Felix Kratz graduated in Chemistry from the University of Heidelberg in 1991. He then carried out postdoctoral research at the Bioinorganic Institute of the University of Florence and developed tumor-specifi c carrier systems with ruthenium(III) complexes. Since 1994 he has been Head of Macromolecular Prodrugs at the Tumor Biology Center in Freiburg, Germany, where he is now in charge of organizing and managing translational research from the laboratory to the clinic. His research areas are drug targeting, drug-delivery systems in oncology, prodrugs, receptor targeting, bioconjugate chemistry, and nanocarriers. Peter Senter earned his PhD in Chemistry from the University of Illinois in Urbana, and then carried out postdoctoral research at the Max Planck Institute in Gottingen, Germany. After various positions at the Dana Farber Cancer Institute, Bristol-Myers Squibb, and Cytokine Networks, he joined Seattle Genetics in 1998, and initiated research programs that led to the technology used for SGN-35 and other promising antibody drug conjugates. Henning Steinhagen graduated in Organic Chemistry from the University of Heidelberg, Germany in 1998. He then joined the group of Prof. E.J. Corey at Harvard University, Cambridge, USA as postdoctoral fellow. After that he continued his career, working in Discovery Research in Medicinal Chemistry at Bayer, Wuppertal and at Aventis, Frankfurt. In 2009, he joined Grunenthal in Aachen, Germany where he currently acts as Vice President and Global Head of Drug Discovery.

“The book is easy to follow, and the majority of chapters have an updated bibliography. Furthermore, most of them contain diagrams and figures that allow the topic to be easily followed. In short, it is a book where actual issues regarding the use of controlled drug-delivery systems in pathology like cancer are described in a detailed way.”  (ChemMedChem, 1 October 2012)

• Contents to Volume 1Foreword vPreface xviiList of Contributors xixDrug Delivery in Oncology – Challenge and Perspectives Part I Principles of Tumor Targeting 11 Limits of Conventional Cancer Chemotherapy 3Klaus Mross and Felix Kratz1.1 Introduction: The Era of Cancer Chemotherapy 31.2 Dilemma and Challenge of Treating Malignant Diseases 141.3 Adverse Effects 161.3.1 Common Side-Effects 181.3.1.1 Depression of the Immune System 181.3.1.2 Fatigue 191.3.1.3 Tendency to Bleed Easily 191.3.1.4 Gastrointestinal Distress 191.3.1.5 Hair Loss 201.3.2 Damage to Specific Organs 201.3.2.1 Cardiotoxicity 201.3.2.2 Hepatotoxicity 211.3.2.3 Nephrotoxicity 221.3.2.4 Pulmonary Side-Effects 221.3.2.5 Vascular Adverse Effects 231.3.2.6 Tissue Damage (Extravasation) 231.3.2.7 Neurological Side-Effects 241.3.2.8 Secondary Neoplasms 251.3.2.9 Infertility 251.3.2.10 Other Side-Effects 251.4 Supportive Care 251.5 New Approaches Complementing Current Cancer Chemotherapy 261.6 Conclusions and Perspectives 28References 292 Pathophysiological and Vascular Characteristics of Solid Tumors in Relation to Drug Delivery 33Peter Vaupel2.1 Introduction 332.2 Basic Principles of Blood Vessel Formation in Solid Tumors 342.2.1 Angiogenesis 342.2.2 Vascular Co-option 362.2.3 Vasculogenesis 362.2.4 Intussusception 362.2.5 Vascular Mimicry 362.2.6 Microvessel Formation by Myeloid Cells 362.3 Tumor Lymphangiogenesis 372.4 Tumor Vascularity and Blood Flow 372.5 Arteriovenous Shunt Perfusion in Tumors 382.6 Volume and Characteristics of the Tumor Interstitial Space 402.7 Interstitial Fluid Pressure in Tumors 422.8 Role of the Disorganized, Compromised Microcirculation as an Obstacle in Drug Delivery 432.8.1 Blood-Borne Delivery 432.8.2 Extravasation of Anticancer Agents 452.9 Interstitial Barriers to Drug Delivery 462.10 Pathophysiological Tumor Microenvironment as an Obstacle in Tumor Therapy 472.10.1 Hypoxia as an Obstacle in Drug Therapy 482.10.1.1 Direct Effects 482.10.1.2 Indirect Effects Based on Changes in the Transcriptome, in Differential Regulation of Gene Expression, and in Alterations of the Proteome 492.10.1.3 Indirect Effects Based on Enhanced Mutagenesis, Genomic Instability, and Clonal Selection 512.10.1.4 Tumor Hypoxia: An Adverse Parameter in Chemotherapy 512.10.2 Tumor Acidosis and Drug Resistance 532.11 Conclusions 56Acknowledgments 56References 563 Enhanced Permeability and Retention Effect in Relation to Tumor Targeting 65Hiroshi Maeda3.1 Background and Status Quo 653.2 What is the EPR Effect: Mechanism, Uniqueness, and Factors Involved 663.3 Heterogeneity of the EPR Effect: A Problem in Drug Delivery 723.4 Overcoming the Heterogeneity of the EPR Effect for Drug Delivery and How to Enhance the EPR Effect 753.4.1 Angiotensin II-Induced High Blood Pressure 753.4.2 Use of NO-Releasing Agents 783.4.3 Use of Other Vascular Modulators 793.5 PEG Dilemma: Stealth Effect and Anti-PEG IgM Antibody 793.6 Concluding Remarks 80Acknowledgments 81References 814 Pharmacokinetics of Immunoglobulin G and Serum Albumin: Impact of the Neonatal Fc Receptor on Drug Design 85Jan Terje Andersen and Inger Sandlie4.1 Introduction 854.2 Discovery of FcRn 874.3 FcRn Structure 884.4 FcRn–Ligand Interactions 894.5 FcRn as a Multiplayer with Therapeutic Utilities 904.5.1 Directional Placental Transport 904.5.2 FcRn at Mucosal Surfaces 914.5.3 Systemic FcRn-Mediated Recycling 924.5.4 Role of FcRn in Antigen Presentation 934.5.5 FcRn at Immune-Privileged Sites 944.5.6 FcRn in the Kidneys 944.5.7 FcRn Expressed by the Liver 954.6 Engineering IgG for Altered FcRn Binding and Pharmacokinetics 954.6.1 IgG Fc Fusions 954.6.2 Engineered IgG