Advances in Photodynamic TherapyBasic, Translational, and Clinical -- Contents vii -- Preface xix -- CHAPTER 1 -- History of PDT: The First Hundred Years 1 -- 1.1 Introduction 1 -- 1.2 Early Studies with Dyes 1 -- 1.3 Studies with Hematoporphyrin 2 -- 1.4 Discovery of Hematoporphyrin Derivative 3 -- 1.5 Clinical Photodection Studies with HpD 4 -- 1.6 Cancer Treatment with Porphyrins and Light in Animal Models 6 -- 1.7 Early Clinical Studies with HpD and Light 7 -- 1.8 Explosion of Interest in PDT from 1980s Onwards -- CHAPTER 2 -- Photosensitizers for Photodynamic Therapy and Imaging 13 -- 2.1 Introduction 13 -- 2.2 Ideal Properties of Photosensitizers 13 -- 2.3 Porphyrins as Photosensitizers in PDT 16 -- 2.4 Effect of Central Metal in Photosensitizing Efficacy 18 -- 2.5 Problems Associated with Porphyrin-Based Photosensitizers 34 -- 2.6 Importance of Bifunctional Agents (Imaging and PDT) 35 -- 2.7 Conclusions 37 -- CHAPTER 3 -- Photophysics and Photochemistry in Photodynamic Therapy 41 -- 3.1 Introduction 41 -- 3.2 Electronic Excitation and Excited States 41 -- 3.3 Rates of Excited State Processes 43 -- 3.4 Two Photon Excitation 44 -- 3.5 Singlet Oxygen Generation 45 -- 3.6 Type I and Type II Photochemistry 48 -- 3.7 Spectroscopic Methods to Determine Reaction Mechanisms 49 -- 3.8 Influence of Biological Environment 51 -- 3.9 Rate Constants and Biological Reality 54 -- 3.10 Secondary Reactive Oxygen Species (ROS) 54 -- CHAPTER 4 -- Pharmaceutical and Biological Considerations in 5-Aminolevulinic Acid in PDT 59 -- 4.1 Introduction 59 -- 4.2 Heme Biosynthesis 63 -- 4.3 Selective PpIX Formation in Neoplastic Tissue 62 -- 4.4 Pharmaceutical and Biopharmaceutical Considerations60 -- 4.5 Conclusions 80 -- CHAPTER 5 -- Light Dosimetry and Light Sources for Photodynamic Therapy 93 -- 5.1 Introduction 93 -- 5.2 Light Dosimetry 96.

5.3 Light Sources and Delivery 102 -- 5.4 Summary 107 -- CHAPTER 6 -- Cell Killing by Photodynamic Therapy 115 -- 6.1 Introduction: Direct and Indirect Modes of Cell Death After PDT 115 -- 6.2 How Cells Die After Direct Exposure to PDT 115 -- 6.3 Subcellular Photosensitizer Localization and Biomolecular Targets 118 -- 6.4 Conclusions 126 -- CHAPTER 7 -- The Role of Oxygen in Photodynamic Therapy 135 -- 7.1 Introduction 135 -- 7.2 The Primary Effect: Singlet Oxygen Generation 135 -- 7.3 Concentrations of Oxygen in Tumors and Other Tissues 137 -- 7.4 Methods to Increase Tumor Oxygenation 137 -- 7.5 Photosensitization under Anoxia 137 -- 7.6 Reduction of the Oxygen Concentration by PDT Itself 138 -- 7.7 Reoxygenation After PDT 138 -- 7.8 Fluence Rate Effects 139 -- 7.9 Fractionated Light Exposure 139 -- 7.10 Changes of Quantum Yield Related to Sensitizer Relocalization 139 -- 7.11 Oxygen Effects on Sensitizer Photobleaching 140 -- 7.12 Changes of Optical Penetration Caused by Changes in Oxygen Concentration 140 -- 7.13 Conclusions 140 -- CHAPTER 8 -- Photodynamic Therapy and Oxidative Stress 151 -- 8.1 Introduction 151 -- 8.2 Biochemistry of Reactive Oxygen Species 151 -- 8.3 Reactive Oxygen Species and Signal Transduction 155 -- 8.4 Generation of Reactive Oxygen Species During Photodynamic Therapy 155 -- 8.5 ROS-Mediated Damage During Photodynamic Therapy 157 -- 8.6 Intracellular Mechanisms of ROS Scavenging 160 -- 8.7 Cytoprotective Mechanisms Not Directly Associated with ROS Scavenging 164 -- 8.8 Summary 169 -- CHAPTER 9 -- Vascular Targeting in Photodynamic Therapy 179 -- 9.1 Introduction 179 -- 9.2 Tumor Vascular Targeting 179 -- 9.3 Principle of Photodynamic Vascular Targeting 180 -- 9.4 Mechanisms of Photodynamic Vascular Targeting 181 -- 9.5 Therapeutic Challenges of Photodynamic Vascular Targeting 185.

