Yogeshwar Bachhav is a pharmacist by training and holds a PhD in drug delivery systems from ICT, Mumbai (India). He has worked as research scientist for several years on a collaborative project between Pantec Biosolutions and Geneva University (Switzerland), and as formulation manager at Debiopharm Group, Lausanne (Switzerland). For the last 9 years he has been associated with AiCuris Anti-infective Cures AG (Germany) as in-charge for Pharmaceutical development of new drugs. In total, he has around 16 years of experience in the preformulation and formulation development of small molecules and peptides for oral, dermal and parenteral application and in drug substance manufacturing.

• A Personal Foreword xiiiPreface xv1 Basics of Targeted Drug Delivery 1Kshama A. Doshi1.1 Introduction 11.1.1 Concept of Bioavailability and Therapeutic Index 21.2 Targeted Drug Delivery 21.3 Strategies for Drug Targeting 31.3.1 Passive Targeting 41.3.1.1 Reticuloendothelial System (RES) System 41.3.1.2 Enhanced Permeability and Retention (EPR) Effect 41.3.1.3 Localized Delivery 41.3.2 Active Targeting 51.3.3 Physical Targeting 51.3.3.1 Ultrasound for Targeting 61.3.3.2 Magnetic Field for Targeting 61.4 Therapeutic Applications of Targeted Drug Delivery 61.4.1 Diabetes Management 61.4.2 Neurological Diseases 71.4.3 Cardiovascular Diseases 81.4.4 Respiratory Diseases 91.4.5 Cancer Indications 91.5 Targeted Dug-Delivery Products 101.6 Challenges 111.6.1 Passive Targeting and EPR Effect 121.6.2 Active Targeting 121.7 Scale-up and Challenges 131.8 Current Status 141.9 Conclusion and Prospects 15References 162 Addressing Unmet Medical Needs Using Targeted Drug-Delivery Systems: Emphasis on Nanomedicine-Based Applications 21Chandrakantsing Pardeshi, Raju Sonawane, and Yogeshwar Bachhav2.1 Introduction 212.2 Targeted Drug-Delivery Systems for Unmet Medical Needs 232.2.1 Targeting Ligands 252.2.1.1 Small Molecules as Targeting Ligands 252.2.1.2 Aptamers as Targeting Ligands 272.2.1.3 Antibodies as Targeting Ligands 282.2.1.4 Lectins as Targeting Ligands 282.2.1.5 Lactoferrins as Targeting Ligands 292.2.2 Targeting Approaches 292.2.2.1 Disease-Based Targeting 292.2.2.2 Location-Based Targeting 322.3 Regulatory Aspects and Clinical Perspectives 352.4 Conclusion and Future Outlook 38List of Abbreviations 38References 393 Nanocarriers-Based Targeted Drug Delivery Systems: Small and Macromolecules 45Preshita Desai3.1 Nanocarriers (Nanomedicine) – Overview and Role in Targeted Drug Delivery 453.2 Passive Targeting Approaches 503.2.1 Enhanced Permeability and Retention-Effect-Based Targeting 503.3 Active Targeting Approaches 523.4 Stimuli Responsive Targeted NCs 543.4.1 Redox Stimuli Responsive Targeted NCs 553.4.2 pH Stimuli Responsive Targeted NCs 563.4.3 Enzyme Stimuli Responsive Targeted NCs 573.4.4 Temperature Stimuli Responsive Targeted NCs 583.4.5 Ultrasound Stimuli Responsive Targeted NCs 593.4.6 Magnetic Field Stimuli Responsive Targeted NCs 593.5 Conclusion and Future Prospects 60References 604 Liposomes as Targeted Drug-Delivery Systems 69Raghavendra C. Mundargi, Neetika Taneja, Jayeshkumar J. Hadia, and Ajay J. Khopade4.1 Introduction 694.2 Liposome Commercial Landscape 724.3 Important Considerations in Development and Characterization of Liposomes 804.3.1 Selection of Lipids 804.3.2 Drug: Lipid Ratio 814.3.3 PEGylation 824.3.4 Ligand Anchoring 834.3.5 Drug-Loading Techniques 844.3.6 Physicochemical Characterization 854.3.7 Manufacturing Process 864.3.8 Product Stability 874.4 Targeted Delivery of Liposomes 884.4.1 Passive Targeting 894.4.2 Active-Targeted Delivery 924.4.2.1 Cancer Cell Targeting 944.4.2.2 Tumor Endothelium Targeting 984.5 Recent Clinical Trials with Liposomes with Investigational Liposome Candidates 1024.6 Factors Influencing the Clinical Translation of Liposomes for Targeted Delivery 1034.7 Conclusions and Future of Prospects of Targeted Liposomal-Delivery Systems 108List of Abbreviations 110References 1125 Antibody–Drug Conjugates: Development and Applications 127Rajesh Pradhan, Meghna Pandey, Siddhanth Hejmady, Rajeev Taliyan, Gautam Singhvi, Sunil K. Dubey, and Sachin Dubey5.1 Introduction 1275.2 Design of ADCs 1285.2.1 Antibody 1295.2.2 Linker 1305.2.3 Payload 1325.3 Mechanism of Action 1335.4 Pharmacokinetic Considerations for ADCs 1345.4.1 Heterogeneity of ADCs 1345.4.2 Bioanalytical