NANOPLATFORM-BASED MOLECULAR IMAGING

NANOPLATFORM-BASED

MOLECULAR IMAGING

NANOPLATFORM-BASED

MOLECULAR IMAGING

Edited by

Xiaoyuan Chen

Laboratory of Molecular Imaging and Nanomedicine

National Institute of Biomedical Imaging and Bioengineering National Institutes of Health

Bethesda, Maryland

A JOHN WILEY & SONS, INC., PUBLICATION

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^C2011 by John Wiley & Sons, Inc. All rights reserved.

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Nanoplatform-based molecular imaging / edited by Xiaoyuan Chen.

p. ; cm.

Includes bibliographical references and index.

ISBN 978-0-470-52115-1

1. Molecular probes. 2. Diagnostic imaging. I. Chen, Xiaoyuan.

[DNLM: 1. Molecular Imaging–methods. 2. Molecular Imaging–trends. 3. Molecular Probes–diagnostic use. 4. Nanoparticles–diagnostic use. 5. Nanotechnology–trends. WN 180 N1865 2010]

QP519.9.M64N36 2010 616.07^54–dc22

2010007984 Printed in the United States of America

eBook ISBN: 978-0-470-76703-0 oBook ISBN: 978-0-470-76704-7

10 9 8 7 6 5 4 3 2 1

CONTENTS

Preface ix

Acknowledgments xi

Contributors xiii

PART I BASICS OF MOLECULAR IMAGING AND NANOBIOTECHNOLOGY

1. Basic Principles of Molecular Imaging 3

Sven H. Hausner

2. Synthesis of Nanomaterials as a Platform for Molecular Imaging 25 Jinhao Gao, Jin Xie, Bing Xu, and Xiaoyuan Chen

3. Nanoparticle Surface Modification and Bioconjugation 47 Jin Xie, Jinhao Gao, Mark Michalski, and Xiaoyuan Chen

4. Biodistribution and Pharmacokinetics of Nanoprobes 75 Nagesh Kolishetti, Frank Alexis, Eric M. Pridgen, and Omid C. Farokhzad

PART II NANOPARTICLES FOR SINGLE MODALITY MOLECULAR IMAGING

5. Computed Tomography as a Tool for Anatomical and Molecular Imaging 107 Pingyu Liu, Hu Zhou, and Lei Xing

6. Carbon Nanotube X-Ray for Dynamic Micro-CT Imaging of Small

Animal Models 139

Otto Zhou, Guohua Cao, Yueh Z. Lee, and Jianping Lu

7. Quantum Dots for In Vivo Molecular Imaging 159

Yun Xing

8. Biopolymer, Dendrimer, and Liposome Nanoplatforms for Optical

Molecular Imaging 183

David Pham, Ling Zhang, Bo Chen, and Ella Fung Jones

v

vi CONTENTS

9. Nanoplatforms for Raman Molecular Imaging in Biological Systems 197 Zhuang Liu

10. Single-Walled Carbon Nanotube Near-Infrared Fluorescent Sensors

for Biological Systems 217

Jingqing Zhang and Michael S. Strano

11. Microparticle- and Nanoparticle-Based Contrast-Enhanced

Ultrasound Imaging 233

Nirupama Deshpande and J¨urgen K. Willmann

12. Ultrasound-Based Molecular Imaging Using Nanoagents 263 Srivalleesha Mallidi, Mohammad Mehrmohammadi, Kimberly Homan, Bo Wang,

Min Qu, Timothy Larson, Konstantin Sokolov, and Stanislav Emelianov

13. MRI Contrast Agents Based on Inorganic Nanoparticles 279 Hyon Bin Na and Taeghwan Hyeon

14. Cellular Magnetic Labeling with Iron Oxide Nanoparticles 309 S´ebastien Boutry, Sophie Laurent, Luce Vander Elst, and Robert N. Muller

15. Nanoparticles Containing Rare Earth Ions: A Tunable Tool for MRI 333 C. Rivi`ere, S. Roux, R. Bazzi, J.-L. Bridot, C. Billotey, P. Perriat, and O. Tillement

16. Microfabricated Multispectral MRI Contrast Agents 375 Gary Zabow and Alan Koretsky

17. Radiolabeled Nanoplatforms: Imaging Hot Bullets Hitting Their Target 399 Raffaella Rossin

PART III NANOPARTICLE PLATFORMS AS MULTIMODALITY IMAGING AND THERAPY AGENTS

18. Lipoprotein-Based Nanoplatforms for Cancer Molecular Imaging 433 Ian R. Corbin, Kenneth Ng, and Gang Zheng

19. Protein Cages as Multimode Imaging Agents 463

Masaki Uchida, Lars Liepold, Mark Young, and Trevor Douglas

20. Biomedical Applications of Single-Walled Carbon Nanotubes 481 Weibo Cai, Ting Gao, and Hao Hong

21. Multifunctional Nanoparticles for Multimodal Molecular Imaging 529 Yanglong Hou and Rui Hao

22. Multifunctional Nanoparticles for Cancer Theragnosis 541 Seulki Lee, Ick Chan Kwon, and Kwangmeyung Kim

CONTENTS vii

23. Nanoparticles for Combined Cancer Imaging and Therapy 565 Vaishali Bagalkot, Mi Kyung Yu, and Sangyong Jon

24. Multimodal Imaging and Therapy with Magnetofluorescent Nanoparticles 593 Jason R. McCarthy and Ralph Weissleder

25. Gold Nanocages: A Multifunctional Platform for Molecular Optical

Imaging and Photothermal Treatment 615

Leslie Au, Claire M. Cobley, Jingyi Chen, and Younan Xia

26. Theranostic Applications of Gold Nanoparticles in Cancer 639 Parmeswaran Diagaradjane, Pranshu Mohindra, and Sunil Krishnan