Variants 964.6.3 Blocking FcRn Recycling 1024.7 Targeting FcRn by SA 1024.7.1 SA Fusions 1024.7.2 Targeting SA 1054.8 Considering Cross-Species Binding 1114.9 Concluding Remarks 113Acknowledgment 113References 1135 Development of Cancer-Targeting Ligands and Ligand–Drug Conjugates 121Ruiwu Liu, Kai Xiao, Juntao Luo, and Kit S. Lam5.1 Introduction 1215.2 Overview of Cancer-Targeting Ligand–Drug Conjugates 1225.3 Cancer-Targeting Ligands 1255.3.1 Introduction 1255.3.2 Phage-Display Library Approach 1255.3.2.1 Phage-Display Library Screening and Decoding 1275.3.2.2 Examples 1275.3.3 OBOC Combinatorial Library Approach 1315.3.3.1 OBOC Library Design 1325.3.3.2 OBOC Library Construction 1355.3.3.3 OBOC Library Screening 1375.3.3.4 OBOC Library Decoding 1385.3.3.5 Ligand Optimization 1395.3.3.6 Examples 1405.4 Linkers 1435.4.1 Acid-Sensitive Linkers 1435.4.2 Enzymatic Cleavage 1435.4.3 Self-Immolative Spacers 1455.4.4 Reductive Cleavage 1465.4.5 On-Demand Cleavable Linker 1465.5 Examples of Cancer-Targeting Ligand–Drug Conjugates 1475.5.1 Folic Acid–Drug Conjugates 1475.5.2 Peptide Ligand–Drug Conjugates 1485.5.3 Peptide Hormone–Drug Conjugates 1505.5.4 Antibody–Drug Conjugates 1515.5.5 Adept 1545.5.6 Polymer–Drug Conjugates 1565.5.7 Targeting Liposomes and Nanoparticles 1585.6 Conclusions and Perspectives 159Acknowledgments 160References 1606 Antibody-Directed Enzyme Prodrug Therapy (ADEPT) – Basic Principles and its Practice So Far 169Kenneth D. Bagshawe6.1 Introduction 1696.2 Principles and the Components of ADEPT 1706.2.1 Target 1706.2.2 Antibody 1716.2.3 Enzyme 1726.2.4 Prodrug and Drug 1736.3 Third Essential 1736.4 ADEPT Studies Elsewhere 1756.5 Reagents for First Clinical Trials in London (1990–1995) 1766.5.1 First ADEPT Clinical Trial 1776.5.2 Subsequent ADEPT Clinical Studies in London 1786.5.3 Two-Phase ADEPT Clinical Studies in London 1796.6 Technology Advances 1796.7 ADEPT Future 181References 181Part II Tumor Imaging 1877 Imaging Techniques in Drug Development and Clinical Practice 189John C. Chang, Sanjiv S. Gambhir, and Jürgen K. Willmann7.1 Introduction 1897.2 Cancer Biology 1917.2.1 Tumor Genetic Heterogeneity 1917.2.2 Altered Tumor Metabolism 1917.2.3 Tumor Angiogenesis 1927.2.4 Receptor Pathologies 1947.3 Cancer Biomarkers 1947.3.1 Histological Biomarkers 1947.3.2 Hematological Biomarkers 1967.3.3 Imaging Biomarkers 1967.4 Imaging Techniques 1977.4.1 Spect 1977.4.2 Pet/pet-ct 1987.4.3 Mri 1987.4.4 Ct 1997.4.5 Ultrasound 1997.4.6 Fluorescence/Bioluminescence 2007.5 Examples of Imaging Assessment of Tumor Response 2007.5.1 Spect 2007.5.2 Pet/pet-ct 2017.5.2.1 Microdosing 2017.5.2.2 Cancer Metabolism and Proliferation 2027.5.2.3 Hypoxia 2047.5.2.4 Biomarker Imaging 2057.5.2.5 Angiogenesis 2077.5.2.6 Apoptosis 2077.5.3 Mri 2077.5.3.1 Cellular Structure 2097.5.3.2 Metabolic Response 2097.5.3.3 Tumor Perfusion 2107.5.4 CT Imaging 2117.5.5 Ultrasound 2127.5.6 Fluorescence/Bioluminescence 2137.6 Challenges of Imaging in Drug Development and Validation 2147.7 Conclusions and Future Perspectives 215References 2178 Magnetic Nanoparticles in Magnetic Resonance Imaging and Drug Delivery 225Patrick D. Sutphin, Efrén J. Flores, and Mukesh Harisinghani8.1 Introduction 2258.2 Passive Targeting of Nanoparticles 2278.2.1 Mechanism of Action 2298.2.2 Lymphotropic Nanoparticle MRI 2298.3 Active SPIO Nanoparticle Targeting 2328.3.1 Creating the Targeted Imaging Agents 2338.3.1.1 Transferrin–USPIO Nanoparticles 2338.3.1.2 Folate Receptor 2358.3.1.3 Integrins 2358.4 Nanoparticles in Targeted Therapy 2368.4.1 Nanoparticles in Gene Therapy 2378.4.2 Nanoparticles in Molecularly Targeted Drug Delivery 2388.4.3 Conversion of Therapeutic Agent to Imaging Agent 2398.4.4 Toxic Payload 2408.5 Conclusions 240References 2429 Preclinical and Clinical Tumor Imaging with SPECT/CT and Pet/ct 247Andreas K. Buck, Florian Gärtner, Ambros Beer, Ken Herrmann, Sibylle Ziegler, and Markus Schwaiger9.1 Introduction 2479.2 Technical Aspects of Functional and Molecular Imaging with SPECT and PET 2499.2.1 Principles of Clinical PET and Hybrid PET/CT Imaging 2499.2.2 Biomarkers for PET and PET/CT Imaging 2509.2.3 Principles of Clinical SPECT and Hybrid SPECT CT Imaging 2529.2.4 Biomarkers for SPECT and SPECT/CT Imaging 2589.2.5 Principles of Preclinical Imaging with SPECT and PET 2589.3 Preclinical and Clinical Developments 2609.3.1 Imaging Neoangiogenesis 2609.3.1.1 VEGF/VEGFR Imaging 2619.3.1.2 Radiolabeled Integrin Antagonists (RGD Peptides) 2629.3.1.3 Monomeric Tracer Labeling Strategies 2629.3.2 Imaging the Proliferative Activity of Tumors 2649.3.3 Imaging the Hypoxic Cell Fraction of Tumors 2679.3.4 Imaging Receptor Expression 2699.4 Clinical Applications of SPECT/CT and PET 2729.4.1 Differentiation of Benign from Malignant Tumors and Cancer Detection 2729.4.2 Staging of Cancer: Prognostic Potential of Imaging Biomarkers 2739.4.3 Assessment of Response to Therapy 2749.4.4 Restaging of Cancer and Detection of Recurrence 2749.4.5 PET for Radiation Treatment Planning 2759.4.6 PET for Cancer Drug Development 2759.4.7 SPECT/CT for Mapping of SLNs 2769.4.8 SPECT/CT for Detection of Bone Metastases 2779.4.9 SPECT/CT in Thyroid Cancer 2789.4.10 SPECT/CT for Imaging of Adrenocortical Tumors 2799.4.11 SPECT/CT in Neuroendocrine Tumors 2819.5 Conclusions and Perspectives 281References 282Contents to Volume 2Part III Macromolecular Drug Delivery Systems 289Antibody-Based Systems 28910 Empowered Antibodies for Cancer Therapy 291Stephen C. Alley, Simone Jeger, Robert P. Lyon, Django Sussman, and Peter