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NANOPLATFORM-BASEDMOLECULAR IMAGING


NANOPLATFORM-BASEDMOLECULAR IMAGING

Edited by

Xiaoyuan ChenLaboratory of Molecular Imaging and NanomedicineNational Institute of Biomedical Imaging and BioengineeringNational Institutes of HealthBethesda, Maryland

A JOHN WILEY & SONS, INC., PUBLICATION


Copyright C© 2011 by John Wiley & Sons, Inc. All rights reserved.

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Library of Congress Cataloging-in-Publication Data:

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–dc222010007984

Printed in the United States of America

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

10 9 8 7 6 5 4 3 2 1

http://www.copyright.com

http://www.wiley.com/go/permission

http://www.wiley.com


CONTENTS

Preface ix

Acknowledgments xi

Contributors xiii

PART I BASICS OF MOLECULAR IMAGING ANDNANOBIOTECHNOLOGY

1. Basic Principles of Molecular Imaging 3Sven H. Hausner

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

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

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

PART II NANOPARTICLES FOR SINGLE MODALITYMOLECULAR IMAGING

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

6. Carbon Nanotube X-Ray for Dynamic Micro-CT Imaging of SmallAnimal Models 139Otto Zhou, Guohua Cao, Yueh Z. Lee, and Jianping Lu

7. Quantum Dots for In Vivo Molecular Imaging 159Yun Xing

8. Biopolymer, Dendrimer, and Liposome Nanoplatforms for OpticalMolecular Imaging 183David Pham, Ling Zhang, Bo Chen, and Ella Fung Jones

v


vi CONTENTS

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

10. Single-Walled Carbon Nanotube Near-Infrared Fluorescent Sensorsfor Biological Systems 217Jingqing Zhang and Michael S. Strano

11. Microparticle- and Nanoparticle-Based Contrast-EnhancedUltrasound Imaging 233Nirupama Deshpande and Jurgen K. Willmann

12. Ultrasound-Based Molecular Imaging Using Nanoagents 263Srivalleesha Mallidi, Mohammad Mehrmohammadi, Kimberly Homan, Bo Wang,Min Qu, Timothy Larson, Konstantin Sokolov, and Stanislav Emelianov

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

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

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

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

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

PART III NANOPARTICLE PLATFORMS AS MULTIMODALITYIMAGING AND THERAPY AGENTS

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

19. Protein Cages as Multimode Imaging Agents 463Masaki Uchida, Lars Liepold, Mark Young, and Trevor Douglas

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

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

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


CONTENTS vii

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

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

25. Gold Nanocages: A Multifunctional Platform for Molecular OpticalImaging and Photothermal Treatment 615Leslie Au, Claire M. Cobley, Jingyi Chen, and Younan Xia

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

27. Gold Nanorods as Theranostic Agents 659Alexander Wei, Qingshan Wei, and Alexei P. Leonov

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

29. Magnetic Nanoparticle Carrier for Targeted Drug Delivery:Perspective, Outlook, and Design 709R. D. K. Misra

30. Perfluorocarbon Nanoparticles: A Multidimensional Platform forTargeted Image-Guided Drug Delivery 725Gregory M. Lanza, Shelton D. Caruthers, Anne H. Schmieder, Patrick M. Winter,Tillmann Cyrus, and Samuel A. Wickline

31. Radioimmunonanoparticles for Cancer Imaging and Therapy 755Arutselvan Natarajan

PART IV TRANSLATIONAL NANOMEDICINE

32. Current Status and Future Prospects for Nanoparticle-Based Technologyin Human Medicine 783Nuria Sanvicens, Fatima Fernandez, J.-Pablo Salvador, and M.-Pilar Marco

Index 815


PREFACE

This book focuses on the rational design of water-soluble, biocompatible nanoparticles forthe visualization of the cellular function and follow-up of the molecular processes in livingorganisms without perturbing them. Molecular imaging probes based on nanotechnologyhold great potential in diagnosis, imaging guided intervention, and treatment response mon-itoring of diseases. This book is logically organized by including the basics of molecularimaging, 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 molecularimaging using nanoparticles. This book consists of 32 chapters and was contributed bynearly 100 authors worldwide, who are among the world’s prominent scientists in materialscience and/or molecular imaging.