27. Gold Nanorods as Theranostic Agents 659

Alexander Wei, Qingshan Wei, and Alexei P. Leonov

28. Theranostic Applications of Gold Core–Shell Structured Nanoparticles 683 Wei Lu, Marites P. Melancon, and Chun Li

29. Magnetic Nanoparticle Carrier for Targeted Drug Delivery:

Perspective, Outlook, and Design 709

R. D. K. Misra

30. Perfluorocarbon Nanoparticles: A Multidimensional Platform for

Targeted Image-Guided Drug Delivery 725

Gregory M. Lanza, Shelton D. Caruthers, Anne H. Schmieder, Patrick M. Winter, Tillmann Cyrus, and Samuel A. Wickline

31. Radioimmunonanoparticles for Cancer Imaging and Therapy 755 Arutselvan Natarajan

PART IV TRANSLATIONAL NANOMEDICINE

32. Current Status and Future Prospects for Nanoparticle-Based Technology

in Human Medicine 783

Nuria Sanvicens, F´atima Fern´andez, J.-Pablo Salvador, and M.-Pilar Marco

Index 815

PREFACE

This book focuses on the rational design of water-soluble, biocompatible nanoparticles for the visualization of the cellular function and follow-up of the molecular processes in living organisms without perturbing them. Molecular imaging probes based on nanotechnology hold great potential in diagnosis, imaging guided intervention, and treatment response mon- itoring of diseases. This book is logically organized by including the basics of molecular imaging, general strategies of particle synthesis and surface chemistry, applications in com- puted tomography (CT), optical imaging, magnetic resonance imaging (MRI), ultrasound, multimodality imaging, and theranostics, and finally clinical perspectives of nanoimaging.

This comprehensive title provides expert opinions on the latest developments in molecular imaging using nanoparticles. This book consists of 32 chapters and was contributed by nearly 100 authors worldwide, who are among the world’s prominent scientists in material science and/or molecular imaging.

Part I consists of Chapters 1–4 Chapter 1 describes the basic principles of molecular imaging, how nanoparticles can be applied to different molecular imaging modalities, and challenges in developing nanoparticle-based molecular imaging probes; Chapter 2 high- lights the general strategies to produce narrowly dispersed nanomaterials for molecular imaging; Chapter 3 emphasizes the importance of surface modification to render nanopar- ticles biocompatible and suitable for molecular imaging applications; and Chapter 4 talks about the toxicity and factors such as size, shape, coating, and surface charge that affect the biodistribution and pharmacokinetics of nanoprobes.

Part II consists of Chapters 5–17 Chapter 5 illustrates the basic principles of CT, the evolution of CT imaging technology, and the rationale for nanoparticle-based CT contrast agents; Chapter 6 describes the advantages of fascinating carbon nanotube field emission X-ray technology over conventional thermionic X-ray tubes that are used in current X-ray imaging systems; Chapter 7 describes the use of unique optical properties of semiconductor quantum dots (QDs) for near-infrared fluorescence imaging in living animals; Chapter 8 in- troduces macromolecular nanoconstructs such as biopolymers, dendrimers, and liposomes as carriers for fluorophore conjugation and optical imaging; Chapter 9 summarizes recent progress in developing nanoplatforms for Raman imaging of biological systems; Chapter 10 summarizes the work in using single-walled carbon nanotubes (SWNTs) as near-infrared fluorescent sensors for biomolecule detection; Chapter 11 describes the use of micro- and nanoparticles as ultrasound contrast agents; Chapter 12 proposes the use of metal nanopar- ticles in ultrasound-based photoacoustic and magnetoacoustic imaging modalities; Chapter 13 reports the progress on magnetic resonance imaging (MRI) contrast agents based on inorganic nanoparticles; Chapter 14 emphasizes the use of iron oxide nanoparticles for cellular labeling followed by T₂- and T^∗₂-weighted MRI; Chapter 15 covers the use of rare earth based nanoparticles for MR imaging as positive contrast agents; Chapter 16 reviews the top–down microfabrication technology to synthesize multispectral MRI contrast agents;

ix

x PREFACE

and Chapter 17 gives an overview of the strategies to label nanoparticles with radionuclides to study in vivo distribution.

Part III consists of Chapters 18–31 Chapter 18 introduces techniques to incorporate imaging agents into lipoproteins and to reroute lipoproteins to cancer specific epitopes;

Chapter 19 exemplifies the use of protein cages such as virus capsids and ferritins as platforms for MRI contrast agents and fluorescent imaging agents; Chapter 20 provides a comprehensive summary of the state-of-the-art of SWNTs for multimodality biomedical imaging applications; Chapter 21 reviews the progress in the controlled synthesis, surface modification, and multimodality imaging applications of multifunctional nanoparticles in recent years; Chapter 22 argues the use of cancer theranostics as a promising new strategy in cancer management, permitting simultaneous cancer diagnosis, drug delivery, and real-time monitoring of therapeutic efficacy; Chapter 23 provides more examples of multifunctional nanoparticles for combined cancer imaging and therapy (theranostics); Chapter 24 describes the recent progress in modifying magnetic nanoparticles for multimodality imaging as well as targeted treatment of a number of diseases; Chapter 25 introduces gold nanocages as contrast agents for optical bioimaging (such as optical and spectroscopic coherence tomog- raphy amd photoacoustic tomography) and photothermal treatment; Chapter 26 describes the biological inertness, ease of manufacture and bioconjugation, and presumed lack of toxicity of gold nanoparticles for simultaneous sensing, imaging, and treatment of tumors;