D. Senter11 Mapping Accessible Vascular Targets to Penetrate Organs and Solid Tumors 325Kerri A. Massey and Jan E. Schnitzer12 Considerations of Linker Technologies 355Laurent Ducry13 Antibody–Maytansinoid Conjugates: From the Bench to the Clinic 375Hans Erickson14 Calicheamicin Antibody–Drug Conjugates and Beyond 395Puja Sapra, John DiJoseph, and Hans-Peter Gerber15 Antibodies for the Delivery of Radionuclides 411Anna M. Wu16 Bispecific Antibodies and Immune Therapy Targeting 441Sergej M. KiprijanovPolymer-Based Systems 48317 Design of Polymer–Drug Conjugates 485Jindřich Kopeček and Pavla Kopečková18 Dendritic Polymers in Oncology: Facts, Features, and Applications 513Mohiuddin Abdul Quadir, Marcelo Calderón, and Rainer Haag19 Site-Specific Prodrug Activation and the Concept of Self-Immolation 553André Warnecke20 Ligand-Assisted Vascular Targeting of Polymer Therapeutics 591Anat Eldar-Boock, Dina Polyak, and Ronit Satchi-Fainaro21 Drug Conjugates with Poly(Ethylene Glycol) 627Hong Zhao, Lee M. Greenberger, and Ivan D. Horak22 Thermo-Responsive Polymers 667Drazen Raucher and Shama Moktan23 Polysaccharide-Based Drug Conjugates for Tumor Targeting 701Gurusamy Saravanakumar, Jae Hyung Park, Kwangmeyung Kim, and Ick Chan Kwon24 Serum Proteins as Drug Carriers of Anticancer Agents 747Felix Kratz, Andreas Wunder, and Bakheet Elsadek25 Future Trends, Challenges, and Opportunities with Polymer-Based Combination Therapy in Cancer 805Coralie Deladriere, Rut Lucas, and María J. Vicent26 Clinical Experience with Drug–Polymer Conjugates 839Khalid Abu Ajaj and Felix KratzPart IV Nano- and Microparticulate Drug Delivery Systems 885Lipid-Based Systems 88527 Overview on Nanocarriers as Delivery Systems 887Haifa Shen, Elvin Blanco, Biana Godin, Rita E. Serda, Agathe K. Streiff, and Mauro Ferrari28 Development of PEGylated Liposomes 907I. Craig Henderson29 Immunoliposomes 951Vladimir P. Torchilin30 Responsive Liposomes (for Solid Tumor Therapy) 989Stavroula Sofou31 Nanoscale Delivery Systems for Combination Chemotherapy 1013Barry D. Liboiron, Paul G. Tardi, Troy O. Harasym, and Lawrence, D. MayerPolymer-Based Systems 105132 Micellar Structures as Drug Delivery Systems 1053Nobuhiro Nishiyama, Horacio Cabral, and Kazunori Kataoka33 Tailor-Made Hydrogels for Tumor Delivery 1071Sungwon Kim and Kinam Park34 pH-Triggered Micelles for Tumor Delivery 1099Haiqing Yin and You Han Bae35 Albumin–Drug Nanoparticles 1133Neil Desai36 Carbon Nanotubes 1163David A. Scheinberg, Carlos H. Villa, Freddy Escorcia, and Michael R. McDevittContents to Volume 3Part V Ligand-Based Drug Delivery Systems 118737 Cell-Penetrating Peptides in Cancer Targeting 1189Kaido Kurrikoff, Julia Suhorutšenko, and Ülo Langel38 Targeting to Peptide Receptors 1219Andrew V. Schally and Gabor Halmos39 Aptamer Conjugates: Emerging Delivery Platforms for Targeted Cancer Therapy 1263Zeyu Xiao, Jillian Frieder, Benjamin A. Teply, and Omid C. Farokhzad40 Design and Synthesis of Drug Conjugates of Vitamins and Growth Factors 1283Iontcho R. Vlahov, Paul J. Kleindl, and Fei You41 Drug Conjugates with Polyunsaturated Fatty Acids 1323Joshua Seitz and Iwao OjimaPart VI Special Topics 135942 RNA Drug Delivery Approaches 1361Yuan Zhang and Leaf Huang43 Local Gene Delivery for Therapy of Solid Tumors 1391Wolfgang Walther, Peter M. Schlag, and Ulrike Stein44 Viral Vectors for RNA Interference Applications in Cancer Research and Therapy 1415Henry Fechner and Jens Kurreck45 Design of Targeted Protein Toxins 1443Hendrik Fuchs and Christopher Bachran46 Drug Targeting to the Central Nervous System 1489Gert Fricker, Anne Mahringer, Melanie Ott, and Valeska Reichel47 Liver Tumor Targeting 1519Katrin Hochdörffer, Giuseppina Di Stefano, Hiroshi Maeda, and Felix Kratz48 Photodynamic Therapy: Photosensitizer Targeting and Delivery 1569Pawel Mroz, Sulbha K. Sharma, Timur Zhiyentayev, Ying-Ying Huang, and Michael R. Hamblin49 Tumor-Targeting Strategies with Anticancer Platinum Complexes 1605Mathea Sophia Galanski and Bernhard K. KepplerIndex 1631

Felix Kratz graduated in Chemistry from the University of Heidelberg in 1991. He then carried out postdoctoral research at the Bioinorganic Institute of the University of Florence and developed tumor-specifi c carrier systems with ruthenium(III) complexes. Since 1994 he has been Head of Macromolecular Prodrugs at the Tumor Biology Center in Freiburg, Germany, where he is now in charge of organizing and managing translational research from the laboratory to the clinic. His research areas are drug targeting, drug-delivery systems in oncology, prodrugs, receptor targeting, bioconjugate chemistry, and nanocarriers. Peter Senter earned his PhD in Chemistry from the University of Illinois in Urbana, and then carried out postdoctoral research at the Max Planck Institute in Gottingen, Germany. After various positions at the Dana Farber Cancer Institute, Bristol-Myers Squibb, and Cytokine Networks, he joined Seattle Genetics in 1998, and initiated research programs that led to the technology used for SGN-35 and other promising antibody drug conjugates. Henning Steinhagen graduated in Organic Chemistry from the University of Heidelberg, Germany in 1998. He then joined the group of Prof. E.J. Corey at Harvard University, Cambridge, USA as postdoctoral fellow. After that he continued his career, working in Discovery Research in Medicinal Chemistry at Bayer, Wuppertal and at Aventis, Frankfurt. In 2009, he joined Grunenthal in Aachen, Germany where he currently acts as Vice President and Global Head of Drug Discovery.

