Novel approaches in targeted drug delivery for both small molecule and biopharmaceutical drugs
Targeted Drug Delivery explores a new frontier in drug research that has become a focus for developing novel medications. The work discusses a wide range of approaches for targeting small molecules as well as peptide and macromolecular drugs, from prodrugs to drug conjugates to drug carriers and devices, helping readers to stay up to date on the latest developments in the field.
The following key topics are addressed: - Antibody conjugates, prodrugs, and suicide gene therapeutics - Protac technology for selectively degrading target proteins - Delivery of nucleic acid drugs - Novel drug carriers, such as liposomes, vesicles, and nanoparticles - Unmet medical needs for which there is a large market potential, such as viral infections and cancer
For chemists, pharmacologists, and professionals in the wider pharmaceutical industry, Targeted Drug Delivery is a comprehensive guide on how to solve the greatest challenge in treating many diseases: delivering a pharmaceutically active substance to the target tissue in the body.
Table of Contents
A Personal Foreword xiii
Preface xv
1 Basics of Targeted Drug Delivery 1
Kshama A. Doshi
1.1 Introduction 1
1.1.1 Concept of Bioavailability and Therapeutic Index 2
1.2 Targeted Drug Delivery 2
1.3 Strategies for Drug Targeting 3
1.3.1 Passive Targeting 4
1.3.1.1 Reticuloendothelial System (RES) System 4
1.3.1.2 Enhanced Permeability and Retention (EPR) Effect 4
1.3.1.3 Localized Delivery 4
1.3.2 Active Targeting 5
1.3.3 Physical Targeting 5
1.3.3.1 Ultrasound for Targeting 6
1.3.3.2 Magnetic Field for Targeting 6
1.4 Therapeutic Applications of Targeted Drug Delivery 6
1.4.1 Diabetes Management 6
1.4.2 Neurological Diseases 7
1.4.3 Cardiovascular Diseases 8
1.4.4 Respiratory Diseases 9
1.4.5 Cancer Indications 9
1.5 Targeted Dug-Delivery Products 10
1.6 Challenges 11
1.6.1 Passive Targeting and EPR Effect 12
1.6.2 Active Targeting 12
1.7 Scale-up and Challenges 13
1.8 Current Status 14
1.9 Conclusion and Prospects 15
References 16
2 Addressing Unmet Medical Needs Using Targeted Drug-Delivery Systems: Emphasis on Nanomedicine-Based Applications 21
Chandrakantsing Pardeshi, Raju Sonawane, and Yogeshwar Bachhav
2.1 Introduction 21
2.2 Targeted Drug-Delivery Systems for Unmet Medical Needs 23
2.2.1 Targeting Ligands 25
2.2.1.1 Small Molecules as Targeting Ligands 25
2.2.1.2 Aptamers as Targeting Ligands 27
2.2.1.3 Antibodies as Targeting Ligands 28
2.2.1.4 Lectins as Targeting Ligands 28
2.2.1.5 Lactoferrins as Targeting Ligands 29
2.2.2 Targeting Approaches 29
2.2.2.1 Disease-Based Targeting 29
2.2.2.2 Location-Based Targeting 32
2.3 Regulatory Aspects and Clinical Perspectives 35
2.4 Conclusion and Future Outlook 38
List of Abbreviations 38
References 39
3 Nanocarriers-Based Targeted Drug Delivery Systems: Small and Macromolecules 45
Preshita Desai
3.1 Nanocarriers (Nanomedicine) - Overview and Role in Targeted Drug Delivery 45
3.2 Passive Targeting Approaches 50
3.2.1 Enhanced Permeability and Retention-Effect-Based Targeting 50
3.3 Active Targeting Approaches 52
3.4 Stimuli Responsive Targeted NCs 54
3.4.1 Redox Stimuli Responsive Targeted NCs 55
3.4.2 pH Stimuli Responsive Targeted NCs 56
