential of SPIONs is further explored, much more work is urgently needed to clarify the better usage and safety limits of SPIONs to understand their performance and toxicity. In summary, the comprehensive characterization of SPIONs is often neglected prior to using them. It is crucial to encourage interdisciplinary research in the nanomedicine from the clinical, biological, engineering and toxicological point of view. Through the persistent efforts by multidisciplinary approaches, there is a great potential for further breakthrough developments in SPION designs for nanomedicine, which could solve the problem of “nanotoxicity” in the near future.

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Perspective Yanglong Houa)† , Jing Yub) , Song Gaoc) a)

Department of Materials Science and Engineering, College of Engineer-

ing, Peking University, Beijing 100871, China b)

College of Materials Science and Engineering, Zhejiang University of

Technology, Hangzhou, 310014, China c)

College of Chemistry and Molecular Engineering, Peking University, Bei-

jing 100871, China † Corresponding author. E-mail: [email protected].

With the development of fabrication nanotechnology, magnetic nanomaterials designed and synthesized recently got better performances. For example, relaxations in magnetic resonance imaging (MRI) by novel contrasts agents are multiple of that produced by traditional ones due to the enhancement in saturation magnetization (Ms ). As a result, newly developed magnetic nanomaterials such as iron carbide nanoparticles, a kind of intermetallic compound that consists of carbon atoms occupying the interstices between close-packed iron atoms, which possess much higher Ms value than iron oxide nanoparticles, can induce greater hypo-intensities on T2 weighted MRI.[1−3] These novel nanomaterials showed great promise in MRI-based diagnosis with higher sensitivity and accuracy in different organs such as liver, ovary and breast.[4−7] Specific absorption ratio (SAR) values in magnetic hyperthermia from magnetic nanomaterials with specific nanostructure such as heterostructure or nanorings can be significantly improved even to orders of magnitude higher than that of conventional MNPs,[8,9] promoting the therapeutic pros-pect of magnetic nanomaterials. However, balancing between the good suspension and improved SAR value remains a challenging obstacle for the development of magnetic nanomaterials in biomedicine. Neoteric magnetic nanomaterials such as nanorings have emerged as a potential

Perspective

377

solution to bridge the gap. These nanomaterials possess a unique ferrimagnetic vortex-domain structure, in which magnetization is circumferential to the ring without stray fields, endowing a negligible remanence and coercivity for good colloidal stability, while still having a much higher saturation magnetization, and being an efficient “nano heater” for magnetic hyperthermia in physiological environment.[10,11] Another hurdle for the clinical applications of magnetic nanomaterials in magnetic hyperthermia are the high magnetic field amplitudes needed to generate heat, which always reach beyond the tissue tolerance. Take Fe2.2 C nanoparticles for example, even though they exhibit an improved SAR value compared with Fe3 O4 nanoparticles, heat release at safe magnetic field (20 mT) was extremely low, as the anisotropy axis of the nanoparticles are being randomly oriented in space. Interestingly, it was found that by optimizing the construction of nanoparticles to form a core/shell structure (an iron core and the shell composed of iron carbide), the anisotropy of nanoparticles decreased, keeping this unique material still in the ferromagnetic regime at a reduced magnetic field. Therefore, an abrupt increase of SAR value was observed under a magnetic field of only 17 mT, which is 3 times improved compared to the best chemically synthesized nanoparticles, giving a bright promise of magnetic nanomaterials in clinically applied hyperthermia.[12] Integration of magnetic components with non-magnetic parts is another effective way to broaden the biomedical applications of magnetic nanomaterials. Firstly, it can increase the applicability of materials for multifunctionality such as multi-mode imaging and imaging-guided therapy, showing potential in early diagnosis and precision medicine. Among the various nanomaterials such as Fe3 O4 -carbon,[13,14] FePtAu[15,16] and FeCo-graphitic,[17] Fe3 O4 -Au heterostructures in the form of core/shell, dimer or Janus are the most widely applied ones.[18−21] In addition, the interaction between magnetic and non-magnetic regions can further enhance the performance in imaging and/or therapy. For example, the formation of both spiky Fe3 O4 -Au and Fe5 C2 -Au superparticles are proved beneficial for realizing a synergistic effect with better photothermal conversion efficiency.[22,23] Moreover, an interesting phenomenon was reported recently that the existence of non-magnetic components can even reduce the toxicity of magnetic nanomaterials deriving from preventing release of harmful elements.[24] All these factors are beneficial for applying complex but efficient magnetic nanomaterials in biomedicine which exhibit better properties and are flexibility, and bound to make more progress in the future. Deep understanding of magnetic nanomaterials physically and chemically promoted the discovery of new properties in materials, and some novel applications are exploited accordingly. Typically, magnetic particle imaging (MPI) is a new