“The book is easy to follow, and the majority of chapters have an updated bibliography. Furthermore, most of them contain diagrams and figures that allow the topic to be easily followed. In short, it is a book where actual issues regarding the use of controlled drug-delivery systems in pathology like cancer are described in a detailed way.”  (ChemMedChem, 1 October 2012)

• Contents to Volume 1Foreword vPreface xviiList of Contributors xixDrug Delivery in Oncology – Challenge and Perspectives Part I Principles of Tumor Targeting 11 Limits of Conventional Cancer Chemotherapy 3Klaus Mross and Felix Kratz1.1 Introduction: The Era of Cancer Chemotherapy 31.2 Dilemma and Challenge of Treating Malignant Diseases 141.3 Adverse Effects 161.3.1 Common Side-Effects 181.3.1.1 Depression of the Immune System 181.3.1.2 Fatigue 191.3.1.3 Tendency to Bleed Easily 191.3.1.4 Gastrointestinal Distress 191.3.1.5 Hair Loss 201.3.2 Damage to Specific Organs 201.3.2.1 Cardiotoxicity 201.3.2.2 Hepatotoxicity 211.3.2.3 Nephrotoxicity 221.3.2.4 Pulmonary Side-Effects 221.3.2.5 Vascular Adverse Effects 231.3.2.6 Tissue Damage (Extravasation) 231.3.2.7 Neurological Side-Effects 241.3.2.8 Secondary Neoplasms 251.3.2.9 Infertility 251.3.2.10 Other Side-Effects 251.4 Supportive Care 251.5 New Approaches Complementing Current Cancer Chemotherapy 261.6 Conclusions and Perspectives 28References 292 Pathophysiological and Vascular Characteristics of Solid Tumors in Relation to Drug Delivery 33Peter Vaupel2.1 Introduction 332.2 Basic Principles of Blood Vessel Formation in Solid Tumors 342.2.1 Angiogenesis 342.2.2 Vascular Co-option 362.2.3 Vasculogenesis 362.2.4 Intussusception 362.2.5 Vascular Mimicry 362.2.6 Microvessel Formation by Myeloid Cells 362.3 Tumor Lymphangiogenesis 372.4 Tumor Vascularity and Blood Flow 372.5 Arteriovenous Shunt Perfusion in Tumors 382.6 Volume and Characteristics of the Tumor Interstitial Space 402.7 Interstitial Fluid Pressure in Tumors 422.8 Role of the Disorganized, Compromised Microcirculation as an Obstacle in Drug Delivery 432.8.1 Blood-Borne Delivery 432.8.2 Extravasation of Anticancer Agents 452.9 Interstitial Barriers to Drug Delivery 462.10 Pathophysiological Tumor Microenvironment as an Obstacle in Tumor Therapy 472.10.1 Hypoxia as an Obstacle in Drug Therapy 482.10.1.1 Direct Effects 482.10.1.2 Indirect Effects Based on Changes in the Transcriptome, in Differential Regulation of Gene Expression, and in Alterations of the Proteome 492.10.1.3 Indirect Effects Based on Enhanced Mutagenesis, Genomic Instability, and Clonal Selection 512.10.1.4 Tumor Hypoxia: An Adverse Parameter in Chemotherapy 512.10.2 Tumor Acidosis and Drug Resistance 532.11 Conclusions 56Acknowledgments 56References 563 Enhanced Permeability and Retention Effect in Relation to Tumor Targeting 65Hiroshi Maeda3.1 Background and Status Quo 653.2 What is the EPR Effect: Mechanism, Uniqueness, and Factors Involved 663.3 Heterogeneity of the EPR Effect: A Problem in Drug Delivery 723.4 Overcoming the Heterogeneity of the EPR Effect for Drug Delivery and How to Enhance the EPR Effect 753.4.1 Angiotensin II-Induced High Blood Pressure 753.4.2 Use of NO-Releasing Agents 783.4.3 Use of Other Vascular Modulators 793.5 PEG Dilemma: Stealth Effect and Anti-PEG IgM Antibody 793.6 Concluding Remarks 80Acknowledgments 81References 814 Pharmacokinetics of Immunoglobulin G and Serum Albumin: Impact of the Neonatal Fc Receptor on Drug Design 85Jan Terje Andersen and Inger Sandlie4.1 Introduction 854.2 Discovery of FcRn 874.3 FcRn Structure 884.4 FcRn–Ligand Interactions 894.5 FcRn as a Multiplayer with Therapeutic Utilities 904.5.1 Directional Placental Transport 904.5.2 FcRn at Mucosal Surfaces 914.5.3 Systemic FcRn-Mediated Recycling 924.5.4 Role of FcRn in Antigen Presentation 934.5.5 FcRn at Immune-Privileged Sites 944.5.6 FcRn in the Kidneys 944.5.7 FcRn Expressed by the Liver 954.6 Engineering IgG for Altered FcRn Binding and Pharmacokinetics 954.6.1 IgG Fc Fusions 954.6.2 Engineered IgG Variants 964.6.3 Blocking FcRn Recycling 1024.7 Targeting FcRn by SA 1024.7.1 SA Fusions 1024.7.2 Targeting SA 1054.8 Considering Cross-Species Binding 1114.9 Concluding Remarks 113Acknowledgment 113References 1135 Development of Cancer-Targeting Ligands and Ligand–Drug Conjugates 121Ruiwu Liu, Kai Xiao, Juntao Luo, and Kit S. Lam5.1 Introduction 1215.2 Overview of Cancer-Targeting Ligand–Drug Conjugates 1225.3 Cancer-Targeting Ligands 1255.3.1 Introduction 1255.3.2 Phage-Display Library Approach 1255.3.2.1 Phage-Display Library Screening and Decoding 1275.3.2.2 Examples 1275.3.3 OBOC Combinatorial Library Approach 1315.3.3.1 OBOC Library Design 1325.3.3.2 OBOC Library Construction 1355.3.3.3 OBOC Library Screening 1375.3.3.4 OBOC Library Decoding 1385.3.3.5 Ligand Optimization 1395.3.3.6 Examples 1405.4 Linkers 1435.4.1 Acid-Sensitive Linkers 1435.4.2 Enzymatic Cleavage 1435.4.3 Self-Immolative Spacers 1455.4.4 Reductive Cleavage 1465.4.5 On-Demand Cleavable Linker 1465.5 Examples of Cancer-Targeting Ligand–Drug Conjugates 1475.5.1 Folic Acid–Drug Conjugates 1475.5.2 Peptide Ligand–Drug Conjugates 1485.5.3 Peptide Hormone–Drug Conjugates 1505.5.4 Antibody–Drug Conjugates 1515.5.5 Adept 1545.5.6 Polymer–Drug Conjugates 1565.5.7 Targeting Liposomes and Nanoparticles 1585.6 Conclusions and Perspectives 159Acknowledgments 160References 1606 Antibody-Directed Enzyme Prodrug Therapy (ADEPT) – Basic Principles and its Practice So Far 169Kenneth D. Bagshawe6.1 Introduction 1696.2 Principles and the Components of ADEPT 1706.2.1 Target 1706.2.2 Antibody 1716.2.3 Enzyme 1726.2.4 Prodrug and Drug 1736.3 Third Essential 1736.4 ADEPT Studies Elsewhere 1756.5 Reagents for First Clinical Trials in London (1990–1995) 