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

Part II consists of Chapters 5–17 Chapter 5 illustrates the basic principles of CT, theevolution of CT imaging technology, and the rationale for nanoparticle-based CT contrastagents; Chapter 6 describes the advantages of fascinating carbon nanotube field emissionX-ray technology over conventional thermionic X-ray tubes that are used in current X-rayimaging systems; Chapter 7 describes the use of unique optical properties of semiconductorquantum dots (QDs) for near-infrared fluorescence imaging in living animals; Chapter 8 in-troduces macromolecular nanoconstructs such as biopolymers, dendrimers, and liposomesas carriers for fluorophore conjugation and optical imaging; Chapter 9 summarizes recentprogress in developing nanoplatforms for Raman imaging of biological systems; Chapter10 summarizes the work in using single-walled carbon nanotubes (SWNTs) as near-infraredfluorescent sensors for biomolecule detection; Chapter 11 describes the use of micro- andnanoparticles as ultrasound contrast agents; Chapter 12 proposes the use of metal nanopar-ticles in ultrasound-based photoacoustic and magnetoacoustic imaging modalities; Chapter13 reports the progress on magnetic resonance imaging (MRI) contrast agents based oninorganic nanoparticles; Chapter 14 emphasizes the use of iron oxide nanoparticles forcellular labeling followed by T2- and T∗

2-weighted MRI; Chapter 15 covers the use of rareearth based nanoparticles for MR imaging as positive contrast agents; Chapter 16 reviewsthe 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 radionuclidesto study in vivo distribution.

Part III consists of Chapters 18–31 Chapter 18 introduces techniques to incorporateimaging 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 asplatforms for MRI contrast agents and fluorescent imaging agents; Chapter 20 provides acomprehensive summary of the state-of-the-art of SWNTs for multimodality biomedicalimaging applications; Chapter 21 reviews the progress in the controlled synthesis, surfacemodification, and multimodality imaging applications of multifunctional nanoparticles inrecent years; Chapter 22 argues the use of cancer theranostics as a promising new strategy incancer management, permitting simultaneous cancer diagnosis, drug delivery, and real-timemonitoring of therapeutic efficacy; Chapter 23 provides more examples of multifunctionalnanoparticles for combined cancer imaging and therapy (theranostics); Chapter 24 describesthe recent progress in modifying magnetic nanoparticles for multimodality imaging as wellas targeted treatment of a number of diseases; Chapter 25 introduces gold nanocages ascontrast agents for optical bioimaging (such as optical and spectroscopic coherence tomog-raphy amd photoacoustic tomography) and photothermal treatment; Chapter 26 describesthe biological inertness, ease of manufacture and bioconjugation, and presumed lack oftoxicity of gold nanoparticles for simultaneous sensing, imaging, and treatment of tumors;Chapter 27 presents the recent developments in the chemistry and photophysics of goldnanorods and their applications toward biological imaging and photothertmally activatedtherapies; Chapter 28 describes a number of gold core–shell nanostructures for cancermolecular optical imaging, controlled drug delivery, and photothermal ablation therapy;Chapter 29 describes a novel temperature and pH-responsive magnetic nanocarrier thatcombines tumor targeting and controlled drug release capabilities; Chapter 30 deals withperfluorocarbon nanoparticles as a multidimensional platform for targeted image-guideddrug 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-basednovel technologies for molecular imaging, diagnosis, and drug delivery formulations. Thelimitations and future challenges of nanoparticle-based systems are also discussed.