Considerations for ADCs 1355.4.3 Pharmacokinetic Parameters of ADCs 1365.4.3.1 Absorption 1365.4.3.2 Distribution 1365.4.3.3 Metabolism and Elimination 1365.5 Applications of ADCs 1375.5.1 Approved ADCs in the Market 1375.5.1.1 Gemtuzumab Ozogamicin 1375.5.1.2 Brentuximab Vedotin 1395.5.1.3 Ado-Trastuzumab Emtansine (T-DM1) 1395.5.1.4 Inotuzumab Ozogamicin 1395.5.1.5 Polatuzumab Vedotin-piiq 1405.5.1.6 Enfortumab Vedotin 1405.5.1.7 Trastuzumab Deruxtecan 1405.5.2 Use of ADCs in Rheumatoid Arthritis 1415.5.3 Use of ADCs in Bacterial Infections 1415.5.4 Use of ADCs in Ophthalmology 1415.6 Resistance of ADC 1425.7 Regulatory Aspects for ADCs 1435.7.1 Role of ONDQA 1435.7.2 Role of OBP 1445.8 Conclusion and Future Direction 144References 1456 Gene-Directed Enzyme–Prodrug Therapy (GDEPT) as a Suicide Gene Therapy Modality for Cancer Treatment 155Prashant S. Kharkar and Atul L. Jadhav6.1 Introduction 1556.2 GDEPT for Difficult-to-Treat Cancers 1596.2.1 High-Grade Gliomas (HGGs) 1596.2.2 Triple-Negative Breast Cancer (TNBC) 1616.2.3 Other Cancers 1626.3 Novel Enzymes for GDEPT 1646.4 Conclusions 165References 1657 Targeted Prodrugs in Oral Drug Delivery 169Milica Markovic, Shimon Ben-Shabat, and Arik Dahan7.1 Introduction 1697.1.1 Classic vs. Modern Prodrug Approach 1707.2 Modern, Targeted Prodrug Approach 1717.2.1 Prodrug Approach-Targeting Enzymes 1717.2.1.1 Valacyclovirase-Mediated Prodrug Activation 1727.2.1.2 Phospholipase A 2 -Mediated Prodrug Activation 1737.2.1.3 Antibody, Gene, and Virus-Directed Enzyme–Prodrug Therapy 1757.2.2 Prodrug Approach Targeting Transporters 1767.2.2.1 Peptide Transporter 1 1777.2.2.2 Monocarboxylate Transporter Type 1 1797.2.2.3 Bile Acid Transporters 1807.3 Computational Approaches in Targeted Prodrug Design 1817.4 Discussion 1827.5 Future Prospects and Clinical Applications 1837.6 Conclusion 183References 1848 Exosomes for Drug Delivery Applications in Cancer and Cardiac Indications 193Anjali Pandya, Sreeranjini Pulakkat, and Vandana Patravale8.1 Extracellular Vesicles: An Overview 1938.1.1 Evolution of Exosomes 1948.1.2 Exosomes as Delivery Vehicles for Therapeutics 1958.1.2.1 Endogenous Loading Methods 1988.1.2.2 Exogenous Loading Methods 1988.2 Exosomes as Cancer Therapeutics 1998.2.1 Influence of Donor Cells 2028.2.2 Different Therapeutic Cargo Explored in Cancer Therapy 2028.2.2.1 Delivery of Proteins and Peptides 2038.2.2.2 Delivery of Chemotherapeutic Cargo 2048.2.2.3 Delivery of RNA 2048.3 Exosome Based Drug Delivery for Cardiovascular Diseases 2068.3.1 Delivery of Cardioprotective RNAs 2078.3.2 Exosomes Modified with Cardiac Targeting Peptides 2088.4 Clinical Evaluations and Future Aspects 2108.5 Conclusion 211Acknowledgments 212References 2129 Delivery of Nucleic Acids, Such as siRNA and mRNA, Using Complex Formulations 221Ananya Pattnaik, Swarnaparabha Pany, A. S. Sanket, Sudiptee Das, Sanghamitra Pati, and Sangram K. Samal9.1 Introduction 2219.2 NA-Based Complex Delivery System 2289.2.1 Classical NA-Based Complex Delivery System 2299.2.1.1 Polymer-Based NA-Complex Delivery System 2299.2.1.2 Lipid-Based Complex NA Delivery System 2309.2.1.3 Peptide-Based Complex NA Delivery System 2319.2.2 Advanced NA-Based Complex Delivery Systems 2329.2.2.1 Inorganic and Hybrid NPs 2329.2.2.2 Self-Assembled NA Nanostructures 2339.2.2.3 Exosomes and NanoCells 2339.3 Applications of NA-Complex Delivery Systems 2349.3.1 Genome Editing 2359.3.2 Cancer Therapy 2379.3.3 Protein Therapy 2389.4 Future Prospective 2399.5 Conclusion 240Acknowledgments 240References 24010 Application of PROTAC Technology in Drug Development 247Prashant S. Kharkar and Atul L. Jadhav10.1 Introduction 24710.2 Design of PROTACS: A Brief Overview 25210.3 Therapeutic Applications of PROTACs 25410.3.1 Cancer 25510.3.2 Neurodegenerative Disorders 26110.3.3 Immunological Diseases 26310.3.4 Viral Infections 26410.4 Challenges and Limitations in the Development PROTACs 26510.5 Future Perspectives 266References 26611 Metal Complexes as the Means or the End of Targeted Delivery for Unmet Needs 271Trevor W. Hambley11.1 Introduction 27111.2 Class 1: Chaperones 27211.2.1 Chaperones that Protect Drugs 27311.2.2 Delivery to the Cells or Environments to Be Targeted 27511.2.3 Release from the Metal Where and When Required 27611.3 Class 2: Active Metal Complexes 27611.3.1 Targeted Platinum Agents 27711.4 