1766.5.1 First ADEPT Clinical Trial 1776.5.2 Subsequent ADEPT Clinical Studies in London 1786.5.3 Two-Phase ADEPT Clinical Studies in London 1796.6 Technology Advances 1796.7 ADEPT Future 181References 181Part II Tumor Imaging 1877 Imaging Techniques in Drug Development and Clinical Practice 189John C. Chang, Sanjiv S. Gambhir, and Jürgen K. Willmann7.1 Introduction 1897.2 Cancer Biology 1917.2.1 Tumor Genetic Heterogeneity 1917.2.2 Altered Tumor Metabolism 1917.2.3 Tumor Angiogenesis 1927.2.4 Receptor Pathologies 1947.3 Cancer Biomarkers 1947.3.1 Histological Biomarkers 1947.3.2 Hematological Biomarkers 1967.3.3 Imaging Biomarkers 1967.4 Imaging Techniques 1977.4.1 Spect 1977.4.2 Pet/pet-ct 1987.4.3 Mri 1987.4.4 Ct 1997.4.5 Ultrasound 1997.4.6 Fluorescence/Bioluminescence 2007.5 Examples of Imaging Assessment of Tumor Response 2007.5.1 Spect 2007.5.2 Pet/pet-ct 2017.5.2.1 Microdosing 2017.5.2.2 Cancer Metabolism and Proliferation 2027.5.2.3 Hypoxia 2047.5.2.4 Biomarker Imaging 2057.5.2.5 Angiogenesis 2077.5.2.6 Apoptosis 2077.5.3 Mri 2077.5.3.1 Cellular Structure 2097.5.3.2 Metabolic Response 2097.5.3.3 Tumor Perfusion 2107.5.4 CT Imaging 2117.5.5 Ultrasound 2127.5.6 Fluorescence/Bioluminescence 2137.6 Challenges of Imaging in Drug Development and Validation 2147.7 Conclusions and Future Perspectives 215References 2178 Magnetic Nanoparticles in Magnetic Resonance Imaging and Drug Delivery 225Patrick D. Sutphin, Efrén J. Flores, and Mukesh Harisinghani8.1 Introduction 2258.2 Passive Targeting of Nanoparticles 2278.2.1 Mechanism of Action 2298.2.2 Lymphotropic Nanoparticle MRI 2298.3 Active SPIO Nanoparticle Targeting 2328.3.1 Creating the Targeted Imaging Agents 2338.3.1.1 Transferrin–USPIO Nanoparticles 2338.3.1.2 Folate Receptor 2358.3.1.3 Integrins 2358.4 Nanoparticles in Targeted Therapy 2368.4.1 Nanoparticles in Gene Therapy 2378.4.2 Nanoparticles in Molecularly Targeted Drug Delivery 2388.4.3 Conversion of Therapeutic Agent to Imaging Agent 2398.4.4 Toxic Payload 2408.5 Conclusions 240References 2429 Preclinical and Clinical Tumor Imaging with SPECT/CT and Pet/ct 247Andreas K. Buck, Florian Gärtner, Ambros Beer, Ken Herrmann, Sibylle Ziegler, and Markus Schwaiger9.1 Introduction 2479.2 Technical Aspects of Functional and Molecular Imaging with SPECT and PET 2499.2.1 Principles of Clinical PET and Hybrid PET/CT Imaging 2499.2.2 Biomarkers for PET and PET/CT Imaging 2509.2.3 Principles of Clinical SPECT and Hybrid SPECT CT Imaging 2529.2.4 Biomarkers for SPECT and SPECT/CT Imaging 2589.2.5 Principles of Preclinical Imaging with SPECT and PET 2589.3 Preclinical and Clinical Developments 2609.3.1 Imaging Neoangiogenesis 2609.3.1.1 VEGF/VEGFR Imaging 2619.3.1.2 Radiolabeled Integrin Antagonists (RGD Peptides) 2629.3.1.3 Monomeric Tracer Labeling Strategies 2629.3.2 Imaging the Proliferative Activity of Tumors 2649.3.3 Imaging the Hypoxic Cell Fraction of Tumors 2679.3.4 Imaging Receptor Expression 2699.4 Clinical Applications of SPECT/CT and PET 2729.4.1 Differentiation of Benign from Malignant Tumors and Cancer Detection 2729.4.2 Staging of Cancer: Prognostic Potential of Imaging Biomarkers 2739.4.3 Assessment of Response to Therapy 2749.4.4 Restaging of Cancer and Detection of Recurrence 2749.4.5 PET for Radiation Treatment Planning 2759.4.6 PET for Cancer Drug Development 2759.4.7 SPECT/CT for Mapping of SLNs 2769.4.8 SPECT/CT for Detection of Bone Metastases 2779.4.9 SPECT/CT in Thyroid Cancer 2789.4.10 SPECT/CT for Imaging of Adrenocortical Tumors 2799.4.11 SPECT/CT in Neuroendocrine Tumors 2819.5 Conclusions and Perspectives 281References 282Contents to Volume 2Part III Macromolecular Drug Delivery Systems 289Antibody-Based Systems 28910 Empowered Antibodies for Cancer Therapy 291Stephen C. Alley, Simone Jeger, Robert P. Lyon, Django Sussman, and Peter D. Senter11 Mapping Accessible Vascular Targets to Penetrate Organs and Solid Tumors 325Kerri A. Massey and Jan E. Schnitzer12 Considerations of Linker Technologies 355Laurent Ducry13 Antibody–Maytansinoid Conjugates: From the Bench to the Clinic 375Hans Erickson14 Calicheamicin Antibody–Drug Conjugates and Beyond 395Puja Sapra, John DiJoseph, and Hans-Peter Gerber15 Antibodies for the Delivery of Radionuclides 411Anna M. Wu16 Bispecific Antibodies and Immune Therapy Targeting 441Sergej M. KiprijanovPolymer-Based Systems 48317 Design of Polymer–Drug Conjugates 485Jindřich Kopeček and Pavla Kopečková18 Dendritic Polymers in Oncology: Facts, Features, and Applications 513Mohiuddin Abdul Quadir, Marcelo Calderón, and Rainer Haag19 Site-Specific Prodrug Activation and the Concept of Self-Immolation 553André Warnecke20 Ligand-Assisted Vascular Targeting of Polymer Therapeutics 591Anat Eldar-Boock, Dina Polyak, and Ronit Satchi-Fainaro21 Drug Conjugates with Poly(Ethylene Glycol) 627Hong Zhao, Lee M. Greenberger, and Ivan D. Horak22 Thermo-Responsive Polymers 667Drazen Raucher and Shama Moktan23 Polysaccharide-Based Drug Conjugates for Tumor Targeting 701Gurusamy Saravanakumar, Jae Hyung Park, Kwangmeyung Kim, and Ick Chan Kwon24 Serum Proteins as Drug Carriers of Anticancer Agents 747Felix Kratz, Andreas Wunder, and Bakheet Elsadek25 Future Trends, Challenges, and Opportunities with Polymer-Based Combination Therapy in Cancer 805Coralie Deladriere, Rut Lucas, and María J. Vicent26 Clinical Experience with Drug–Polymer Conjugates 839Khalid Abu Ajaj and Felix KratzPart IV Nano- and Microparticulate Drug Delivery Systems 885Lipid-Based Systems 88527 Overview on Nanocarriers as Delivery Systems 887Haifa Shen, Elvin Blanco, Biana Godin, Rita E. Serda, Agathe K. Streiff, and Mauro Ferrari28 Development of PEGylated Liposomes 907I. Craig Henderson29 Immunoliposomes 951Vladimir P. Torchilin30 Responsive