Xiaoyuan ChenBethesda, Maryland


ACKNOWLEDGMENTS

The editor thanks the nearly 100 authors throughout the world for their contributions andcollaboration on this book project. The editing work of this book was accomplished usinga significant amount of the editor’s spare time including family time. Therefore the editoralso thanks his wife, Michelle Ji, and his daughter, Grace Chen, for their wonderful supportand 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,Universite Pierre et Marie Curie, Paris, France

C. Billotey, Laboratoire CREATIS–Animage, Universite Claude Bernard, Lyon, France

Sebastien Boutry, Department of General, Organic and Biomedical Chemistry, NMR andMolecular Imaging Laboratory, University of Mons, Mons, Belgium

J.-L. Bridot, Service de Chimie Generale, Organique et Biomedicale, Laboratoire de RMNet d’Imagerie Moleculaire, Universite de Mons-Hainaut, Mons, Belgium

Weibo Cai, Departments of Radiology and Medical Physics, School of Medicine andPublic Health, University of Wisconsin–Madison, and University of Wisconsin CarboneCancer Center, Madison, Wisconsin, USA

Guohua Cao, Department of Physics and Astronomy, University of North Carolina atChapel 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 andBiomedical 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, andLaboratory for Molecular Imaging and Nanomedicine, National Institute of BiomedicalImaging 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 atStanford, Stanford University School of Medicine, Stanford, California, USA

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

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

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

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

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

Fatima Fernandez, Applied Molecular Receptors Group, CIBER de Bioingenierıa,Biomateriales y Nanotecnologıa, IQAC-CSIC, Barcelona, Spain

Jinhao Gao, Molecular Imaging Program at Stanford and Bio-X Program, Department ofRadiology, 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 andPublic 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 NanocrystallineMaterials, 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 Radiologyand 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 ofNeurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland,USA

Sunil Krishnan, Department of Radiation Oncology, University of Texas M.D. AndersonCancer 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 andMolecular 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 PlantSciences, 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 andEngineering, 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 atAustin, Austin, Texas, USA

M.-Pilar Marco, Applied Molecular Receptors Group, CIBER de Bioingenierıa,Biomateriales y Nanotecnologıa, IQAC-CSIC, Barcelona, Spain

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

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

Marites P. Melancon, Department of Experimental Diagnostic Imaging, University ofTexas 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 Louisianaat 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 andMolecular 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 atStanford, 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 Metallurgie Physique et de Physique des Materiaox, Uni-versite Claude Bernard, Lyon, France

David Pham, Center for Molecular and Functional Imaging, Department of Radiologyand 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. Riviere, Laboratoire de Physique de la Matiere Condensee et Nanostructures, Universitede Lyon, Lyon, France

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

S. Roux, Laboratoire de Physico-Chimie des Materiaux Luminescents, Universite de Lyon,Lyon, France


CONTRIBUTORS xvii

J.-Pablo Salvador, Applied Molecular Receptors Group, CIBER de Bioingenierıa,Biomateriales y Nanotecnologıa, IQAC-CSIC, Barcelona, Spain

Nuria Sanvicens, Applied Molecular Receptors Group, CIBER de Bioingenierıa,Biomateriales y Nanotecnologıa, 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 atAustin, 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 Materiaux Luminescents, Universite deLyon, Lyon, France

Masaki Uchida, Department of Chemistry and Biochemistry and Department of PlantScience, 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 andMassachusetts 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 atStanford, 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 ofRadiology, 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 ofNeurological 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 andBiomedical Imaging, University of California, San Francisco, California, USA

Gang Zheng, Department of Medical Biophysics and Institute of Biomaterials andBiomedical 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 andEngineering, and Lineberger Comprehensive Cancer Center, University of North Car-olina at Chapel Hill, Chapel Hill, North Carolina, USA

P1: OTA/XYZ P2: ABCc01 JWBS037-Chen February 2, 2011 21:44 Printer Name: Yet to Come

PART I

BASICS OF MOLECULAR IMAGINGAND 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 goalfor medical research. Several noninvasive or minimally invasive diagnostic modalities havebeen developed which allow one to obtain anatomical, physiological, and molecular infor-mation. “Molecular imaging” can be defined as in situ visualization, characterization, andmeasurement of biological processes in the living organism at the molecular or cellularlevel. Diagnosis and visualization at the molecular level, that is, detection of a disease in itsinfancy, may significantly improve treatment and patient care. By combining two or moreimaging modalities, each with its different strengths, high-quality complementary (e.g.,molecular and anatomical) information can be obtained and analyzed in the context of eachother. This has led to the rise of dual- and multimodality imaging approaches. Dependingon the modality, imaging probes or contrast agents are required or highly desirable; they canrange in size from single atoms to cell-sized constructs. Nanoparticles, that is, entities withdimensions 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, surfacecoatings, enclosed payload) in a single unit. The inclusion of a therapeutic componentyields “theranostics.” Taken together, nanotechnology-based molecular probes offer thepromise for tailor-made clinical tools required for “personalized medicine.” This chapterprovides an introductory overview of molecular imaging, major imaging modalities, andimaging probes, with particular focus on the promises and challenges of nanoparticle-basedcompounds.