Chapter 27 presents the recent developments in the chemistry and photophysics of gold nanorods and their applications toward biological imaging and photothertmally activated therapies; Chapter 28 describes a number of gold core–shell nanostructures for cancer molecular optical imaging, controlled drug delivery, and photothermal ablation therapy;

Chapter 29 describes a novel temperature and pH-responsive magnetic nanocarrier that combines tumor targeting and controlled drug release capabilities; Chapter 30 deals with perfluorocarbon nanoparticles as a multidimensional platform for targeted image-guided drug delivery; and Chapter 31 describes the use of radiolabeled nanoparticles and radiola- beled immunonanoparticles for imaging and therapy.

Part IV is the concluding Chapter 32 that highlights some of the nanoparticle-based novel technologies for molecular imaging, diagnosis, and drug delivery formulations. The limitations and future challenges of nanoparticle-based systems are also discussed.

Xiaoyuan Chen Bethesda, Maryland

ACKNOWLEDGMENTS

The editor thanks the nearly 100 authors throughout the world for their contributions and collaboration on this book project. The editing work of this book was accomplished using a significant amount of the editor’s spare time including family time. Therefore the editor also thanks his wife, Michelle Ji, and his daughter, Grace Chen, for their wonderful support and understanding.

xi

CONTRIBUTORS

Frank Alexis, Department of Bioengineering, Clemson University, Clemson, South Car- olina, USA

Leslie Au, Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA

Vaishali Bagalkot, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, South Korea

R. Bazzi, Laboratoire Physico-Chimie des Electrolytes, Colloides et Sciences Analytiques, Universit´e Pierre et Marie Curie, Paris, France

C. Billotey, Laboratoire CREATIS–Animage, Universit´e Claude Bernard, Lyon, France S´ebastien Boutry, Department of General, Organic and Biomedical Chemistry, NMR and

Molecular Imaging Laboratory, University of Mons, Mons, Belgium

J.-L. Bridot, Service de Chimie G´en´erale, Organique et Biom´edicale, Laboratoire de RMN et d’Imagerie Mol´eculaire, Universit´e de Mons-Hainaut, Mons, Belgium

Weibo Cai, Departments of Radiology and Medical Physics, School of Medicine and Public Health, University of Wisconsin–Madison, and University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA

Guohua Cao, Department of Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Shelton D. Caruthers, Department of Medicine, Washington University Medical School, St. Louis, Missouri, and Philips Healthcare, Andover, Massachusetts, USA

Bo Chen, Center for Molecular and Functional Imaging, Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA

Jingyi Chen, Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA

Xiaoyuan Chen, Molecular Imaging Program at Stanford and Bio-X Program, Depart- ment of Radiology, Stanford University School of Medicine, Stanford, California, and Laboratory for Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA Claire M. Cobley, Department of Biomedical Engineering, Washington University, St.

Louis, Missouri, USA

xiii

xiv CONTRIBUTORS

Ian R. Corbin, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, and Division of Biophysics and Bioimaging, Ontario Cancer Institute, Toronto, Ontario, Canada

Tillmann Cyrus, Department of Medicine, Washington University Medical School, St.

Louis, Missouri, USA

Nirupama Deshpande, Department of Radiology and Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, California, USA

Parmeswaran Diagaradjane, Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Trevor Douglas, Department of Chemistry and Biochemistry and Department of Plant Science, Center for Bio-inspired Nanomaterials, Montana State University, Bozeman, Montana, USA

Luce Vander Elst, Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Mons, Belgium

Stanislav Emelianov, Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, USA

Omid C. Farokhzad, Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

F´atima Fern´andez, Applied Molecular Receptors Group, CIBER de Bioingenier´ıa, Biomateriales y Nanotecnolog´ıa, IQAC-CSIC, Barcelona, Spain

Jinhao Gao, Molecular Imaging Program at Stanford and Bio-X Program, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA Ting Gao, Tyco Electronics Corporation, Menlo Park, California, USA

Rui Hao, Department of Advanced Materials and Nanotechnology, College of Engineer- ing, Peking University, Beijing, China

Sven H. Hausner, Department of Biomedical Engineering, University of California–

Davis, Davis, California, USA

Kimberly Homan, Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, USA

Hao Hong, Departments of Radiology and Medical Physics, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, Wisconsin, USA

Yanglong Hou, Department of Advanced Materials and Nanotechnology, College of En- gineering, Peking University, Beijing, China

Taeghwan Hyeon, National Creative Research Initiative Center for Oxide Nanocrystalline Materials, and School of Chemical and Biological Engineering, Seoul National Univer- sity, Seoul, South Korea

Sangyong Jon, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, South Korea

CONTRIBUTORS xv

Ella Fung Jones, Center for Molecular and Functional Imaging, Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA Kwangmeyung Kim, Biomedical Research Center, Korea Institute of Science and Tech-

nology, Seoul, South Korea

Nagesh Kolishetti, Department of Anesthesiology, Brigham and Women’s Hospital, Har- vard Medical School, Boston, Massachusetts, USA

Alan Koretsky, Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA

Sunil Krishnan, Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Ick Chan Kwon, Biomedical Research Center, Korea Institute of Science and Technology, Seoul, South Korea

Gregory M. Lanza, Department of Medicine, Washington University Medical School, St.