Liposomes (for Solid Tumor Therapy) 989Stavroula Sofou31 Nanoscale Delivery Systems for Combination Chemotherapy 1013Barry D. Liboiron, Paul G. Tardi, Troy O. Harasym, and Lawrence, D. MayerPolymer-Based Systems 105132 Micellar Structures as Drug Delivery Systems 1053Nobuhiro Nishiyama, Horacio Cabral, and Kazunori Kataoka33 Tailor-Made Hydrogels for Tumor Delivery 1071Sungwon Kim and Kinam Park34 pH-Triggered Micelles for Tumor Delivery 1099Haiqing Yin and You Han Bae35 Albumin–Drug Nanoparticles 1133Neil Desai36 Carbon Nanotubes 1163David A. Scheinberg, Carlos H. Villa, Freddy Escorcia, and Michael R. McDevittContents to Volume 3Part V Ligand-Based Drug Delivery Systems 118737 Cell-Penetrating Peptides in Cancer Targeting 1189Kaido Kurrikoff, Julia Suhorutšenko, and Ülo Langel38 Targeting to Peptide Receptors 1219Andrew V. Schally and Gabor Halmos39 Aptamer Conjugates: Emerging Delivery Platforms for Targeted Cancer Therapy 1263Zeyu Xiao, Jillian Frieder, Benjamin A. Teply, and Omid C. Farokhzad40 Design and Synthesis of Drug Conjugates of Vitamins and Growth Factors 1283Iontcho R. Vlahov, Paul J. Kleindl, and Fei You41 Drug Conjugates with Polyunsaturated Fatty Acids 1323Joshua Seitz and Iwao OjimaPart VI Special Topics 135942 RNA Drug Delivery Approaches 1361Yuan Zhang and Leaf Huang43 Local Gene Delivery for Therapy of Solid Tumors 1391Wolfgang Walther, Peter M. Schlag, and Ulrike Stein44 Viral Vectors for RNA Interference Applications in Cancer Research and Therapy 1415Henry Fechner and Jens Kurreck45 Design of Targeted Protein Toxins 1443Hendrik Fuchs and Christopher Bachran46 Drug Targeting to the Central Nervous System 1489Gert Fricker, Anne Mahringer, Melanie Ott, and Valeska Reichel47 Liver Tumor Targeting 1519Katrin Hochdörffer, Giuseppina Di Stefano, Hiroshi Maeda, and Felix Kratz48 Photodynamic Therapy: Photosensitizer Targeting and Delivery 1569Pawel Mroz, Sulbha K. Sharma, Timur Zhiyentayev, Ying-Ying Huang, and Michael R. Hamblin49 Tumor-Targeting Strategies with Anticancer Platinum Complexes 1605Mathea Sophia Galanski and Bernhard K. KepplerIndex 1631

Felix Kratz graduated in Chemistry from the University of Heidelberg in 1991. He then carried out postdoctoral research at the Bioinorganic Institute of the University of Florence and developed tumor-specifi c carrier systems with ruthenium(III) complexes. Since 1994 he has been Head of Macromolecular Prodrugs at the Tumor Biology Center in Freiburg, Germany, where he is now in charge of organizing and managing translational research from the laboratory to the clinic. His research areas are drug targeting, drug-delivery systems in oncology, prodrugs, receptor targeting, bioconjugate chemistry, and nanocarriers. Peter Senter earned his PhD in Chemistry from the University of Illinois in Urbana, and then carried out postdoctoral research at the Max Planck Institute in Gottingen, Germany. After various positions at the Dana Farber Cancer Institute, Bristol-Myers Squibb, and Cytokine Networks, he joined Seattle Genetics in 1998, and initiated research programs that led to the technology used for SGN-35 and other promising antibody drug conjugates. Henning Steinhagen graduated in Organic Chemistry from the University of Heidelberg, Germany in 1998. He then joined the group of Prof. E.J. Corey at Harvard University, Cambridge, USA as postdoctoral fellow. After that he continued his career, working in Discovery Research in Medicinal Chemistry at Bayer, Wuppertal and at Aventis, Frankfurt. In 2009, he joined Grunenthal in Aachen, Germany where he currently acts as Vice President and Global Head of Drug Discovery.

“The book is easy to follow, and the majority of chapters have an updated bibliography. Furthermore, most of them contain diagrams and figures that allow the topic to be easily followed. In short, it is a book where actual issues regarding the use of controlled drug-delivery systems in pathology like cancer are described in a detailed way.”  (ChemMedChem, 1 October 2012)

• Contents to Volume 1Foreword vPreface xviiList of Contributors xixDrug Delivery in Oncology – Challenge and Perspectives Part I Principles of Tumor Targeting 11 Limits of Conventional Cancer Chemotherapy 3Klaus Mross and Felix Kratz1.1 Introduction: The Era of Cancer Chemotherapy 31.2 Dilemma and Challenge of Treating Malignant Diseases 141.3 Adverse Effects 161.3.1 Common Side-Effects 181.3.1.1 Depression of the Immune System 181.3.1.2 Fatigue 191.3.1.3 Tendency to Bleed Easily 191.3.1.4 Gastrointestinal Distress 191.3.1.5 Hair Loss 201.3.2 Damage to Specific Organs 201.3.2.1 Cardiotoxicity 201.3.2.2 Hepatotoxicity 211.3.2.3 Nephrotoxicity 221.3.2.4 Pulmonary Side-Effects 221.3.2.5 Vascular Adverse Effects 231.3.2.6 Tissue Damage (Extravasation) 231.3.2.7 Neurological Side-Effects 241.3.2.8 Secondary Neoplasms 251.3.2.9 Infertility 251.3.2.10 Other Side-Effects 251.4 Supportive Care 251.5 New Approaches Complementing Current Cancer Chemotherapy 261.6 Conclusions and Perspectives 28References 292 Pathophysiological and Vascular Characteristics of Solid Tumors in Relation to Drug Delivery 33Peter Vaupel2.1 Introduction 332.2 Basic Principles of Blood Vessel Formation in Solid Tumors 342.2.1 Angiogenesis 342.2.2 Vascular Co-option 362.2.3 Vasculogenesis 362.2.4 Intussusception 362.2.5 Vascular Mimicry 362.2.6 Microvessel Formation by Myeloid Cells 362.3 Tumor Lymphangiogenesis 372.4 Tumor Vascularity and Blood Flow 372.5 Arteriovenous Shunt Perfusion in Tumors 382.6 Volume and Characteristics of the Tumor Interstitial Space 402.7 Interstitial Fluid Pressure in Tumors 422.8 Role of the Disorganized, Compromised Microcirculation as an Obstacle in Drug Delivery 432.8.1 Blood-Borne Delivery 432.8.2 Extravasation