Class 3: Dual-Threat Metal Complexes 27911.5 Targeting Strategies: The Chemical and Physical Environment 28011.5.1 Hypoxia 28111.5.2 pH-Based Targeting 28211.5.3 The EPR Effect 28311.6 Targeting Strategies: Transporters 28411.7 Targeting Strategies: Enzyme Activation 28611.8 Other Targeting Strategies 28711.9 Conclusions 288References 28912 Formulation of Peptides for Targeted Delivery 299Pankti Ganatra, Karen Saiswani, Nikita Nair, Avinash Gunjal, Ratnesh Jain, and Prajakta Dandekar12.1 Introduction 29912.2 Peptides Used in Cancer Therapy 30212.2.1 Lung Cancer 30312.2.2 Melanoma 30412.2.3 Pancreatic Cancer 30612.2.4 Brain Cancer 30712.2.5 Breast Cancer 30912.2.6 Leukemia 31212.3 Peptide-Targeting Based on Site of Action 31512.3.1 Topical Delivery of Peptides 31512.3.2 Ocular Delivery of Peptides 31712.3.3 Brain Delivery of Peptides 31912.3.4 Lung-Targeted Delivery of Peptides 32112.4 Conclusion and Future Prospects 323References 32413 Antibody-Based Targeted T-Cell Therapies 327Manoj Bansode, Kaushik Deb, and Sarmistha Deb13.1 Introduction 32713.2 Immune-Directed Cancer Cell Death 32813.3 Immunotherapy Strategies in Cancer 32813.4 T-Cell Therapy 32913.5 Naturally Occurring T Cells 32913.6 Genetically Modified Occurring T Cells 33013.7 Clinical Implication of T-Cell and CAR-T-Cell Therapy: 33013.8 Antibody-Induced T-Cell Therapy 33213.9 A Bispecific Antibody (BsAbs)-Induced T-Cell Therapy 33213.10 Formats of BsAbs 33513.11 Triomab Antibodies in T-Cell Therapy 33513.12 Bispecific Antibodies in T-Cell Therapy 33613.13 Clinically Approved T-Cell-Activating Antibodies 33713.14 Prospects 33713.15 Conclusion 339References 33914 Devices for Active Targeted Delivery: A Way to Control the Rate and Extent of Drug Administration 349Jonathan Faro Barros, Phedra F. Sahraoui, Yogeshvar N. Kalia, and Maria Lapteva14.1 Introduction 34914.2 Macrofabricated Devices – Drug Infusion Pumps 35114.2.1 Peristaltic Pumps 35114.2.2 Gas-Driven Pumps 35214.2.3 Osmotic Pumps 35314.2.4 Insulin Pumps 35414.2.4.1 Diabetes and Insulin Product Development 35414.2.4.2 Open-Loop Insulin Delivery Systems 35514.2.4.3 Closed-Loop Insulin Delivery Systems 36014.3 Microfabricated and Nanofabricated Drug Delivery Devices 36414.3.1 Microelectromechanical Systems (MEMS) 36414.3.1.1 Microchip-Based MEMS 36414.3.1.2 Pump-Based MEMS 36614.3.1.3 MEMS – Efforts to Close the Loop 36814.3.2 Nanofabricated Drug Delivery Devices 36914.4 Noninvasive Active Drug Delivery Systems: Iontophoresis 37214.5 Conclusions 376Acknowledgments 377List of Abbreviations 377References 37815 Drug Delivery to the Brain: Targeting Technologies to Deliver Therapeutics to Brain Lesions 389Nishit Pathak, Sunil K. Vimal, Cao Hongyi, and Sanjib Bhattacharyya15.1 Introduction 38915.2 Brain Tumor 39015.2.1 Obstacles to Brain Tumor-Targeted Delivery 39115.2.2 Brain-Tumor-Focused Nano-Drug Delivery 39315.3 Neurodegenerative Diseases 39615.3.1 Alzheimer’s Disease (AD) 39615.3.1.1 Alzheimer’s Disease Focused on Drug Delivery 39615.3.2 Parkinson’s Disease 39915.3.2.1 Drug Delivery Focussed on Parkinson’s Drug Disease 39915.3.3 Cerebrovascular Disease 40015.3.3.1 Drug Delivery for Cerebrovascular Disease 40015.3.4 Inflammatory Diseases (ID) 40215.3.4.1 Inflammatory Diseases (ID) Focused on Drug Delivery 40215.3.4.2 Drug Delivery for the Treatment of Neuro-AIDS 40315.3.5 Drug Delivery for Multiple Sclerosis (MS) 40315.4 Drug Delivery for CNS Disorders 40415.4.1 Tau Therapy 40515.4.2 Immunotherapy 40715.4.3 Gene Immunotherapy (GIT) 40715.4.4 Chemotherapy (CT) 40815.4.5 Photoimmunotherapy (PIT) 40815.5 Future Prospects 41015.6 Conclusions 410List of Abbreviations 411References 412Index 425

Yogeshwar Bachhav is a pharmacist by training and holds a PhD in drug delivery systems from ICT, Mumbai (India). He has worked as research scientist for several years on a collaborative project between Pantec Biosolutions and Geneva University (Switzerland), and as formulation manager at Debiopharm Group, Lausanne (Switzerland). For the last 9 years he has been associated with AiCuris Anti-infective Cures AG (Germany) as in-charge for Pharmaceutical development of new drugs. In total, he has around 16 years of experience in the preformulation and formulation development of small molecules and peptides for oral, dermal and parenteral application and in drug substance manufacturing.

