Drug Delivery

Binghe Wang, PhD, is Regents’ Professor of Chemistry and Associate Dean for Natural and Computational Sciences at Georgia State University as well as Georgia Research Alliance Eminent Scholar in Drug Discovery. He is Editor-in-Chief of the journal Medicinal Research Review and founding series editor of the Wiley Series in Drug Discovery and Development. He has published over 230 papers in medicinal chemistry, pharmaceutical chemistry, new diagnostics, and chemosensing. Longqin Hu, PhD, is Professor of Medicinal Chemistry and Director of the Graduate Program in Medicinal Chemistry at Rutgers University. Among his major research interests are the synthesis and evaluation of anticancer prodrugs for the targeted activation in tumor tissues and the discovery of novel small molecule inhibitors of protein-protein interactions.  He has published over 80 papers and 8 patents in bioorganic and medicinal chemistry. Teruna Siahaan, PhD, is a Professor and Associate Chair of the Department of Pharmaceutical Chemistry and serves as the Director of the NIH Biotechnology Training Program at the University of Kansas. In addition to co-editing the first edition of Drug Delivery, he has written almost 195 journal papers and book chapters and received the 2014 PhRMA Foundation Award in Excellence in Pharmaceutics.

List of Contributors xvii

Preface xxi

1 Factors that Impact the Developability of Drug Candidates 1
Chao Han and Binghe Wang

1.1 Challenges Facing the Pharmaceutical Industry 1

1.2 Factors that Impact Developability 5

1.2.1 Commercial Goal 5

1.2.2 The Chemistry Efforts 6

1.2.3 Biotechnology in the Discovery of Medicine 7

1.2.4 Target Validation in Animal Models 8

1.2.5 Drug Metabolism and Pharmacokinetics 9

1.2.6 Preparation for Pharmaceutical Products 11

1.3 Remarks on Developability 12

1.4 Drug Delivery Factors that Impact Developability 13

References 15

2 Physiological, Biochemical, and Chemical Barriers to Oral Drug Delivery 19
Paul Kiptoo, Anna M. Calcagno, and Teruna J. Siahaan

2.1 Introduction 19

2.2 Physiological Barriers to Drug Delivery 20

2.2.1 Paracellular Pathway 22

2.2.2 Transcellular Pathway 25

2.3 Biochemical Barriers to Drug Delivery 25

2.3.1 Metabolizing Enzymes 25

2.3.2 Transporters and Efflux Pumps 27

2.4 Chemical Barriers to Drug Delivery 28

2.4.1 Hydrogen‐Bonding Potential 28

2.4.2 Other Properties 29

2.5 Drug Modifications to Enhance Transport Across Biological Barriers 29

2.5.1 Prodrugs and Structural Modifications 29

2.5.2 Formulations 30

2.6 Conclusions 31

Acknowledgment 31

References 31

3 Physicochemical Properties, Formulation, and Drug Delivery 35
Dewey H. Barich, Mark T. Zell, and Eric J. Munson

3.1 Introduction 35

3.2 Physicochemical Properties 36

3.2.1 Solubility 37

3.2.2 Stability 40

3.3 Formulations 42

3.3.1 Processing Steps 42

3.3.2 Influence of Physicochemical Properties on Drugs in Formulations 43

3.3.3 Other Issues 43

3.4 Drug Delivery 43

3.4.1 Duration of Release 44

3.4.2 Site of Administration 45

3.4.3 Methods of Administration 46

3.5 Conclusion 47

References 47

4 Targeted Bioavailability: A Fresh Look at Pharmacokinetic and Pharmacodynamic Issues in Drug Discovery and Development 49
Christine Xu