of Anticancer Agents 452.9 Interstitial Barriers to Drug Delivery 462.10 Pathophysiological Tumor Microenvironment as an Obstacle in Tumor Therapy 472.10.1 Hypoxia as an Obstacle in Drug Therapy 482.10.1.1 Direct Effects 482.10.1.2 Indirect Effects Based on Changes in the Transcriptome, in Differential Regulation of Gene Expression, and in Alterations of the Proteome 492.10.1.3 Indirect Effects Based on Enhanced Mutagenesis, Genomic Instability, and Clonal Selection 512.10.1.4 Tumor Hypoxia: An Adverse Parameter in Chemotherapy 512.10.2 Tumor Acidosis and Drug Resistance 532.11 Conclusions 56Acknowledgments 56References 563 Enhanced Permeability and Retention Effect in Relation to Tumor Targeting 65Hiroshi Maeda3.1 Background and Status Quo 653.2 What is the EPR Effect: Mechanism, Uniqueness, and Factors Involved 663.3 Heterogeneity of the EPR Effect: A Problem in Drug Delivery 723.4 Overcoming the Heterogeneity of the EPR Effect for Drug Delivery and How to Enhance the EPR Effect 753.4.1 Angiotensin II-Induced High Blood Pressure 753.4.2 Use of NO-Releasing Agents 783.4.3 Use of Other Vascular Modulators 793.5 PEG Dilemma: Stealth Effect and Anti-PEG IgM Antibody 793.6 Concluding Remarks 80Acknowledgments 81References 814 Pharmacokinetics of Immunoglobulin G and Serum Albumin: Impact of the Neonatal Fc Receptor on Drug Design 85Jan Terje Andersen and Inger Sandlie4.1 Introduction 854.2 Discovery of FcRn 874.3 FcRn Structure 884.4 FcRn–Ligand Interactions 894.5 FcRn as a Multiplayer with Therapeutic Utilities 904.5.1 Directional Placental Transport 904.5.2 FcRn at Mucosal Surfaces 914.5.3 Systemic FcRn-Mediated Recycling 924.5.4 Role of FcRn in Antigen Presentation 934.5.5 FcRn at Immune-Privileged Sites 944.5.6 FcRn in the Kidneys 944.5.7 FcRn Expressed by the Liver 954.6 Engineering IgG for Altered FcRn Binding and Pharmacokinetics 954.6.1 IgG Fc Fusions 954.6.2 Engineered IgG Variants 964.6.3 Blocking FcRn Recycling 1024.7 Targeting FcRn by SA 1024.7.1 SA Fusions 1024.7.2 Targeting SA 1054.8 Considering Cross-Species Binding 1114.9 Concluding Remarks 113Acknowledgment 113References 1135 Development of Cancer-Targeting Ligands and Ligand–Drug Conjugates 121Ruiwu Liu, Kai Xiao, Juntao Luo, and Kit S. Lam5.1 Introduction 1215.2 Overview of Cancer-Targeting Ligand–Drug Conjugates 1225.3 Cancer-Targeting Ligands 1255.3.1 Introduction 1255.3.2 Phage-Display Library Approach 1255.3.2.1 Phage-Display Library Screening and Decoding 1275.3.2.2 Examples 1275.3.3 OBOC Combinatorial Library Approach 1315.3.3.1 OBOC Library Design 1325.3.3.2 OBOC Library Construction 1355.3.3.3 OBOC Library Screening 1375.3.3.4 OBOC Library Decoding 1385.3.3.5 Ligand Optimization 1395.3.3.6 Examples 1405.4 Linkers 1435.4.1 Acid-Sensitive Linkers 1435.4.2 Enzymatic Cleavage 1435.4.3 Self-Immolative Spacers 1455.4.4 Reductive Cleavage 1465.4.5 On-Demand Cleavable Linker 1465.5 Examples of Cancer-Targeting Ligand–Drug Conjugates 1475.5.1 Folic Acid–Drug Conjugates 1475.5.2 Peptide Ligand–Drug Conjugates 1485.5.3 Peptide Hormone–Drug Conjugates 1505.5.4 Antibody–Drug Conjugates 1515.5.5 Adept 1545.5.6 Polymer–Drug Conjugates 1565.5.7 Targeting Liposomes and Nanoparticles 1585.6 Conclusions and Perspectives 159Acknowledgments 160References 1606 Antibody-Directed Enzyme Prodrug Therapy (ADEPT) – Basic Principles and its Practice So Far 169Kenneth D. Bagshawe6.1 Introduction 1696.2 Principles and the Components of ADEPT 1706.2.1 Target 1706.2.2 Antibody 1716.2.3 Enzyme 1726.2.4 Prodrug and Drug 1736.3 Third Essential 1736.4 ADEPT Studies Elsewhere 1756.5 Reagents for First Clinical Trials in London (1990–1995) 1766.5.1 First ADEPT Clinical Trial 1776.5.2 Subsequent ADEPT Clinical Studies in London 1786.5.3 Two-Phase ADEPT Clinical Studies in London 1796.6 Technology Advances 1796.7 ADEPT Future 181References 181Part II Tumor Imaging 1877 Imaging Techniques in Drug Development and Clinical Practice 189John C. Chang, Sanjiv S. Gambhir, and Jürgen K. Willmann7.1 Introduction 1897.2 Cancer Biology 1917.2.1 Tumor Genetic Heterogeneity 1917.2.2 Altered Tumor Metabolism 1917.2.3 Tumor Angiogenesis 1927.2.4 Receptor Pathologies 1947.3 Cancer Biomarkers 1947.3.1 Histological Biomarkers 1947.3.2 Hematological Biomarkers 1967.3.3 Imaging Biomarkers 1967.4 Imaging Techniques 1977.4.1 Spect 1977.4.2 Pet/pet-ct 1987.4.3 Mri 1987.4.4 Ct 1997.4.5 Ultrasound 1997.4.6 Fluorescence/Bioluminescence 2007.5 Examples of Imaging Assessment of Tumor Response 2007.5.1 Spect 2007.5.2 Pet/pet-ct 2017.5.2.1 Microdosing 2017.5.2.2 Cancer Metabolism and Proliferation 2027.5.2.3 Hypoxia 2047.5.2.4 Biomarker Imaging 2057.5.2.5 Angiogenesis 2077.5.2.6 Apoptosis 2077.5.3 Mri 2077.5.3.1 Cellular Structure 2097.5.3.2 Metabolic Response 2097.5.3.3 Tumor Perfusion 2107.5.4 CT Imaging 2117.5.5 Ultrasound 2127.5.6 Fluorescence/Bioluminescence 2137.6 Challenges of Imaging in Drug Development and Validation 2147.7 Conclusions and Future Perspectives 215References 2178 Magnetic Nanoparticles in Magnetic Resonance Imaging and Drug Delivery 225Patrick D. Sutphin, Efrén J. Flores, and Mukesh Harisinghani8.1 Introduction 2258.2 Passive Targeting of Nanoparticles 2278.2.1 Mechanism of Action 2298.2.2 Lymphotropic Nanoparticle MRI 2298.3 Active SPIO Nanoparticle Targeting 2328.3.1 Creating the Targeted Imaging Agents 2338.3.1.1 Transferrin–USPIO Nanoparticles 2338.3.1.2 Folate Receptor 2358.3.1.3 Integrins 2358.4 Nanoparticles in Targeted Therapy 2368.4.1 Nanoparticles in Gene Therapy 2378.4.2 Nanoparticles in Molecularly Targeted Drug Delivery 2388.4.3 Conversion of Therapeutic Agent to Imaging Agent 2398.4.4 Toxic Payload 2408.5 Conclusions 240References 2429 Preclinical and Clinical Tumor Imaging with SPECT/CT and Pet/ct 