Louis, Missouri, USA

Timothy Larson, Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, USA

Sophie Laurent, Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Mons, Belgium

Seulki Lee, Biomedical Research Center, Korea Institute of Science and Technology, Seoul, South Korea

Yueh Z. Lee, Department of Physics and Astronomy and Department of Radiology, Uni- versity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Alexei P. Leonov, Department of Chemistry, Purdue University, West Lafayette, Indiana, USA

Chun Li, Department of Experimental Diagnostic Imaging, University of Texas M.D.

Anderson Cancer, Houston, Texas, USA

Lars Liepold, Department of Chemistry and Biochemistry and Department of Plant Sciences, Center for Bio-Inspired Nanomaterials, Montana State University, Bozeman, Montana, USA

Pingyu Liu, Palo Alto Unified School District, Palo Alto, California, USA

Zhuang Liu, Institute of Functional Nano & Soft Materials, Soochow University, Suzhou, Jiangsu, China

Jianping Lu, Department of Physics and Astronomy, Curriculum in Applied Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Wei Lu, Department of Experimental Diagnostic Imaging, University of Texas M. D.

Anderson Cancer Center, Houston, Texas, USA

xvi CONTRIBUTORS

Srivalleesha Mallidi, Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, USA

M.-Pilar Marco, Applied Molecular Receptors Group, CIBER de Bioingenier´ıa, Biomateriales y Nanotecnolog´ıa, IQAC-CSIC, Barcelona, Spain

Jason R. McCarthy, Center for Molecular Imaging Research, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA

Mohammad Mehrmohammadi, Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, USA

Marites P. Melancon, Department of Experimental Diagnostic Imaging, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

Mark Michalski, Molecular Imaging Program at Stanford and Bio-X Program, Depart- ment of Radiology, Stanford University School of Medicine, Stanford, California, USA R. D. K. Misra, Center for Structural and Functional Materials, University of Louisiana

at Lafayette, Lafayette, Louisiana, USA

Pranshu Mohindra, Department of Radiation Oncology, University of Texas M.D. An- derson Cancer Center, Houston, Texas, USA

Robert N. Muller, Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons, Mons, Belgium

Hyon Bin Na, National Creative Research Initiative Center for Oxide Nanocrystalline Ma- terials, and School of Chemical and Biological Engineering, Seoul National University, Seoul, South Korea

Arutselvan Natarajan, Department of Radiology and Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, California, USA

Kenneth Ng, Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada

P. Perriat, Groupe d’Etudes de M´etallurgie Physique et de Physique des Mat´eriaox, Uni- versit´e Claude Bernard, Lyon, France

David Pham, Center for Molecular and Functional Imaging, Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA Eric M. Pridgen, Department of Chemical Engineering, Massachusetts Institute of Tech-

nology, Cambridge, Massachusetts, USA

Min Qu, Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, USA

C. Rivi`ere, Laboratoire de Physique de la Mati`ere Condens´ee et Nanostructures, Universit´e de Lyon, Lyon, France

Raffaella Rossin, Department of Biomolecular Engineering, Philips Research Europe, Eindhoven, The Netherlands

S. Roux, Laboratoire de Physico-Chimie des Mat´eriaux Luminescents, Universit´e de Lyon, Lyon, France

CONTRIBUTORS xvii

J.-Pablo Salvador, Applied Molecular Receptors Group, CIBER de Bioingenier´ıa, Biomateriales y Nanotecnolog´ıa, IQAC-CSIC, Barcelona, Spain

Nuria Sanvicens, Applied Molecular Receptors Group, CIBER de Bioingenier´ıa, Biomateriales y Nanotecnolog´ıa, IQAC-CSIC, Barcelona, Spain

Anne H. Schmieder, Department of Medicine, Washington University Medical School, St. Louis, Missouri, USA

Konstantin Sokolov, Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, and Department of Medical Physics, University of Texas M.D.

Anderson Cancer Center, Houston, Texas, USA

Michael Strano, Department of Chemical Engineering, Massachusetts Institute of Tech- nology, Cambridge, Massachusetts, USA

O. Tillement, Laboratoire de Physico-Chimie des Mat´eriaux Luminescents, Universit´e de Lyon, Lyon, France

Masaki Uchida, Department of Chemistry and Biochemistry and Department of Plant Science, Center for Bio-Inspired Nanomaterials, Montana State University, Bozeman, Montana, USA

Bo Wang, Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, USA

Alexander Wei, Department of Chemistry, Purdue University, West Lafayette, Indiana, USA

Qingshan Wei, Department of Chemistry, Purdue University, West Lafayette, Indiana, USA

Ralph Weissleder, Center for Molecular Imaging Research, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts, USA

Samuel A. Wickline, Department of Medicine, Washington University Medical School, St. Louis, Missouri, USA

Jurgen K. Willmann, Department of Radiology and Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, California, USA

Patrick M. Winter, Department of Medicine, Washington University Medical School, St.