9.6 Current Status of Photodynamic Vascular Targeting 187 -- 9.7 Strategies to Enhance Photodynamic Vascular Targeting 187 -- 9.8 Summary and Conclusions 188 -- CHAPTER 10 -- Covalent Photosensitizer Conjugates, Part 1: Antibodies and Other Proteins for Targeted Photodynamic Therapy 193 -- 10.1 Introduction: Photosensitizer Delivery Strategies 193 -- 10.2 Monoclonal Antibody PS Conjugates 194 -- 10.3 Protein-Photosensitizer Conjugates Recognized by Receptors 206 -- 10.4 Scavenger Receptor Targeted Photodynamic Therapy 208 -- 10.5 Conclusion 211 -- CHAPTER 11 -- Covalent Photosensitizer Conjugates, Part 2: Peptides, Polymers, and Small Molecules for Targeted Photodynamic Therapy 217 -- 11.1 Introduction 217 -- 11.2 Peptide or Growth Factor Conjugates 217 -- 11.3 Polymer-PS Conjugates 220 -- 11.4 Enzyme Cleavable PS Conjugates 225 -- 11.5 Small Molecule-PS Conjugates 227 -- 11.6 Conclusion 230 -- CHAPTER 12 -- Emerging Strategies in Photodynamic Therapy 235 -- 12.1 Introduction 235 -- 12.2 Photosensitizer-Based Strategies 235 -- 12.3 Light-Based Strategies 243 -- 12.4 Photosensitizer and Light Dose-Rate Strategies 246 -- 12.5 Photobiology-Based Strategies 248 -- 12.6 Summary and Conclusions 250 -- CHAPTER 13 -- PDT and Inflammation 255 -- 13.1 Introduction 255 -- 13.2 Cause and Origin 255 -- 13.3 The Onset of Inflammation 257 -- 13.4 Contribution of Complement System and Toll-Like Receptor Signaling 258 -- 13.5 Elimination of Damaged Tissue 259 -- 13.6 Engagement of Acute Phase Response 260 -- 13.7 Downregulation of Inflammation and Healing 261 -- 13.8 Relevance for Immune Response and Therapy Outcome 261 -- 13.9 Conclusions 262 -- CHAPTER 14 -- PDT and Cellular Immunity 267 -- 14.1 Introduction 267 -- 14.2 PDT and Antigen-Presenting Cells (APCs) 268 -- 14.3 PDT and other Innate Immune Cells 271 -- 14.4 PDT and T Lymphocytes 273.