• A Personal Foreword xiiiPreface xv1 Basics of Targeted Drug Delivery 1Kshama A. Doshi1.1 Introduction 11.1.1 Concept of Bioavailability and Therapeutic Index 21.2 Targeted Drug Delivery 21.3 Strategies for Drug Targeting 31.3.1 Passive Targeting 41.3.1.1 Reticuloendothelial System (RES) System 41.3.1.2 Enhanced Permeability and Retention (EPR) Effect 41.3.1.3 Localized Delivery 41.3.2 Active Targeting 51.3.3 Physical Targeting 51.3.3.1 Ultrasound for Targeting 61.3.3.2 Magnetic Field for Targeting 61.4 Therapeutic Applications of Targeted Drug Delivery 61.4.1 Diabetes Management 61.4.2 Neurological Diseases 71.4.3 Cardiovascular Diseases 81.4.4 Respiratory Diseases 91.4.5 Cancer Indications 91.5 Targeted Dug-Delivery Products 101.6 Challenges 111.6.1 Passive Targeting and EPR Effect 121.6.2 Active Targeting 121.7 Scale-up and Challenges 131.8 Current Status 141.9 Conclusion and Prospects 15References 162 Addressing Unmet Medical Needs Using Targeted Drug-Delivery Systems: Emphasis on Nanomedicine-Based Applications 21Chandrakantsing Pardeshi, Raju Sonawane, and Yogeshwar Bachhav2.1 Introduction 212.2 Targeted Drug-Delivery Systems for Unmet Medical Needs 232.2.1 Targeting Ligands 252.2.1.1 Small Molecules as Targeting Ligands 252.2.1.2 Aptamers as Targeting Ligands 272.2.1.3 Antibodies as Targeting Ligands 282.2.1.4 Lectins as Targeting Ligands 282.2.1.5 Lactoferrins as Targeting Ligands 292.2.2 Targeting Approaches 292.2.2.1 Disease-Based Targeting 292.2.2.2 Location-Based Targeting 322.3 Regulatory Aspects and Clinical Perspectives 352.4 Conclusion and Future Outlook 38List of Abbreviations 38References 393 Nanocarriers-Based Targeted Drug Delivery Systems: Small and Macromolecules 45Preshita Desai3.1 Nanocarriers (Nanomedicine) – Overview and Role in Targeted Drug Delivery 453.2 Passive Targeting Approaches 503.2.1 Enhanced Permeability and Retention-Effect-Based Targeting 503.3 Active Targeting Approaches 523.4 Stimuli Responsive Targeted NCs 543.4.1 Redox Stimuli Responsive Targeted NCs 553.4.2 pH Stimuli Responsive Targeted NCs 563.4.3 Enzyme Stimuli Responsive Targeted NCs 573.4.4 Temperature Stimuli Responsive Targeted NCs 583.4.5 Ultrasound Stimuli Responsive Targeted NCs 593.4.6 Magnetic Field Stimuli Responsive Targeted NCs 593.5 Conclusion and Future Prospects 60References 604 Liposomes as Targeted Drug-Delivery Systems 69Raghavendra C. Mundargi, Neetika Taneja, Jayeshkumar J. Hadia, and Ajay J. Khopade4.1 Introduction 694.2 Liposome Commercial Landscape 724.3 Important Considerations in Development and Characterization of Liposomes 804.3.1 Selection of Lipids 804.3.2 Drug: Lipid Ratio 814.3.3 PEGylation 824.3.4 Ligand Anchoring 834.3.5 Drug-Loading Techniques 844.3.6 Physicochemical Characterization 854.3.7 Manufacturing Process 864.3.8 Product Stability 874.4 Targeted Delivery of Liposomes 884.4.1 Passive Targeting 894.4.2 Active-Targeted Delivery 924.4.2.1 Cancer Cell Targeting 944.4.2.2 Tumor Endothelium Targeting 984.5 Recent Clinical Trials with Liposomes with Investigational Liposome Candidates 1024.6 Factors Influencing the Clinical Translation of Liposomes for Targeted Delivery 1034.7 Conclusions and Future of Prospects of Targeted Liposomal-Delivery Systems 108List of Abbreviations 110References 1125 Antibody–Drug Conjugates: Development and Applications 127Rajesh Pradhan, Meghna Pandey, Siddhanth Hejmady, Rajeev Taliyan, Gautam Singhvi, Sunil K. Dubey, and Sachin Dubey5.1 Introduction 1275.2 Design of ADCs 1285.2.1 Antibody 1295.2.2 Linker 1305.2.3 Payload 1325.3 Mechanism of Action 1335.4 Pharmacokinetic Considerations for ADCs 1345.4.1 Heterogeneity of ADCs 1345.4.2 Bioanalytical Considerations for ADCs 1355.4.3 Pharmacokinetic Parameters of ADCs 1365.4.3.1 Absorption 1365.4.3.2 Distribution 1365.4.3.3 Metabolism and Elimination 1365.5 Applications of ADCs 1375.5.1 Approved ADCs in the Market 1375.5.1.1 Gemtuzumab Ozogamicin 1375.5.1.2 Brentuximab Vedotin 1395.5.1.3 Ado-Trastuzumab Emtansine (T-DM1) 1395.5.1.4 Inotuzumab Ozogamicin 1395.5.1.5 Polatuzumab Vedotin-piiq 1405.5.1.6 Enfortumab Vedotin 1405.5.1.7 Trastuzumab Deruxtecan 1405.5.2 Use of ADCs in Rheumatoid Arthritis 1415.5.3 Use of ADCs in Bacterial Infections 1415.5.4 Use of ADCs in Ophthalmology 1415.6 Resistance of ADC 1425.7 Regulatory Aspects for ADCs 1435.7.1 Role of ONDQA 1435.7.2 Role of OBP 1445.8 Conclusion and Future Direction 144References 1456 Gene-Directed Enzyme–Prodrug Therapy (GDEPT) as a Suicide Gene Therapy Modality for Cancer Treatment 155Prashant S. Kharkar and Atul L. Jadhav6.1 Introduction 1556.2 GDEPT for Difficult-to-Treat Cancers 1596.2.1 High-Grade Gliomas (HGGs) 1596.2.2 Triple-Negative Breast Cancer (TNBC) 1616.2.3 Other Cancers 1626.3 Novel Enzymes for GDEPT 1646.4 Conclusions 165References 1657 Targeted Prodrugs in