Louis, Missouri, USA

Younan Xia, Department of Biomedical Engineering, Washington University, St. Louis, Missouri, USA

Jin Xie, Molecular Imaging Program at Stanford and Bio-X Program, Department of Radiology, Stanford University School of Medicine, Stanford, California, and Lab- oratory for Molecular Imaging and Nanomedicine, National Institute of Biomedi- cal Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA

Lei Xing, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California, USA

xviii CONTRIBUTORS

Yun Xing, Department of Material Science and Engineering, University of Dayton, Day- ton, Ohio, USA

Bing Xu, Department of Chemistry, Brandeis University, Waltham, Massachusetts, USA Mark Young, Department of Chemistry and Biochemistry and Department of Plant Sci-

ence, Center for Bio-Inspired Nanomaterials, Montana State University, Bozeman, Mon- tana, USA

Mi Kyung Yu, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, South Korea

Gary Zabow, Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA

Jingqing Zhang, Department of Chemical Engineering, Massachusetts Institute of Tech- nology, Cambridge, Massachusetts, USA

Ling Zhang, Center for Molecular and Functional Imaging, Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA

Gang Zheng, Department of Medical Biophysics and Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, and Division of Bio- physics and Bioimaging, Ontario Cancer Institute, Toronto, Ontario, Canada

Hu Zhou, Community Cancer Center of Roseburg, Roseburg, Oregon, USA

Otto Zhou, Department of Physics and Astronomy, Curriculum in Applied Sciences and Engineering, and Lineberger Comprehensive Cancer Center, University of North Car- olina at Chapel Hill, Chapel Hill, North Carolina, USA

PART I

BASICS OF MOLECULAR IMAGING

AND NANOBIOTECHNOLOGY

CHAPTER 1

Basic Principles of Molecular Imaging

SVEN H. HAUSNER

Department of Biomedical Engineering, University of California–Davis, Davis, California, USA

1.1 INTRODUCTION

The ability to identify diseased tissue for detection and treatment remains a central goal for medical research. Several noninvasive or minimally invasive diagnostic modalities have been developed which allow one to obtain anatomical, physiological, and molecular infor- mation. “Molecular imaging” can be defined as in situ visualization, characterization, and measurement of biological processes in the living organism at the molecular or cellular level. Diagnosis and visualization at the molecular level, that is, detection of a disease in its infancy, may significantly improve treatment and patient care. By combining two or more imaging modalities, each with its different strengths, high-quality complementary (e.g., molecular and anatomical) information can be obtained and analyzed in the context of each other. This has led to the rise of dual- and multimodality imaging approaches. Depending on the modality, imaging probes or contrast agents are required or highly desirable; they can range in size from single atoms to cell-sized constructs. Nanoparticles, that is, entities with dimensions in the range of several tens of nanometers, can display desirable pharmacoki- netic properties and permit the combination of different clinically relevant moieties (e.g., targeting groups, molecular beacons, and contrast agents for different modalities, surface coatings, enclosed payload) in a single unit. The inclusion of a therapeutic component yields “theranostics.” Taken together, nanotechnology-based molecular probes offer the promise for tailor-made clinical tools required for “personalized medicine.” This chapter provides an introductory overview of molecular imaging, major imaging modalities, and imaging probes, with particular focus on the promises and challenges of nanoparticle-based compounds.

1.2 IMAGING IN MEDICINE

Most areas of clinical practice require identification and localization of diseased tis- sue for detection and treatment. Ideally, reliable, specific, and noninvasive high-contrast

Nanoplatform-Based Molecular Imaging Edited by Xiaoyuan Chen Copyright
^C 2011 John Wiley & Sons, Inc.

3

4 BASIC PRINCIPLES OF MOLECULAR IMAGING

whole-body evaluations would allow physicians to detect serious abnormalities before pa- tients present with symptoms, thus permitting early intervention, thereby increasing the chance for cure or, at a minimum, allow for better patient management and improved qual- ity of life. Given these incentives, it is clear that practical (i.e., minimally inconvenient for the patient) and affordable (i.e., overall cost-saving to the health care system and society) diagnostic approaches are highly desirable. Ever since Wilhelm R¨ontgen’s first use in 1895 of the then newly discovered X-rays to noninvasively image the interior of the body, the keen interest in medical imaging has been met by increasingly sophisticated technologies (Fig. 1.1). While R¨ontgen’s X-ray image was a grainy two-dimensional anatomical projec- tion, physicians nowadays have access to tomographic (three-dimensional) imaging modal- ities with, depending on the technique, submillimeter resolution, which allows visualization of anatomical, physiological, and, increasingly, molecular (cellular) biological information.

Since diseases often arise from changes on the molecular and cellular levels, long before manifesting themselves in detectable large-scale physiological or anatomical changes, molecular imaging is gaining increasing attention. If a disease can be diagnosed and visual- ized at the molecular level, that is, detected in its infancy, it can be treated at a much earlier stage, the treatment’s efficacy can be determined much sooner and, if necessary, the treat- ment plan can be adjusted accordingly. This benefits the individual patient and society as a

FIGURE 1.1 (Left) Wilhelm R¨ontgen’s (1845–1923) first X-ray image, depicting the hand of his wife, Anna, taken on 22 December 1895. (Right) A slice of a modern whole-body multimodality positron emission tomography/computed tomography (PET/CT) scan showing glucose metabolism within the body, including a large, metabolically active tumor (arrow). (PET/CT image courtesy of Dr. Cameron Foster and Dr. Ramsey Badawi, UC Davis Medical Center, Davis, California.)