3.4.3 Enzyme Stimuli Responsive Targeted NCs 57
3.4.4 Temperature Stimuli Responsive Targeted NCs 58
3.4.5 Ultrasound Stimuli Responsive Targeted NCs 59
3.4.6 Magnetic Field Stimuli Responsive Targeted NCs 59
3.5 Conclusion and Future Prospects 60
References 60
4 Liposomes as Targeted Drug-Delivery Systems 69
Raghavendra C. Mundargi, Neetika Taneja, Jayeshkumar J. Hadia, and Ajay J. Khopade
4.1 Introduction 69
4.2 Liposome Commercial Landscape 72
4.3 Important Considerations in Development and Characterization of Liposomes 80
4.3.1 Selection of Lipids 80
4.3.2 Drug: Lipid Ratio 81
4.3.3 PEGylation 82
4.3.4 Ligand Anchoring 83
4.3.5 Drug-Loading Techniques 84
4.3.6 Physicochemical Characterization 85
4.3.7 Manufacturing Process 86
4.3.8 Product Stability 87
4.4 Targeted Delivery of Liposomes 88
4.4.1 Passive Targeting 89
4.4.2 Active-Targeted Delivery 92
4.4.2.1 Cancer Cell Targeting 94
4.4.2.2 Tumor Endothelium Targeting 98
4.5 Recent Clinical Trials with Liposomes with Investigational Liposome Candidates 102
4.6 Factors Influencing the Clinical Translation of Liposomes for Targeted Delivery 103
4.7 Conclusions and Future of Prospects of Targeted Liposomal-Delivery Systems 108
List of Abbreviations 110
References 112
5 Antibody-Drug Conjugates: Development and Applications 127
Rajesh Pradhan, Meghna Pandey, Siddhanth Hejmady, Rajeev Taliyan, Gautam Singhvi, Sunil K. Dubey, and Sachin Dubey
5.1 Introduction 127
5.2 Design of ADCs 128
5.2.1 Antibody 129
5.2.2 Linker 130
5.2.3 Payload 132
5.3 Mechanism of Action 133
5.4 Pharmacokinetic Considerations for ADCs 134
5.4.1 Heterogeneity of ADCs 134
5.4.2 Bioanalytical Considerations for ADCs 135
5.4.3 Pharmacokinetic Parameters of ADCs 136
5.4.3.1 Absorption 136
5.4.3.2 Distribution 136
5.4.3.3 Metabolism and Elimination 136
5.5 Applications of ADCs 137
5.5.1 Approved ADCs in the Market 137
5.5.1.1 Gemtuzumab Ozogamicin 137
5.5.1.2 Brentuximab Vedotin 139
5.5.1.3 Ado-Trastuzumab Emtansine (T-DM1) 139
5.5.1.4 Inotuzumab Ozogamicin 139
5.5.1.5 Polatuzumab Vedotin-piiq 140
5.5.1.6 Enfortumab Vedotin 140
5.5.1.7 Trastuzumab Deruxtecan 140
5.5.2 Use of ADCs in Rheumatoid Arthritis 141
5.5.3 Use of ADCs in Bacterial Infections 141
5.5.4 Use of ADCs in Ophthalmology 141
5.6 Resistance of ADC 142
5.7 Regulatory Aspects for ADCs 143
5.7.1 Role of ONDQA 143
5.7.2 Role of OBP 144
5.8 Conclusion and Future Direction 144
References 145
6 Gene-Directed Enzyme-Prodrug Therapy (GDEPT) as a Suicide Gene Therapy Modality for Cancer Treatment 155
Prashant S. Kharkar and Atul L. Jadhav
6.1 Introduction 155
6.2 GDEPT for Difficult-to-Treat Cancers 159
6.2.1 High-Grade Gliomas (HGGs) 159
6.2.2 Triple-Negative Breast Cancer (TNBC) 161
6.2.3 Other Cancers 162
6.3 Novel Enzymes for GDEPT 164
6.4 Conclusions 165
References 165
7 Targeted Prodrugs in Oral Drug Delivery 169
Milica Markovic, Shimon Ben-Shabat, and Arik Dahan
7.1 Introduction 169
7.1.1 Classic vs. Modern Prodrug Approach 170
7.2 Modern, Targeted Prodrug Approach 171
7.2.1 Prodrug Approach-Targeting Enzymes 171
7.2.1.1 Valacyclovirase-Mediated Prodrug Activation 172
7.2.1.2 Phospholipase A 2 -Mediated Prodrug Activation 173
7.2.1.3 Antibody, Gene, and Virus-Directed Enzyme-Prodrug Therapy 175
7.2.2 Prodrug Approach Targeting Transporters 176
7.2.2.1 Peptide Transporter 1 177