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 ChenCopyright 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 thechance 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 forthe patient) and affordable (i.e., overall cost-saving to the health care system and society)diagnostic approaches are highly desirable. Ever since Wilhelm Rontgen’s first use in 1895of the then newly discovered X-rays to noninvasively image the interior of the body, thekeen interest in medical imaging has been met by increasingly sophisticated technologies(Fig. 1.1). While Rontgen’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 visualizationof anatomical, physiological, and, increasingly, molecular (cellular) biological information.

Since diseases often arise from changes on the molecular and cellular levels, long beforemanifesting 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 earlierstage, 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 Rontgen’s (1845–1923) first X-ray image, depicting the hand of hiswife, Anna, taken on 22 December 1895. (Right) A slice of a modern whole-body multimodalitypositron emission tomography/computed tomography (PET/CT) scan showing glucose metabolismwithin the body, including a large, metabolically active tumor (arrow). (PET/CT image courtesy ofDr. 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 thishas already had significant effects on determining beforehand which patients will benefitfrom 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 oftreatment: expression has been linked to aggressiveness of the disease, but it also providesa target for highly effective treatment with antibodies (Trastuzumab, Herceptin®) [2, 3].Similarly, monitoring glucose metabolism with the imaging agent 18F-fluorodeoxyglucose(18F-FDG) has proved itself to be the preferred approach for staging, restaging, andevaluation of response to treatment for several cancers [4]. Concurrently with the advancesin molecular biology, engineers and physicists are developing increasingly sophisticatedimaging instrumentation capable of localizing imaging agents in the body at high sensitivityand high resolution in short acquisition time [5]. By bridging the clinical and engineeringworlds, research in imaging agents plays a central role. To that end, the developmentof target-specific (and disease-specific) nanoparticle-based molecular probes draws onresearch in several fields including biology, molecular biology, medicine, chemistry, andbiomedical 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 ofimaging probes with the target tissue on a molecular and a cellular level. The goal is thereal-time in situ visualization of biological processes in the living organism. This focusis also reflected in the Society of Nuclear Medicine’s definition of molecular imagingas “an array of non-invasive, diagnostic imaging technologies that can create imagesof both physical and functional aspects of the living body. It can provide informationthat would otherwise require surgery or other invasive procedures to obtain. Molecularimaging 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 radiologicaltechniques in that molecular imaging primarily provides information about biologicalprocesses (function) while [computed tomography] CT, X-rays, [magnetic resonanceimaging] 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 typeevaluated (X-ray, photons, sound; positrons), the resolution that can be achieved, and thetype 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 singlephoton emission computed tomography (SPECT). All of these modalities allow for thenoninvasive imaging of living subjects. Although the first three imaging modalities areprimarily anatomical and not molecular, the two types of modalities can be combinedfor dual- or multimodality imaging. In addition, MRI, US, and CT can be used withmolecular imaging probes, especially as part of nanoplatforms. In addition, a number ofmore specialized optical modalities are being used or are under investigation, includingendoscopic methods [12].


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7



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

The instrumentation for the various modalities has also been adapted for preclinicalapplications [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 specieswith 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, largelyusing endoscopic (or similar fiberoptic intravital) methods or in regions with limited tissuethickness (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-coupleddevice (CCD) camera. A considerable number of optical probes and tags are commerciallyavailable, making optical imaging the most popular preclinical imaging modality [5].