14.5 PDT and Immunosuppression 275 -- 14.6 Conclusion 276 -- CHAPTER 15 -- Photodynamic Therapy in Bone 283 -- Introduction 283 -- 15.1 Photodynamic Therapy for Spinal Metastases 283 -- 15.2 Photodynamic Therapy for Primary Osteosarcoma 289 -- 15.3 Antimicrobial PDT 290 -- 15.4 Bone Growth Modulation 292 -- 15.5 Conclusion 294 -- CHAPTER 16 -- Photochemical Internalization 299 -- 16.1 Introduction 299 -- 16.2 Localization in Endocytic Vesicles and Cytotoxic Effects of Photosensitizers 300 -- 16.3 Photochemical Delivery of Macromolecules 303 -- 16.4 PCI: A Technology for Enhancing the Activity of Macromolecular Therapeutics 304 -- 16.5 Conclusions 300 -- CHAPTER 17 -- Combinations of Photodynamic Therapy with Other Therapeutic Modalities 313 -- 17.1 Introduction 313 -- 17.2 Surgery Combined with PDT 313 -- 17.3 Radiotherapy (RT) Combined with PDT 315 -- 17.4 Chemotherapy (CHT) Combined with PDT 317 -- 17.5 Hyperthermia (HT) Combined with PDT 321 -- 17.6 Sonodynamic Therapy Combined with PDT 322 -- 17.7 Other Methods Combined with PDT 323 -- 17.8 Conclusions 326 -- CHAPTER 18 -- Photodynamic Therapy in Treatment of Infectious Diseases: Basic Aspects and Mechanisms of Action 337 -- 18.1 Introduction 337 -- 18.2 Photodynamic Inactivation of Microbial Cells: The Photosensitizer 18.2.1 Photophysical 339 -- 18.3 Photodynamic Inactivation of Microbial Cells: The Target 346 -- 18.4 Conclusions 353 -- CHAPTER 19 -- Photodynamic Therapy for Infectious Disease 359 -- 19.1 Introduction 359 -- 19.2 PDT in Animal Models of Infection 360 -- 19.3 PDT of Bioluminescent Bacterial Infections in Mice 362 -- 19.4 Clinical Studies in Antimicrobial PDT 368 -- 19.5 Conclusion 371 -- CHAPTER 20 -- PDT for Cardiovascular Disease 375 -- 20.1 Introduction 375 -- 20.2 Cardiovascular PDT In Vitro 376 -- 20.3 Studies on Ex Vivo Arteries 377.

20.4 PDT for Atherosclerosis In Vivo 379 -- 20.5 PDT for Prevention and Treatment of Intimal Hyperplasia 384 -- 20.6 Cardiovascular PDT in Clinical Trials 380 -- 20.7 Conclusions 390 -- CHAPTER 21 -- Photodynamic Therapy for Neovascular Eye Diseases: Past, Present, and Future 395 -- 21.1 Introduction 395 -- 21.2 The Pathogenesis of Wet AMD 395 -- 21.3 Types of AMD 397 -- 21.4 Detection of AMD 397 -- 21.5 Previous Treatments of Exudative (Wet) AMD 398 -- 21.6 Photodynamic Therapy for AMD 399 -- 21.7 Other Therapies for Managing Neovascular AMD 406 -- 21.8 Combination Therapy 409 -- 21.9 Photodynamic Drug Delivery to the Eye 411 -- 21.10 PDT of Polypoidal Choroidal Vasculopathy (PCV) 412 -- 21.11 Conclusions 412 -- CHAPTER 22 -- PDT in Dermatology 419 -- 22.1 Introduction 419 -- 22.2 Cutaneous Applications 419 -- 22.3 Basal Cell Carcinoma 424 -- 22.4 Bowen's Disease 426 -- 22.5 Disseminated Superficial Actinic Porokeratosis (DSAP) 427 -- 22.6 Inflammatory/Immunologic Dermatologic Diseases 427 -- 22.7 Photodynamic Photorejuvenation 432 -- 22.8 Other Disorders 433 -- 22.9 Miscellaneous 436 -- 22.10 Conclusions 436 -- CHAPTER 23 -- Role of Photodynamic Therapy (PDT) in Lung Cancer 443 -- 23.1 Introduction 443 -- 23.2 PDT in Lung Cancer 445 -- 23.3 Bronchoscopic PDT for Lung Cancer: Indications and Selection of Patients 447 -- 23.4 Technique of Bronchoscopic PDT in Lung Cancer 450 -- 23.5 Results of Bronchoscopic PDT 452 -- 23.6 Miscellaneous Indications of Bronchoscopic PDT 455 -- 23.7 PDT for Peripheral Lung Cancer 456 -- 23.8 Conclusion 456 -- CHAPTER 24 -- Photodynamic Therapy of the Gastrointestinal Tract Beyond the Esophagus 461 -- 24.1 Introduction 461 -- 24.2 Stomach 461 -- 24.3 Duodenum and Ampulla 464 -- 24.4 Biliary System 465 -- 24.5 Pancreas 469 -- 24.6 Colon and Rectal Cancers 470 -- 24.7 Conclusion 472 -- CHAPTER 25.

Photodynamic Therapy in the Esophagus 477.