IMAGING IN MEDICINE 5

whole. Molecular biology is discovering a growing number of disease-specific cellular tar- gets and is determining their distribution in patient populations [1]. For certain diseases this has already had significant effects on determining beforehand which patients will benefit from a certain treatment (“patient stratification”). A prime example is testing for the expres- sion of HER2/neu in breast cancer for prognosis, as well as for selection and monitoring of treatment: expression has been linked to aggressiveness of the disease, but it also provides a target for highly effective treatment with antibodies (Trastuzumab, Herceptin^®) [2, 3].

Similarly, monitoring glucose metabolism with the imaging agent¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) has proved itself to be the preferred approach for staging, restaging, and evaluation of response to treatment for several cancers [4]. Concurrently with the advances in molecular biology, engineers and physicists are developing increasingly sophisticated imaging instrumentation capable of localizing imaging agents in the body at high sensitivity and high resolution in short acquisition time [5]. By bridging the clinical and engineering worlds, research in imaging agents plays a central role. To that end, the development of target-specific (and disease-specific) nanoparticle-based molecular probes draws on research in several fields including biology, molecular biology, medicine, chemistry, and biomedical engineering.

1.2.1 Molecular Imaging

Rather than relying only on intrinsic large-scale differences of tissue characteristics (e.g., density) or passive accumulation of administered probes to reveal disease in vivo, molecular imaging strives to make use of disease-specific (“targeted”) interactions of imaging probes with the target tissue on a molecular and a cellular level. The goal is the real-time in situ visualization of biological processes in the living organism. This focus is also reflected in the Society of Nuclear Medicine’s definition of molecular imaging as “an array of non-invasive, diagnostic imaging technologies that can create images of both physical and functional aspects of the living body. It can provide information that would otherwise require surgery or other invasive procedures to obtain. Molecular imaging differs from microscopy, which can also produce images at the molecular level, in that microscopy is used on samples of tissue that have been removed from the body, not on tissues still within a living organism. It differs from X-rays and other radiological techniques in that molecular imaging primarily provides information about biological processes (function) while [computed tomography] CT, X-rays, [magnetic resonance imaging] MRI and ultrasound, image physical structure (anatomy)” [6].

As stated above, the information obtained is linked to which imaging modality is chosen.

Individual imaging modalities can be grouped by the energy spectrum and energy type evaluated (X-ray, photons, sound; positrons), the resolution that can be achieved, and the type of information obtained (anatomical, physiological, cellular/molecular) (Table 1.1).

Widely used clinical imaging modalities include magnetic resonance imaging, ultrasound (US), computed tomography, as well as positron emission tomography (PET) and single photon emission computed tomography (SPECT). All of these modalities allow for the noninvasive imaging of living subjects. Although the first three imaging modalities are primarily anatomical and not molecular, the two types of modalities can be combined for dual- or multimodality imaging. In addition, MRI, US, and CT can be used with molecular imaging probes, especially as part of nanoplatforms. In addition, a number of more specialized optical modalities are being used or are under investigation, including endoscopic methods [12].

TABLE1.1WidelyUsedImagingModalities ImagingModalityaTypebBasisforDetection Sensitivity (Concentrationof Imaging Probe/Contrast Agent)ResolutionDepthQuantitative Modality

TypicalScan Acquisition TimeOther Opticalimaging (fluorescenceand bioluminescence)

M,PFluorescence:External excitationlight absorbedby fluorochromeof imagingprobeand reemittedatlonger wavelength. Bioluminescence: Chemiluminescence ofenzymatic reaction.

Aslowas∼10−15 mole/L∼1to∼10mmCentimeters(Yes,limited quantification possible)

Secondsto minutesPreclinical;limited clinicaltranslation (closetoskinor requiringendoscopic approaches) Lowcost. Depthlimitationbasedon wavelength-dependent absorptionbytissue. Resolutionisdepth dependent. Two-dimensional (surface)image. Positronemission tomography (PET)

M,P511-keVPhotons generatedduring annihilationof positronemittedby radioactiveisotope ofimagingprobe.

∼10−11–10−12 mole/L1–2mm (preclinical) 4–8mm (clinical) NolimitYesMinutesto tensof minutes

Clinicalandpreclinical. Highcost. Versatileimagingprobe chemistry. Singlephoton emission computed tomography (SPECT)

M,PPhotonemittedby radioactiveisotope ofimagingprobe.

∼10−11mole/L[7]0.5–2mm (preclinical) 10–15mm (clinical) NolimitYesMinutesto tensof minutes

Clinicalandpreclinical. Highcost. Versatileimagingprobe chemistry. Possibilitytodistinguish differentradioisotopes basedonphotonenergy.

6

Magneticresonance imaging(MRI)A,P(M)Interactionofexternal magneticfieldand radiofrequencies withatomicnuclear spins(oftissueor contrastagent) dependingon environmentof nuclei.

10−3–10−4mole/L<100␮m (preclinical) <1mm (clinical)[9]

NolimitYesMinutesto hourClinicalandpreclinical. Highcost. Longscanacquisition time. Excellentsofttissue contrast. Ultrasoundimaging (US)A,P(M)Echoesoftissue(or imagingprobe) generatedby high-frequency (∼1–40MHz) soundwaves propagatingthrough tissue.