Oral Drug Delivery 169Milica Markovic, Shimon Ben-Shabat, and Arik Dahan7.1 Introduction 1697.1.1 Classic vs. Modern Prodrug Approach 1707.2 Modern, Targeted Prodrug Approach 1717.2.1 Prodrug Approach-Targeting Enzymes 1717.2.1.1 Valacyclovirase-Mediated Prodrug Activation 1727.2.1.2 Phospholipase A 2 -Mediated Prodrug Activation 1737.2.1.3 Antibody, Gene, and Virus-Directed Enzyme–Prodrug Therapy 1757.2.2 Prodrug Approach Targeting Transporters 1767.2.2.1 Peptide Transporter 1 1777.2.2.2 Monocarboxylate Transporter Type 1 1797.2.2.3 Bile Acid Transporters 1807.3 Computational Approaches in Targeted Prodrug Design 1817.4 Discussion 1827.5 Future Prospects and Clinical Applications 1837.6 Conclusion 183References 1848 Exosomes for Drug Delivery Applications in Cancer and Cardiac Indications 193Anjali Pandya, Sreeranjini Pulakkat, and Vandana Patravale8.1 Extracellular Vesicles: An Overview 1938.1.1 Evolution of Exosomes 1948.1.2 Exosomes as Delivery Vehicles for Therapeutics 1958.1.2.1 Endogenous Loading Methods 1988.1.2.2 Exogenous Loading Methods 1988.2 Exosomes as Cancer Therapeutics 1998.2.1 Influence of Donor Cells 2028.2.2 Different Therapeutic Cargo Explored in Cancer Therapy 2028.2.2.1 Delivery of Proteins and Peptides 2038.2.2.2 Delivery of Chemotherapeutic Cargo 2048.2.2.3 Delivery of RNA 2048.3 Exosome Based Drug Delivery for Cardiovascular Diseases 2068.3.1 Delivery of Cardioprotective RNAs 2078.3.2 Exosomes Modified with Cardiac Targeting Peptides 2088.4 Clinical Evaluations and Future Aspects 2108.5 Conclusion 211Acknowledgments 212References 2129 Delivery of Nucleic Acids, Such as siRNA and mRNA, Using Complex Formulations 221Ananya Pattnaik, Swarnaparabha Pany, A. S. Sanket, Sudiptee Das, Sanghamitra Pati, and Sangram K. Samal9.1 Introduction 2219.2 NA-Based Complex Delivery System 2289.2.1 Classical NA-Based Complex Delivery System 2299.2.1.1 Polymer-Based NA-Complex Delivery System 2299.2.1.2 Lipid-Based Complex NA Delivery System 2309.2.1.3 Peptide-Based Complex NA Delivery System 2319.2.2 Advanced NA-Based Complex Delivery Systems 2329.2.2.1 Inorganic and Hybrid NPs 2329.2.2.2 Self-Assembled NA Nanostructures 2339.2.2.3 Exosomes and NanoCells 2339.3 Applications of NA-Complex Delivery Systems 2349.3.1 Genome Editing 2359.3.2 Cancer Therapy 2379.3.3 Protein Therapy 2389.4 Future Prospective 2399.5 Conclusion 240Acknowledgments 240References 24010 Application of PROTAC Technology in Drug Development 247Prashant S. Kharkar and Atul L. Jadhav10.1 Introduction 24710.2 Design of PROTACS: A Brief Overview 25210.3 Therapeutic Applications of PROTACs 25410.3.1 Cancer 25510.3.2 Neurodegenerative Disorders 26110.3.3 Immunological Diseases 26310.3.4 Viral Infections 26410.4 Challenges and Limitations in the Development PROTACs 26510.5 Future Perspectives 266References 26611 Metal Complexes as the Means or the End of Targeted Delivery for Unmet Needs 271Trevor W. Hambley11.1 Introduction 27111.2 Class 1: Chaperones 27211.2.1 Chaperones that Protect Drugs 27311.2.2 Delivery to the Cells or Environments to Be Targeted 27511.2.3 Release from the Metal Where and When Required 27611.3 Class 2: Active Metal Complexes 27611.3.1 Targeted Platinum Agents 27711.4 Class 3: Dual-Threat Metal Complexes 27911.5 Targeting Strategies: The Chemical and Physical Environment 28011.5.1 Hypoxia 28111.5.2 pH-Based Targeting 28211.5.3 The EPR Effect 28311.6 Targeting Strategies: Transporters 28411.7 Targeting Strategies: Enzyme Activation 28611.8 Other Targeting Strategies 28711.9 Conclusions 288References 28912 Formulation of Peptides for Targeted Delivery 299Pankti Ganatra, Karen Saiswani, Nikita Nair, Avinash Gunjal, Ratnesh Jain, and Prajakta Dandekar12.1 Introduction 29912.2 Peptides Used in Cancer Therapy 30212.2.1 Lung Cancer 30312.2.2 Melanoma 30412.2.3 Pancreatic Cancer 30612.2.4 Brain Cancer 30712.2.5 Breast Cancer 30912.2.6 Leukemia 31212.3 Peptide-Targeting Based on Site of Action 31512.3.1 Topical Delivery of Peptides 31512.3.2 Ocular Delivery of Peptides 31712.3.3 Brain Delivery of Peptides 31912.3.4 Lung-Targeted Delivery of Peptides 32112.4 Conclusion and Future Prospects 323References 32413 Antibody-Based Targeted T-Cell Therapies 327Manoj Bansode, Kaushik Deb, and Sarmistha Deb13.1 Introduction 32713.2 Immune-Directed Cancer Cell Death 32813.3 Immunotherapy Strategies in Cancer 32813.4 T-Cell Therapy 32913.5 Naturally Occurring T Cells 32913.6 Genetically Modified Occurring T Cells 33013.7 Clinical Implication of T-Cell and CAR-T-Cell Therapy: 33013.8 Antibody-Induced T-Cell Therapy 33213.9 A Bispecific Antibody (BsAbs)-Induced T-Cell Therapy 33213.10 Formats of BsAbs 33513.11 Triomab Antibodies in T-Cell Therapy 33513.12 Bispecific Antibodies in T-Cell Therapy 33613.13 Clinically Approved T-Cell-Activating Antibodies 33713.14 