For fluorescence imaging the subject is typically illuminated by an external source withexcitation light that is absorbed by the fluorophore of an imaging probe. The fluorophorethen 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), whereabsorbance by blood is minimal. For bioluminescence imaging, no external excitation isrequired; 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 aluminescent protein (usually luciferase) to the gene of interest and genetically transferringthem 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 similarapproach can also be used for modified fluorescence imaging. In this case, the gene for greenfluorescent 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. Anadvantage of this approach is the possibility of longitudinal studies because injection of asubstrate is not necessary for visualization, whereas the useful window for bioluminescenceafter 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 offin 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 ofbiological markers at sites within the body [18]. This has been used in preclinical tumormodels to monitor treatment response using a near-infrared fluorophore (NIRF)-basedimaging probe responsive to the level of matrix metalloproteinase (MMP)-2. Treatmentreduced the level of MMP-2 expressed by the tumor, which was reflected in a reducedsignal emitted by the imaging probe.

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

Perhaps more than for other imaging modalities, a notable number of new approachesbased 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 theadministration of any exogenous probes. Two examples are coherent anti-Stokes Ramanscattering (CARS) and optical coherence tomography (OCT). CARS is a nonlinear Ramantechnique that measures the vibrational spectra of light scattered from illuminated biolog-ical specimens. Analysis of the spectra allows conclusions about the constituents of thetissue close to the surface. It has been used in vivo to map lipid compartments, proteinclusters, and water distribution at subcellular resolution [22]. OCT is a technique basedon 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 yieldsreal-time very-high resolution (1–15 �m) “optical biopsy” images that are comparableto conventional histopathology. It is finding applications in ophthalmic, gastrointestinal,and intravascular imaging using noninvasive or minimally invasive instrumentation such ashandheld probes, endoscopes, catheters, laparoscopes, or needles [23].

1.3.2 Radionuclide-Based Imaging Modalities:Positron Emission Tomography (PET) andSingle Photon Emission Computed Tomography (SPECT)

Because of high sensitivity and absence of depth limitations, PET and SPECT are thetwo molecular imaging modalities that have risen to prominence in both the clinicaland 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



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, theavailability, the chemistry, and the radioactive half-life of the chosen isotope have to beconsidered. This is illustrated by comparing the two popular PET isotopes [11C]carbonand [18F]fluorine. [11C]Carbon is an attractive isotope because it can directly replace anonradioactive 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 andlimiting preparation of the imaging probe to a handful of very fast chemical reactions. Bycontrast, the nearly 2-h half-life of [18F]fluorine allows a much wider range of chemistriesand even some degree of shipment of the imaging probe from central production facilitiesto outlying hospitals by ground or air. Since the fluorine atom usually takes the place ofanother element (often a hydrogen atom), possible effects on pharmacokinetics have tobe evaluated during drug development. Regardless of which radionuclide-based imagingmodality 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 sufficientlyhigh signal-to-noise ratio at the time of imaging [24]. Since most nanoparticles have longblood circulation times, it may take up to a few days before the level in the target tissue hasrisen significantly over background levels. In order to match the long biological half-lifeof 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 PETisotopes 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 theability to image effectively without depth limitation [25]. As mentioned earlier, especially18F-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 hypermetabolismassociated 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 withminimal disturbance of the molecular processes investigated thanks to the extremely lowamount of imaging probe required. The signal detected by the scanner originates fromthe radioactive decay of a positron-emitting radioisotope prepared in a cyclotron priorto incorporation into the imaging probe. The positron loses energy by scattering throughthe tissue until undergoing annihilation with an electron, resulting in the emission of two511-keV photons at an angle of nearly 180◦. The pair of photons is detected by a cylindricalarray of scintillators connected to photomultiplier tubes (PMTs). Image quality is greatlyimproved by only accepting valid coincidences and rejecting random events stemmingfrom background radiation: only signals obtained in opposite detectors within a narrowtime window, commonly 2–5 ns, are accepted as originating from the same positron-decayevent. Resolution-limiting factors are the average range positrons travel before undergoingannihilation (“positron range”), the noncollinearity of the two photons emitted, and detectorgeometry [26, 27]. The positron range is isotope specific as it depends on the energy withwhich the positrons are emitted. It can range from <1 mm to >5 mm for common PETisotopes; for [18F]fluorine it is approximately 0.7 mm [26, 28]. Clinical PET scanners havea typical resolution on the order of several millimeters. Submillimeter resolution is possible

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