High(single microbubbles— volume∼0.004 pL—canbe detected)[8]

Lessthan ∼50␮m (preclinical) <500␮m (clinical)[9]

Upto ∼25cm [10]

YesSecondsto minutesClinicalandpreclinical. Lowcost. Frequencyused determinesresolution and(inversely) penetrationdepth. Targetedimaginglimited tovasculature. Highoperator dependency. Computed tomography(CT)A,PAbsorptionoffocused externalX-raysby tissue(orcontrast agent).

Low(gramamounts ofcontrastagent required)

<10␮m (preclinical)NolimitYesMinutesClinicalandpreclinical. Excellentboneandlung contrast. Poorsoft-tissuecontrast. aPrimarymolecularimagingmodalitiesarelistedinbold. bA,anatomical;M,molecular/cellular;P,physiological. Source:AdaptedfromWillmann[11]andWeissleder[12].

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8 BASIC PRINCIPLES OF MOLECULAR IMAGING

Regardless of the imaging modality chosen, quantifiable high-resolution images and reasonable acquisition times are highly desired, and if modalities are combined they should yield relevant additional (e.g., anatomical plus molecular) information. Molecular imaging per se is complementary to primarily anatomical imaging (Table 1.1). This is the motivation behind the ongoing push toward dual-/multimodality imaging where molecular imaging data are collected at the same time as anatomical imaging data (Fig. 1.1). This synergistic approach, in which superimposed tomographic images are analyzed, allows the physician interpretation of the molecular imaging data within the anatomical context. The tremendous benefits of this diagnostic approach have also been recognized by the manufacturers of clinical imaging equipment. This has led to the rapid spread of integrated hybrid PET/CT and SPECT/CT scanners in recent years. Dual-modality scanners are now becoming the norm rather than the exception in the clinic [5, 13]. Similarly, hybrid PET/MR scanners are now becoming available; they are eagerly awaited for tasks where the molecular imaging data have to be interpreted in the context of soft tissue, such as, for example, within the brain. Engineering and technical challenges are largely the reason that the availability of hybrid-MR systems has been lagging behind their CT counterparts [14, 15].

The instrumentation for the various modalities has also been adapted for preclinical applications [16]. By using mice, rats, nonhuman primates, or other animal models, spe- cialized small animal scanners allow dedicated imaging in a preclinical research setting.

Spatial resolution is generally higher because the subjects can be moved closer to the de- tectors and the instruments are specifically designed for the reduced dimension required.

Because of their small body size, whole-body imaging is easily possible for several species with many of the imaging modalities.

1.3 MAJOR IMAGING MODALITIES

1.3.1 Optical Imaging (Fluorescence and Bioluminescence)

Optical imaging is finding increasing clinical use in several specialized applications, largely using endoscopic (or similar fiberoptic intravital) methods or in regions with limited tissue thickness (e.g., the breast) [12, 17]. Still, the major application of optical imaging lies in pre- clinical use for small animal studies, chiefly thanks to relatively low cost and simple setup:

the subject is placed in a light-tight box and imaged with a highly sensitive charge-coupled device (CCD) camera. A considerable number of optical probes and tags are commercially available, making optical imaging the most popular preclinical imaging modality [5].

For fluorescence imaging the subject is typically illuminated by an external source with excitation light that is absorbed by the fluorophore of an imaging probe. The fluorophore then emits light at lower energies (longer wavelengths) that is detected by the camera.

Ideally, the light involved should be in the near-infrared range (∼650–900 nm), where absorbance by blood is minimal. For bioluminescence imaging, no external excitation is required; rather, the faint light emitted by certain biological processes is measured directly.

In laboratory studies, this can be achieved by linking a “reporter gene” encoding for a luminescent protein (usually luciferase) to the gene of interest and genetically transferring them into the animal before the study. After administration of an exogenous substrate (e.g., luciferin) light is generated only at sites where the genes are expressed. A similar approach can also be used for modified fluorescence imaging. In this case, the gene for green fluorescent protein (GFP) or one of its derivatives is commonly used as the reporter. Under

MAJOR IMAGING MODALITIES 9

illumination, locally expressed GFP emits light that is detected by the CCD camera. An advantage of this approach is the possibility of longitudinal studies because injection of a substrate is not necessary for visualization, whereas the useful window for bioluminescence after a luciferin injection is usually only about 5–30 minutes.

Owing to the fact that a carefully designed optical probe can be switched on and off in vivo as a result of chemical or physicochemical transformations, “activatable” or “smart”

fluorescent probes have been developed that can respond to the presence and level of biological markers at sites within the body [18]. This has been used in preclinical tumor models to monitor treatment response using a near-infrared fluorophore (NIRF)-based imaging probe responsive to the level of matrix metalloproteinase (MMP)-2. Treatment reduced the level of MMP-2 expressed by the tumor, which was reflected in a reduced signal emitted by the imaging probe.

Several challenges exist for optical imaging. For fluorescence imaging, they include high background signals caused by tissue autofluorescence [19] and limited stability (pho- tobleaching) of many small-molecule fluorophores. Bioluminescence does not have the same problems, but researchers face the tasks of genetically engineering the animal model and detecting very faint signals. Both approaches are constrained by depth limitations due to scattering and absorbance by overlying tissue and the concomitant difficulties with exact quantification. If spatial resolution is not a major concern, whole-body optical imaging is possible for small rodents (especially mice) since scattering and absorption are limited because of the small body size [20].