Prospects 33713.15 Conclusion 339References 33914 Devices for Active Targeted Delivery: A Way to Control the Rate and Extent of Drug Administration 349Jonathan Faro Barros, Phedra F. Sahraoui, Yogeshvar N. Kalia, and Maria Lapteva14.1 Introduction 34914.2 Macrofabricated Devices – Drug Infusion Pumps 35114.2.1 Peristaltic Pumps 35114.2.2 Gas-Driven Pumps 35214.2.3 Osmotic Pumps 35314.2.4 Insulin Pumps 35414.2.4.1 Diabetes and Insulin Product Development 35414.2.4.2 Open-Loop Insulin Delivery Systems 35514.2.4.3 Closed-Loop Insulin Delivery Systems 36014.3 Microfabricated and Nanofabricated Drug Delivery Devices 36414.3.1 Microelectromechanical Systems (MEMS) 36414.3.1.1 Microchip-Based MEMS 36414.3.1.2 Pump-Based MEMS 36614.3.1.3 MEMS – Efforts to Close the Loop 36814.3.2 Nanofabricated Drug Delivery Devices 36914.4 Noninvasive Active Drug Delivery Systems: Iontophoresis 37214.5 Conclusions 376Acknowledgments 377List of Abbreviations 377References 37815 Drug Delivery to the Brain: Targeting Technologies to Deliver Therapeutics to Brain Lesions 389Nishit Pathak, Sunil K. Vimal, Cao Hongyi, and Sanjib Bhattacharyya15.1 Introduction 38915.2 Brain Tumor 39015.2.1 Obstacles to Brain Tumor-Targeted Delivery 39115.2.2 Brain-Tumor-Focused Nano-Drug Delivery 39315.3 Neurodegenerative Diseases 39615.3.1 Alzheimer’s Disease (AD) 39615.3.1.1 Alzheimer’s Disease Focused on Drug Delivery 39615.3.2 Parkinson’s Disease 39915.3.2.1 Drug Delivery Focussed on Parkinson’s Drug Disease 39915.3.3 Cerebrovascular Disease 40015.3.3.1 Drug Delivery for Cerebrovascular Disease 40015.3.4 Inflammatory Diseases (ID) 40215.3.4.1 Inflammatory Diseases (ID) Focused on Drug Delivery 40215.3.4.2 Drug Delivery for the Treatment of Neuro-AIDS 40315.3.5 Drug Delivery for Multiple Sclerosis (MS) 40315.4 Drug Delivery for CNS Disorders 40415.4.1 Tau Therapy 40515.4.2 Immunotherapy 40715.4.3 Gene Immunotherapy (GIT) 40715.4.4 Chemotherapy (CT) 40815.4.5 Photoimmunotherapy (PIT) 40815.5 Future Prospects 41015.6 Conclusions 410List of Abbreviations 411References 412Index 425

Yogeshwar Bachhav is a pharmacist by training and holds a PhD in drug delivery systems from ICT, Mumbai (India). He has worked as research scientist for several years on a collaborative project between Pantec Biosolutions and Geneva University (Switzerland), and as formulation manager at Debiopharm Group, Lausanne (Switzerland). For the last 9 years he has been associated with AiCuris Anti-infective Cures AG (Germany) as in-charge for Pharmaceutical development of new drugs. In total, he has around 16 years of experience in the preformulation and formulation development of small molecules and peptides for oral, dermal and parenteral application and in drug substance manufacturing.

• A Personal Foreword xiiiPreface xv1 Basics of Targeted Drug Delivery 1Kshama A. Doshi1.1 Introduction 11.1.1 Concept of Bioavailability and Therapeutic Index 21.2 Targeted Drug Delivery 21.3 Strategies for Drug Targeting 31.3.1 Passive Targeting 41.3.1.1 Reticuloendothelial System (RES) System 41.3.1.2 Enhanced Permeability and Retention (EPR) Effect 41.3.1.3 Localized Delivery 41.3.2 Active Targeting 51.3.3 Physical Targeting 51.3.3.1 Ultrasound for Targeting 61.3.3.2 Magnetic Field for Targeting 61.4 Therapeutic Applications of Targeted Drug Delivery 61.4.1 Diabetes Management 61.4.2 Neurological Diseases 71.4.3 Cardiovascular Diseases 81.4.4 Respiratory Diseases 91.4.5 Cancer Indications 91.5 Targeted Dug-Delivery Products 101.6 Challenges 111.6.1 Passive Targeting and EPR Effect 121.6.2 Active Targeting 121.7 Scale-up and Challenges 131.8 Current Status 141.9 Conclusion and Prospects 15References 162 Addressing Unmet Medical Needs Using Targeted Drug-Delivery Systems: Emphasis on Nanomedicine-Based Applications 21Chandrakantsing Pardeshi, Raju Sonawane, and Yogeshwar Bachhav2.1 Introduction 212.2 Targeted Drug-Delivery Systems for Unmet Medical Needs 232.2.1 Targeting Ligands 252.2.1.1 Small Molecules as Targeting Ligands 252.2.1.2 Aptamers as Targeting Ligands 272.2.1.3 Antibodies as Targeting Ligands 282.2.1.4 Lectins as Targeting Ligands 282.2.1.5 Lactoferrins as Targeting Ligands 292.2.2 Targeting Approaches 292.2.2.1 Disease-Based Targeting 292.2.2.2 Location-Based Targeting 322.3 Regulatory Aspects and Clinical Perspectives 352.4 Conclusion and Future Outlook 38List of Abbreviations 38References 393 Nanocarriers-Based Targeted Drug Delivery Systems: Small and Macromolecules 45Preshita Desai3.1 Nanocarriers (Nanomedicine) – Overview and Role in Targeted Drug Delivery 453.2 Passive Targeting Approaches 503.2.1 Enhanced Permeability and Retention-Effect-Based Targeting 503.3 Active Targeting Approaches 523.4 Stimuli Responsive Targeted NCs 543.4.1 Redox Stimuli Responsive Targeted NCs 553.4.2 pH Stimuli Responsive Targeted