7.2.2.2 Monocarboxylate Transporter Type 1 179
7.2.2.3 Bile Acid Transporters 180
7.3 Computational Approaches in Targeted Prodrug Design 181
7.4 Discussion 182
7.5 Future Prospects and Clinical Applications 183
7.6 Conclusion 183
References 184
8 Exosomes for Drug Delivery Applications in Cancer and Cardiac Indications 193
Anjali Pandya, Sreeranjini Pulakkat, and Vandana Patravale
8.1 Extracellular Vesicles: An Overview 193
8.1.1 Evolution of Exosomes 194
8.1.2 Exosomes as Delivery Vehicles for Therapeutics 195
8.1.2.1 Endogenous Loading Methods 198
8.1.2.2 Exogenous Loading Methods 198
8.2 Exosomes as Cancer Therapeutics 199
8.2.1 Influence of Donor Cells 202
8.2.2 Different Therapeutic Cargo Explored in Cancer Therapy 202
8.2.2.1 Delivery of Proteins and Peptides 203
8.2.2.2 Delivery of Chemotherapeutic Cargo 204
8.2.2.3 Delivery of RNA 204
8.3 Exosome Based Drug Delivery for Cardiovascular Diseases 206
8.3.1 Delivery of Cardioprotective RNAs 207
8.3.2 Exosomes Modified with Cardiac Targeting Peptides 208
8.4 Clinical Evaluations and Future Aspects 210
8.5 Conclusion 211
Acknowledgments 212
References 212
9 Delivery of Nucleic Acids, Such as siRNA and mRNA, Using Complex Formulations 221
Ananya Pattnaik, Swarnaparabha Pany, A. S. Sanket, Sudiptee Das, Sanghamitra Pati, and Sangram K. Samal
9.1 Introduction 221
9.2 NA-Based Complex Delivery System 228
9.2.1 Classical NA-Based Complex Delivery System 229
9.2.1.1 Polymer-Based NA-Complex Delivery System 229
9.2.1.2 Lipid-Based Complex NA Delivery System 230
9.2.1.3 Peptide-Based Complex NA Delivery System 231
9.2.2 Advanced NA-Based Complex Delivery Systems 232
9.2.2.1 Inorganic and Hybrid NPs 232
9.2.2.2 Self-Assembled NA Nanostructures 233
9.2.2.3 Exosomes and NanoCells 233
9.3 Applications of NA-Complex Delivery Systems 234
9.3.1 Genome Editing 235
9.3.2 Cancer Therapy 237
9.3.3 Protein Therapy 238
9.4 Future Prospective 239
9.5 Conclusion 240
Acknowledgments 240
References 240
10 Application of PROTAC Technology in Drug Development 247
Prashant S. Kharkar and Atul L. Jadhav
10.1 Introduction 247
10.2 Design of PROTACS: A Brief Overview 252
10.3 Therapeutic Applications of PROTACs 254
10.3.1 Cancer 255
10.3.2 Neurodegenerative Disorders 261
10.3.3 Immunological Diseases 263
10.3.4 Viral Infections 264
10.4 Challenges and Limitations in the Development PROTACs 265
10.5 Future Perspectives 266
References 266
11 Metal Complexes as the Means or the End of Targeted Delivery for Unmet Needs 271
Trevor W. Hambley
11.1 Introduction 271
11.2 Class 1: Chaperones 272
11.2.1 Chaperones that Protect Drugs 273
11.2.2 Delivery to the Cells or Environments to Be Targeted 275
11.2.3 Release from the Metal Where and When Required 276
11.3 Class 2: Active Metal Complexes 276
11.3.1 Targeted Platinum Agents 277
11.4 Class 3: Dual-Threat Metal Complexes 279
11.5 Targeting Strategies: The Chemical and Physical Environment 280
11.5.1 Hypoxia 281
11.5.2 pH-Based Targeting 282
11.5.3 The EPR Effect 283
11.6 Targeting Strategies: Transporters 284
11.7 Targeting Strategies: Enzyme Activation 286
11.8 Other Targeting Strategies 287
11.9 Conclusions 288
References 289
12 Formulation of Peptides for Targeted Delivery 299
Pankti Ganatra, Karen Saiswani, Nikita Nair, Avinash Gunjal, Ratnesh Jain, and Prajakta Dandekar