247Andreas K. Buck, Florian Gärtner, Ambros Beer, Ken Herrmann, Sibylle Ziegler, and Markus Schwaiger9.1 Introduction 2479.2 Technical Aspects of Functional and Molecular Imaging with SPECT and PET 2499.2.1 Principles of Clinical PET and Hybrid PET/CT Imaging 2499.2.2 Biomarkers for PET and PET/CT Imaging 2509.2.3 Principles of Clinical SPECT and Hybrid SPECT CT Imaging 2529.2.4 Biomarkers for SPECT and SPECT/CT Imaging 2589.2.5 Principles of Preclinical Imaging with SPECT and PET 2589.3 Preclinical and Clinical Developments 2609.3.1 Imaging Neoangiogenesis 2609.3.1.1 VEGF/VEGFR Imaging 2619.3.1.2 Radiolabeled Integrin Antagonists (RGD Peptides) 2629.3.1.3 Monomeric Tracer Labeling Strategies 2629.3.2 Imaging the Proliferative Activity of Tumors 2649.3.3 Imaging the Hypoxic Cell Fraction of Tumors 2679.3.4 Imaging Receptor Expression 2699.4 Clinical Applications of SPECT/CT and PET 2729.4.1 Differentiation of Benign from Malignant Tumors and Cancer Detection 2729.4.2 Staging of Cancer: Prognostic Potential of Imaging Biomarkers 2739.4.3 Assessment of Response to Therapy 2749.4.4 Restaging of Cancer and Detection of Recurrence 2749.4.5 PET for Radiation Treatment Planning 2759.4.6 PET for Cancer Drug Development 2759.4.7 SPECT/CT for Mapping of SLNs 2769.4.8 SPECT/CT for Detection of Bone Metastases 2779.4.9 SPECT/CT in Thyroid Cancer 2789.4.10 SPECT/CT for Imaging of Adrenocortical Tumors 2799.4.11 SPECT/CT in Neuroendocrine Tumors 2819.5 Conclusions and Perspectives 281References 282Contents to Volume 2Part III Macromolecular Drug Delivery Systems 289Antibody-Based Systems 28910 Empowered Antibodies for Cancer Therapy 291Stephen C. Alley, Simone Jeger, Robert P. Lyon, Django Sussman, and Peter D. Senter11 Mapping Accessible Vascular Targets to Penetrate Organs and Solid Tumors 325Kerri A. Massey and Jan E. Schnitzer12 Considerations of Linker Technologies 355Laurent Ducry13 Antibody–Maytansinoid Conjugates: From the Bench to the Clinic 375Hans Erickson14 Calicheamicin Antibody–Drug Conjugates and Beyond 395Puja Sapra, John DiJoseph, and Hans-Peter Gerber15 Antibodies for the Delivery of Radionuclides 411Anna M. Wu16 Bispecific Antibodies and Immune Therapy Targeting 441Sergej M. KiprijanovPolymer-Based Systems 48317 Design of Polymer–Drug Conjugates 485Jindřich Kopeček and Pavla Kopečková18 Dendritic Polymers in Oncology: Facts, Features, and Applications 513Mohiuddin Abdul Quadir, Marcelo Calderón, and Rainer Haag19 Site-Specific Prodrug Activation and the Concept of Self-Immolation 553André Warnecke20 Ligand-Assisted Vascular Targeting of Polymer Therapeutics 591Anat Eldar-Boock, Dina Polyak, and Ronit Satchi-Fainaro21 Drug Conjugates with Poly(Ethylene Glycol) 627Hong Zhao, Lee M. Greenberger, and Ivan D. Horak22 Thermo-Responsive Polymers 667Drazen Raucher and Shama Moktan23 Polysaccharide-Based Drug Conjugates for Tumor Targeting 701Gurusamy Saravanakumar, Jae Hyung Park, Kwangmeyung Kim, and Ick Chan Kwon24 Serum Proteins as Drug Carriers of Anticancer Agents 747Felix Kratz, Andreas Wunder, and Bakheet Elsadek25 Future Trends, Challenges, and Opportunities with Polymer-Based Combination Therapy in Cancer 805Coralie Deladriere, Rut Lucas, and María J. Vicent26 Clinical Experience with Drug–Polymer Conjugates 839Khalid Abu Ajaj and Felix KratzPart IV Nano- and Microparticulate Drug Delivery Systems 885Lipid-Based Systems 88527 Overview on Nanocarriers as Delivery Systems 887Haifa Shen, Elvin Blanco, Biana Godin, Rita E. Serda, Agathe K. Streiff, and Mauro Ferrari28 Development of PEGylated Liposomes 907I. Craig Henderson29 Immunoliposomes 951Vladimir P. Torchilin30 Responsive Liposomes (for Solid Tumor Therapy) 989Stavroula Sofou31 Nanoscale Delivery Systems for Combination Chemotherapy 1013Barry D. Liboiron, Paul G. Tardi, Troy O. Harasym, and Lawrence, D. MayerPolymer-Based Systems 105132 Micellar Structures as Drug Delivery Systems 1053Nobuhiro Nishiyama, Horacio Cabral, and Kazunori Kataoka33 Tailor-Made Hydrogels for Tumor Delivery 1071Sungwon Kim and Kinam Park34 pH-Triggered Micelles for Tumor Delivery 1099Haiqing Yin and You Han Bae35 Albumin–Drug Nanoparticles 1133Neil Desai36 Carbon Nanotubes 1163David A. Scheinberg, Carlos H. Villa, Freddy Escorcia, and Michael R. McDevittContents to Volume 3Part V Ligand-Based Drug Delivery Systems 118737 Cell-Penetrating Peptides in Cancer Targeting 1189Kaido Kurrikoff, Julia Suhorutšenko, and Ülo Langel38 Targeting to Peptide Receptors 1219Andrew V. Schally and Gabor Halmos39 Aptamer Conjugates: Emerging Delivery Platforms for Targeted Cancer Therapy 1263Zeyu Xiao, Jillian Frieder, Benjamin A. Teply, and Omid C. Farokhzad40 Design and Synthesis of Drug Conjugates of Vitamins and Growth Factors 1283Iontcho R. Vlahov, Paul J. Kleindl, and Fei You41 Drug Conjugates with Polyunsaturated Fatty Acids 1323Joshua Seitz and Iwao OjimaPart VI Special Topics 135942 RNA Drug Delivery Approaches 1361Yuan Zhang and Leaf Huang43 Local Gene Delivery for Therapy of Solid Tumors 1391Wolfgang Walther, Peter M. Schlag, and Ulrike Stein44 Viral Vectors for RNA Interference Applications in Cancer Research and Therapy 1415Henry Fechner and Jens Kurreck45 Design of Targeted Protein Toxins 1443Hendrik Fuchs and Christopher Bachran46 Drug Targeting to the Central Nervous System 1489Gert Fricker, Anne Mahringer, Melanie Ott, and Valeska Reichel47 Liver Tumor Targeting 1519Katrin Hochdörffer, Giuseppina Di Stefano, Hiroshi Maeda, and Felix Kratz48 Photodynamic Therapy: Photosensitizer Targeting and Delivery 1569Pawel Mroz, Sulbha K. Sharma, Timur Zhiyentayev, Ying-Ying Huang, and Michael R. Hamblin49 Tumor-Targeting Strategies with Anticancer Platinum Complexes 1605Mathea Sophia Galanski and Bernhard K. KepplerIndex 1631