Perhaps more than for other imaging modalities, a notable number of new approaches based on different technologies are being investigated for optical imaging [12]. Fluo- rescence lifetime imaging (FLIM), photoaccoustic imaging, multispectral imaging [21], self-illuminating fluorescent imaging probes [19], Raman microscopy techniques, and to- mographic fluorescence systems are among the exciting approaches currently under devel- opment [12]. Some of them rely entirely on endogenous contrast and do not require the administration of any exogenous probes. Two examples are coherent anti-Stokes Raman scattering (CARS) and optical coherence tomography (OCT). CARS is a nonlinear Raman technique that measures the vibrational spectra of light scattered from illuminated biolog- ical specimens. Analysis of the spectra allows conclusions about the constituents of the tissue close to the surface. It has been used in vivo to map lipid compartments, protein clusters, and water distribution at subcellular resolution [22]. OCT is a technique based on light scattering that can be described as an optical version of ultrasound (see below).

Despite a shallow penetration depth of only about 2–3 mm, it is attractive since it yields real-time very-high resolution (1–15␮m) “optical biopsy” images that are comparable to conventional histopathology. It is finding applications in ophthalmic, gastrointestinal, and intravascular imaging using noninvasive or minimally invasive instrumentation such as handheld probes, endoscopes, catheters, laparoscopes, or needles [23].

1.3.2 Radionuclide-Based Imaging Modalities:

Positron Emission Tomography (PET) and

Single Photon Emission Computed Tomography (SPECT)

Because of high sensitivity and absence of depth limitations, PET and SPECT are the two molecular imaging modalities that have risen to prominence in both the clinical and preclinical settings. They require the administration of a positron- or single-photon- emitting radioisotope, usually attached to a larger molecule. Examples are [¹⁸F]fluorine in

10 BASIC PRINCIPLES OF MOLECULAR IMAGING

2-[¹⁸F]fluoro-2-deoxy-glucose (¹⁸F-FDG), [¹²³I]iodine in [¹²³I]metaiodobenzylguanidine (¹²³I-MIBG), or radioactive metal isotopes captured by a chelator (e.g., [⁶⁴Cu]copper or [¹¹¹In]indium in chelator-bearing proteins and antibodies). As such, both imaging modal- ities rely completely on exogenous probes for imaging. For both imaging modalities, the availability, the chemistry, and the radioactive half-life of the chosen isotope have to be considered. This is illustrated by comparing the two popular PET isotopes [¹¹C]carbon and [¹⁸F]fluorine. [¹¹C]Carbon is an attractive isotope because it can directly replace a nonradioactive carbon without changing the molecular structure of a compound. However, it has a half-life (t1/2) of only 20.4 min, necessitating production in an on-site cyclotron and limiting preparation of the imaging probe to a handful of very fast chemical reactions. By contrast, the nearly 2-h half-life of [¹⁸F]fluorine allows a much wider range of chemistries and even some degree of shipment of the imaging probe from central production facilities to outlying hospitals by ground or air. Since the fluorine atom usually takes the place of another element (often a hydrogen atom), possible effects on pharmacokinetics have to be evaluated during drug development. Regardless of which radionuclide-based imaging modality is employed, it is important to use a radioisotope whose physical (radioactive) half-life is matched to the pharmacokinetics of the imaging probe to ensure a sufficiently high signal-to-noise ratio at the time of imaging [24]. Since most nanoparticles have long blood circulation times, it may take up to a few days before the level in the target tissue has risen significantly over background levels. In order to match the long biological half-life of the probe, long-lived radioisotopes are often required. Fortunately, many such radioiso- topes are available. For example, the SPECT isotopes [¹²³I]iodine, [^99mTc]technetium, and [¹¹¹In]indium have half-lives of 13.2 h, 6.0 h, and 67.3 h, respectively, and long-lived PET isotopes include [⁶⁴Cu]copper, [¹²⁴I]iodine, and [⁸⁹Zr]zirconium (t1/2 = 12.7 h, 100.2 h, 78.4 h, respectively).

PET, in particular, distinguishes itself through its high sensitivity combined with the ability to image effectively without depth limitation [25]. As mentioned earlier, especially

18F-FDG has helped clinical PET to play a prominent role in cancer detection and monitor- ing of response to treatment because it allows the visualization of glucose hypermetabolism associated with many malignancies and whole-body PET scans permit the detection of dis- tant metastases (Fig. 1.1). Delicate biological systems (e.g., the brain) can be imaged with minimal disturbance of the molecular processes investigated thanks to the extremely low amount of imaging probe required. The signal detected by the scanner originates from the radioactive decay of a positron-emitting radioisotope prepared in a cyclotron prior to incorporation into the imaging probe. The positron loses energy by scattering through the tissue until undergoing annihilation with an electron, resulting in the emission of two 511-keV photons at an angle of nearly 180^◦. The pair of photons is detected by a cylindrical array of scintillators connected to photomultiplier tubes (PMTs). Image quality is greatly improved by only accepting valid coincidences and rejecting random events stemming from background radiation: only signals obtained in opposite detectors within a narrow time window, commonly 2–5 ns, are accepted as originating from the same positron-decay event. Resolution-limiting factors are the average range positrons travel before undergoing annihilation (“positron range”), the noncollinearity of the two photons emitted, and detector geometry [26, 27]. The positron range is isotope specific as it depends on the energy with which the positrons are emitted. It can range from<1 mm to >5 mm for common PET isotopes; for [¹⁸F]fluorine it is approximately 0.7 mm [26, 28]. Clinical PET scanners have a typical resolution on the order of several millimeters. Submillimeter resolution is possible