NCs 563.4.3 Enzyme Stimuli Responsive Targeted NCs 573.4.4 Temperature Stimuli Responsive Targeted NCs 583.4.5 Ultrasound Stimuli Responsive Targeted NCs 593.4.6 Magnetic Field Stimuli Responsive Targeted NCs 593.5 Conclusion and Future Prospects 60References 604 Liposomes as Targeted Drug-Delivery Systems 69Raghavendra C. Mundargi, Neetika Taneja, Jayeshkumar J. Hadia, and Ajay J. Khopade4.1 Introduction 694.2 Liposome Commercial Landscape 724.3 Important Considerations in Development and Characterization of Liposomes 804.3.1 Selection of Lipids 804.3.2 Drug: Lipid Ratio 814.3.3 PEGylation 824.3.4 Ligand Anchoring 834.3.5 Drug-Loading Techniques 844.3.6 Physicochemical Characterization 854.3.7 Manufacturing Process 864.3.8 Product Stability 874.4 Targeted Delivery of Liposomes 884.4.1 Passive Targeting 894.4.2 Active-Targeted Delivery 924.4.2.1 Cancer Cell Targeting 944.4.2.2 Tumor Endothelium Targeting 984.5 Recent Clinical Trials with Liposomes with Investigational Liposome Candidates 1024.6 Factors Influencing the Clinical Translation of Liposomes for Targeted Delivery 1034.7 Conclusions and Future of Prospects of Targeted Liposomal-Delivery Systems 108List of Abbreviations 110References 1125 Antibody–Drug Conjugates: Development and Applications 127Rajesh Pradhan, Meghna Pandey, Siddhanth Hejmady, Rajeev Taliyan, Gautam Singhvi, Sunil K. Dubey, and Sachin Dubey5.1 Introduction 1275.2 Design of ADCs 1285.2.1 Antibody 1295.2.2 Linker 1305.2.3 Payload 1325.3 Mechanism of Action 1335.4 Pharmacokinetic Considerations for ADCs 1345.4.1 Heterogeneity of ADCs 1345.4.2 Bioanalytical Considerations for ADCs 1355.4.3 Pharmacokinetic Parameters of ADCs 1365.4.3.1 Absorption 1365.4.3.2 Distribution 1365.4.3.3 Metabolism and Elimination 1365.5 Applications of ADCs 1375.5.1 Approved ADCs in the Market 1375.5.1.1 Gemtuzumab Ozogamicin 1375.5.1.2 Brentuximab Vedotin 1395.5.1.3 Ado-Trastuzumab Emtansine (T-DM1) 1395.5.1.4 Inotuzumab Ozogamicin 1395.5.1.5 Polatuzumab Vedotin-piiq 1405.5.1.6 Enfortumab Vedotin 1405.5.1.7 Trastuzumab Deruxtecan 1405.5.2 Use of ADCs in Rheumatoid Arthritis 1415.5.3 Use of ADCs in Bacterial Infections 1415.5.4 Use of ADCs in Ophthalmology 1415.6 Resistance of ADC 1425.7 Regulatory Aspects for ADCs 1435.7.1 Role of ONDQA 1435.7.2 Role of OBP 1445.8 Conclusion and Future Direction 144References 1456 Gene-Directed Enzyme–Prodrug Therapy (GDEPT) as a Suicide Gene Therapy Modality for Cancer Treatment 155Prashant S. Kharkar and Atul L. Jadhav6.1 Introduction 1556.2 GDEPT for Difficult-to-Treat Cancers 1596.2.1 High-Grade Gliomas (HGGs) 1596.2.2 Triple-Negative Breast Cancer (TNBC) 1616.2.3 Other Cancers 1626.3 Novel Enzymes for GDEPT 1646.4 Conclusions 165References 1657 Targeted Prodrugs in Oral Drug Delivery 169Milica Markovic, Shimon Ben-Shabat, and Arik Dahan7.1 Introduction 1697.1.1 Classic vs. Modern Prodrug Approach 1707.2 Modern, Targeted Prodrug Approach 1717.2.1 Prodrug Approach-Targeting Enzymes 1717.2.1.1 Valacyclovirase-Mediated Prodrug Activation 1727.2.1.2 Phospholipase A 2 -Mediated Prodrug Activation 1737.2.1.3 Antibody, Gene, and Virus-Directed Enzyme–Prodrug Therapy 1757.2.2 Prodrug Approach Targeting Transporters 1767.2.2.1 Peptide Transporter 1 1777.2.2.2 Monocarboxylate Transporter Type 1 1797.2.2.3 Bile Acid Transporters 1807.3 Computational Approaches in Targeted Prodrug Design 1817.4 Discussion 1827.5 Future Prospects and Clinical Applications 1837.6 Conclusion 183References 1848 Exosomes for Drug Delivery Applications in Cancer and Cardiac Indications 193Anjali Pandya, Sreeranjini Pulakkat, and Vandana Patravale8.1 Extracellular Vesicles: An Overview 1938.1.1 Evolution of Exosomes 1948.1.2 Exosomes as Delivery Vehicles for Therapeutics 1958.1.2.1 Endogenous Loading Methods 1988.1.2.2 Exogenous Loading Methods 1988.2 Exosomes as Cancer Therapeutics 1998.2.1 Influence of Donor Cells 2028.2.2 Different Therapeutic Cargo Explored in Cancer Therapy 2028.2.2.1 Delivery of Proteins and Peptides 2038.2.2.2 Delivery of Chemotherapeutic Cargo 2048.2.2.3 Delivery of RNA 2048.3 Exosome Based Drug Delivery for Cardiovascular Diseases 2068.3.1 Delivery of Cardioprotective RNAs 2078.3.2 Exosomes Modified with Cardiac Targeting Peptides 2088.4 Clinical Evaluations and Future Aspects 2108.5 Conclusion 211Acknowledgments 212References 2129 Delivery of Nucleic Acids, Such as siRNA and mRNA, Using Complex Formulations 221Ananya Pattnaik, Swarnaparabha Pany, A. S. Sanket, Sudiptee Das, Sanghamitra Pati, and Sangram K. Samal9.1 Introduction 2219.2 NA-Based Complex Delivery System 2289.2.1 Classical NA-Based Complex Delivery System 2299.2.1.1 Polymer-Based NA-Complex Delivery System 2299.2.1.2 Lipid-Based Complex NA Delivery System 2309.2.1.3 Peptide-Based Complex NA Delivery System 2319.2.2 Advanced NA-Based Complex