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Perspective

tracer imaging modality that can perform background-free measurements of particles’ local concentration based on magnetic nanomaterials.[25,26] Compared with the traditional imaging method MRI, this new modality promises a higher sensitivity and better resolution both spatially and temporally. Although only a handful of small animal MPI scanners and contrast agents (iron oxide nanoparticles) have been currently constructed, there is significant interest in this novel imaging modality worldwide, and it has a high potential to improve interventional and image-guided surgical procedures.[27] Another example comes from the interaction of magnetic nanomaterials with alternating magnetic field, which is generally applied in magnetic hyperthermia for cancer therapy. However, the demand of high frequency in alternating field for heat generation limits the wide clinical application due to its influence on the human body.[28] Recently, some studies demonstrated that by reducing the frequency of alternating field, or by altering the magnetic field into a rotating one, almost no heat is generated, but still under which, part of magnetic nanomaterials can induce high cancer cell apoptosis and tumor inhibition, showing great promise in safer cancer therapy based on magnetic nanomaterials.[29−31] One of the main applications of the magnetic nanomaterials is feasible delivery of chemotherapeutic agents to targeted cells. Remarkably, magnetic targeting based on those magnetic carriers can be realized by positioning a gradient of the magnetic field around targeted site, resulting in higher delivery efficiency and lower biological toxicity. More interestingly, magnetic nanomaterials have been widely used as antigen carriers to effectively stimulate immune system and active T cells, leading to the killing of the cancer cells in recent years. In addition, macrophage activated cancer immunotherapy also can be initialed by magnetic nanomaterials. It is reported that iron oxide magnetic nanoparticles can motivate the inflammatory factor of macrophages and prompt the conversion of tumor-associated macrophages to proinflammatory M1-type macrophages which generate reactive oxygen species (ROS) and pro-inflammatory factors, resulting in apoptosis of cancer cells. Immunotherapy is the most promising cancer treatment strategy, thus, exploring and developing the relationship between magnetic nanomaterials and immunotherapy will become a research hotspot. Safety regulations and clinical translation are two essential factors that should be considered for bio-materials. Ensuring the safe use of these magnetic nanomaterials is the responsibility of public health worldwide. To improve the bio-compatibility of magnetic nanomaterials, bio-degradation of nanomaterials at a certain period is demanded. Despite the fact that inorganic magnetic materials need a longer time for bio-degradation compared with organic ones, most of these nanomaterials are

References

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able to be degraded or excreted.[32−35] In addition, apart from the initial inorganic magnetic core, the engineered surface coatings comprising of the ligand shell and the corona of adsorbed biological molecules also have long lasting impact on the material degradability and the kinetics of elimination.[36,37] Therefore, novel ligands that can be firmly conjugated on nanoparticles need to be developed, which should induce less immune stress, escape from the reticuloendothelial system and target to the diseased domain. Ethical issues about magnetic nanomaterials during clinical translation at present mainly involve risk assessment, communication and management, while questions such as social justice and access to health care may be raised in the future. In summary, science and technology in nanomaterials speed ahead, developments in fabrication methods, performances, applications and bio-safety of magnetic nanomaterials struggle to catch up. The interdisciplinary cooperation of nano-materials scientists, magnetists, chemists, physicists and biologists certainly will give a brighter future to magnetic nanomaterials.

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