12.1 Introduction 299
12.2 Peptides Used in Cancer Therapy 302
12.2.1 Lung Cancer 303
12.2.2 Melanoma 304
12.2.3 Pancreatic Cancer 306
12.2.4 Brain Cancer 307
12.2.5 Breast Cancer 309
12.2.6 Leukemia 312
12.3 Peptide-Targeting Based on Site of Action 315
12.3.1 Topical Delivery of Peptides 315
12.3.2 Ocular Delivery of Peptides 317
12.3.3 Brain Delivery of Peptides 319
12.3.4 Lung-Targeted Delivery of Peptides 321
12.4 Conclusion and Future Prospects 323
References 324
13 Antibody-Based Targeted T-Cell Therapies 327
Manoj Bansode, Kaushik Deb, and Sarmistha Deb
13.1 Introduction 327
13.2 Immune-Directed Cancer Cell Death 328
13.3 Immunotherapy Strategies in Cancer 328
13.4 T-Cell Therapy 329
13.5 Naturally Occurring T Cells 329
13.6 Genetically Modified Occurring T Cells 330
13.7 Clinical Implication of T-Cell and CAR-T-Cell Therapy: 330
13.8 Antibody-Induced T-Cell Therapy 332
13.9 A Bispecific Antibody (BsAbs)-Induced T-Cell Therapy 332
13.10 Formats of BsAbs 335
13.11 Triomab Antibodies in T-Cell Therapy 335
13.12 Bispecific Antibodies in T-Cell Therapy 336
13.13 Clinically Approved T-Cell-Activating Antibodies 337
13.14 Prospects 337
13.15 Conclusion 339
References 339
14 Devices for Active Targeted Delivery: A Way to Control the Rate and Extent of Drug Administration 349
Jonathan Faro Barros, Phedra F. Sahraoui, Yogeshvar N. Kalia, and Maria Lapteva
14.1 Introduction 349
14.2 Macrofabricated Devices - Drug Infusion Pumps 351
14.2.1 Peristaltic Pumps 351
14.2.2 Gas-Driven Pumps 352
14.2.3 Osmotic Pumps 353
14.2.4 Insulin Pumps 354
14.2.4.1 Diabetes and Insulin Product Development 354
14.2.4.2 Open-Loop Insulin Delivery Systems 355
14.2.4.3 Closed-Loop Insulin Delivery Systems 360
14.3 Microfabricated and Nanofabricated Drug Delivery Devices 364
14.3.1 Microelectromechanical Systems (MEMS) 364
14.3.1.1 Microchip-Based MEMS 364
14.3.1.2 Pump-Based MEMS 366
14.3.1.3 MEMS - Efforts to Close the Loop 368
14.3.2 Nanofabricated Drug Delivery Devices 369
14.4 Noninvasive Active Drug Delivery Systems: Iontophoresis 372
14.5 Conclusions 376
Acknowledgments 377
List of Abbreviations 377
References 378
15 Drug Delivery to the Brain: Targeting Technologies to Deliver Therapeutics to Brain Lesions 389
Nishit Pathak, Sunil K. Vimal, Cao Hongyi, and Sanjib Bhattacharyya
15.1 Introduction 389
15.2 Brain Tumor 390
15.2.1 Obstacles to Brain Tumor-Targeted Delivery 391
15.2.2 Brain-Tumor-Focused Nano-Drug Delivery 393
15.3 Neurodegenerative Diseases 396
15.3.1 Alzheimer’s Disease (AD) 396
15.3.1.1 Alzheimer’s Disease Focused on Drug Delivery 396
15.3.2 Parkinson’s Disease 399
15.3.2.1 Drug Delivery Focussed on Parkinson’s Drug Disease 399
15.3.3 Cerebrovascular Disease 400
15.3.3.1 Drug Delivery for Cerebrovascular Disease 400
15.3.4 Inflammatory Diseases (ID) 402
15.3.4.1 Inflammatory Diseases (ID) Focused on Drug Delivery 402
15.3.4.2 Drug Delivery for the Treatment of Neuro-AIDS 403
15.3.5 Drug Delivery for Multiple Sclerosis (MS) 403
15.4 Drug Delivery for CNS Disorders 404
15.4.1 Tau Therapy 405
15.4.2 Immunotherapy 407
15.4.3 Gene Immunotherapy (GIT) 407
15.4.4 Chemotherapy (CT) 408
15.4.5 Photoimmunotherapy (PIT) 408
15.5 Future Prospects 410
15.6 Conclusions 410
List of Abbreviations 411
References 412
Index 425