Delivery Systems 2329.2.2.1 Inorganic and Hybrid NPs 2329.2.2.2 Self-Assembled NA Nanostructures 2339.2.2.3 Exosomes and NanoCells 2339.3 Applications of NA-Complex Delivery Systems 2349.3.1 Genome Editing 2359.3.2 Cancer Therapy 2379.3.3 Protein Therapy 2389.4 Future Prospective 2399.5 Conclusion 240Acknowledgments 240References 24010 Application of PROTAC Technology in Drug Development 247Prashant S. Kharkar and Atul L. Jadhav10.1 Introduction 24710.2 Design of PROTACS: A Brief Overview 25210.3 Therapeutic Applications of PROTACs 25410.3.1 Cancer 25510.3.2 Neurodegenerative Disorders 26110.3.3 Immunological Diseases 26310.3.4 Viral Infections 26410.4 Challenges and Limitations in the Development PROTACs 26510.5 Future Perspectives 266References 26611 Metal Complexes as the Means or the End of Targeted Delivery for Unmet Needs 271Trevor W. Hambley11.1 Introduction 27111.2 Class 1: Chaperones 27211.2.1 Chaperones that Protect Drugs 27311.2.2 Delivery to the Cells or Environments to Be Targeted 27511.2.3 Release from the Metal Where and When Required 27611.3 Class 2: Active Metal Complexes 27611.3.1 Targeted Platinum Agents 27711.4 Class 3: Dual-Threat Metal Complexes 27911.5 Targeting Strategies: The Chemical and Physical Environment 28011.5.1 Hypoxia 28111.5.2 pH-Based Targeting 28211.5.3 The EPR Effect 28311.6 Targeting Strategies: Transporters 28411.7 Targeting Strategies: Enzyme Activation 28611.8 Other Targeting Strategies 28711.9 Conclusions 288References 28912 Formulation of Peptides for Targeted Delivery 299Pankti Ganatra, Karen Saiswani, Nikita Nair, Avinash Gunjal, Ratnesh Jain, and Prajakta Dandekar12.1 Introduction 29912.2 Peptides Used in Cancer Therapy 30212.2.1 Lung Cancer 30312.2.2 Melanoma 30412.2.3 Pancreatic Cancer 30612.2.4 Brain Cancer 30712.2.5 Breast Cancer 30912.2.6 Leukemia 31212.3 Peptide-Targeting Based on Site of Action 31512.3.1 Topical Delivery of Peptides 31512.3.2 Ocular Delivery of Peptides 31712.3.3 Brain Delivery of Peptides 31912.3.4 Lung-Targeted Delivery of Peptides 32112.4 Conclusion and Future Prospects 323References 32413 Antibody-Based Targeted T-Cell Therapies 327Manoj Bansode, Kaushik Deb, and Sarmistha Deb13.1 Introduction 32713.2 Immune-Directed Cancer Cell Death 32813.3 Immunotherapy Strategies in Cancer 32813.4 T-Cell Therapy 32913.5 Naturally Occurring T Cells 32913.6 Genetically Modified Occurring T Cells 33013.7 Clinical Implication of T-Cell and CAR-T-Cell Therapy: 33013.8 Antibody-Induced T-Cell Therapy 33213.9 A Bispecific Antibody (BsAbs)-Induced T-Cell Therapy 33213.10 Formats of BsAbs 33513.11 Triomab Antibodies in T-Cell Therapy 33513.12 Bispecific Antibodies in T-Cell Therapy 33613.13 Clinically Approved T-Cell-Activating Antibodies 33713.14 Prospects 33713.15 Conclusion 339References 33914 Devices for Active Targeted Delivery: A Way to Control the Rate and Extent of Drug Administration 349Jonathan Faro Barros, Phedra F. Sahraoui, Yogeshvar N. Kalia, and Maria Lapteva14.1 Introduction 34914.2 Macrofabricated Devices – Drug Infusion Pumps 35114.2.1 Peristaltic Pumps 35114.2.2 Gas-Driven Pumps 35214.2.3 Osmotic Pumps 35314.2.4 Insulin Pumps 35414.2.4.1 Diabetes and Insulin Product Development 35414.2.4.2 Open-Loop Insulin Delivery Systems 35514.2.4.3 Closed-Loop Insulin Delivery Systems 36014.3 Microfabricated and Nanofabricated Drug Delivery Devices 36414.3.1 Microelectromechanical Systems (MEMS) 36414.3.1.1 Microchip-Based MEMS 36414.3.1.2 Pump-Based MEMS 36614.3.1.3 MEMS – Efforts to Close the Loop 36814.3.2 Nanofabricated Drug Delivery Devices 36914.4 Noninvasive Active Drug Delivery Systems: Iontophoresis 37214.5 Conclusions 376Acknowledgments 377List of Abbreviations 377References 37815 Drug Delivery to the Brain: Targeting Technologies to Deliver Therapeutics to Brain Lesions 389Nishit Pathak, Sunil K. Vimal, Cao Hongyi, and Sanjib Bhattacharyya15.1 Introduction 38915.2 Brain Tumor 39015.2.1 Obstacles to Brain Tumor-Targeted Delivery 39115.2.2 Brain-Tumor-Focused Nano-Drug Delivery 39315.3 Neurodegenerative Diseases 39615.3.1 Alzheimer’s Disease (AD) 39615.3.1.1 Alzheimer’s Disease Focused on Drug Delivery 39615.3.2 Parkinson’s Disease 39915.3.2.1 Drug Delivery Focussed on Parkinson’s Drug Disease 39915.3.3 Cerebrovascular Disease 40015.3.3.1 Drug Delivery for Cerebrovascular Disease 40015.3.4 Inflammatory Diseases (ID) 40215.3.4.1 Inflammatory Diseases (ID) Focused on Drug Delivery 40215.3.4.2 Drug Delivery for the Treatment of Neuro-AIDS 40315.3.5 Drug Delivery for Multiple Sclerosis (MS) 40315.4 Drug Delivery for CNS Disorders 40415.4.1 Tau Therapy 40515.4.2 Immunotherapy 40715.4.3 Gene Immunotherapy (GIT) 40715.4.4 Chemotherapy (CT) 40815.4.5 Photoimmunotherapy (PIT) 40815.5 Future Prospects 41015.6 Conclusions 410List of Abbreviations 411References 412Index 425