4.1 Introduction 49

4.2 Target Bioavailability 50

4.3 Drug Delivery Trends and Targets Related to PK and PD 51

4.4 PK–PD in Drug Discovery and Development 51

4.5 Source of Variability of Drug Response 55

4.6 Recent Development and Issues of Bio‐Analytical Methodology 57

4.7 Mechanistic PK–PD Models 58

4.8 Summary 60

References 60

5 The Role of Transporters in Drug Delivery and Excretion 62
Marilyn E. Morris and Xiaowen Guan

5.1 Introduction 62

5.2 Drug Transport in Absorption and Excretion 63

5.2.1 Intestinal Transport 63

5.2.2 Hepatic Transport 64

5.2.3 Renal Transport 67

5.2.4 BBB Transport 67

5.3 ABC (ATP‐Binding Cassette) Transporter Family 67

5.3.1 P‐Glycoprotein (ABCB1) 67

5.3.2 Multidrug Resistance‐Associated Proteins (ABCC) 71

5.3.3 Breast Cancer Resistance Protein (ABCG2) 74

5.3.4 Other ABC Transporters 76

5.4 SlC (Solute Carrier) Transporter Family 76

5.4.1 Organic Anion Transporting Polypeptides (SLCO) 76

5.4.2 Organic Anion Transporters (SLC22A) 80

5.4.3 Organic Cation Transporters (SLC22) 81

5.4.4 Multidrug and Toxin Extrusion Transporters (SLC47A) 83

5.4.5 Monocarboxylate Transporters (SLC16 and SLC5) 84

5.4.6 Peptide Transporters (SLC15A) 86

5.4.7 Other SLC Transporters 88

5.5 Conclusions 88

Acknowledgment 88

References 89

6 Intracellular Delivery and Disposition of Small‐Molecular‐Weight Drugs 103
Jeffrey P. Krise

6.1 Introduction 103

6.2 The Relationship between the Intracellular Distribution of a Drug and its Activity 104

6.3 The Relationship between the Intracellular Distribution of a Drug and its Pharmacokinetic Properties 104

6.4 Overview of Approaches to Study Intracellular Drug Disposition 105

6.4.1 Fluorescence Microscopy 106

6.4.2 Organelle Isolation 106

6.4.3 Indirect Methods 107

6.5 The Accumulation of Drugs in Mitochondria, Lysosomes, and Nuclei 108

6.5.1 Mitochondrial Accumulation of Drugs 108

6.5.2 Lysosomal Accumulation of Drugs 112

6.5.3 Nuclear Accumulation of Drugs 122

6.6 Summary and Future Directions 123

References 124

7 Cell Culture Models for Drug Transport Studies 131
Irina Kalashnikova, Norah Albekairi, Shariq Ali, Sanaalarab Al Enazy, and Erik Rytting

7.1 Introduction 131

7.2 General Considerations 132

7.3 Intestinal Epithelium 133

7.3.1 The Intestinal Epithelial Barrier 133

7.3.2 Intestinal Epithelial Cell Culture Models 134

7.4 The Blood–Brain Barrier 135

7.4.1 The Blood–Brain Endothelial Barrier 135

7.4.2 BBB Cell Culture Models 136

7.5 Nasal and Pulmonary Epithelium 137

7.5.1 The Respiratory Airway Epithelial Barrier 137

7.5.2 The Nasal Epithelial Barrier and Cell Culture Models 138

7.5.3 The Airway Epithelial Barrier and Cell Culture Models 139

7.5.4 The Alveolar Epithelial Barrier and Cell Culture Models 140

7.6 The Ocular Epithelial and Endothelial Barriers 141

7.6.1 The Corneal and Retinal Barriers 141

7.6.2 Cell Culture Models of Ocular Epithelium and Endothelium 142

7.7 The Placental Barrier 142

7.7.1 The Syncytiotrophoblast Barrier 142

7.7.2 Trophoblast Cell Culture Models 143

7.8 The Renal Epithelium 143

7.8.1 The Renal Epithelial Barrier 143

7.8.2 Renal Epithelial Cell Culture Models 144

7.9 3D In Vitro Models 145

7.10 Conclusions 146

References 146

8 Intellectual Property and Regulatory Issues in Drug Delivery Research 152
Shahnam Sharareh and Wansheng Jerry Liu

8.1 Introduction 152

8.2 Pharmaceutical Patents 153

8.3 Statutory Requirements for Obtaining a Patent 154

8.3.1 Patentable Subject Matter 154

8.3.2 Novelty 155

8.3.3 Nonobviousness 155

8.4 Patent Procurement Strategies 157

8.5 Regulatory Regime 158

8.6 FDA Market Exclusivities 160

8.7 Regulatory and Patent Law Linkage 162

References 162

9 Presystemic and First‐Pass Metabolism 164
Qingping Wang and Meng li

9.1 Introduction 164

9.2 Hepatic First‐Pass Metabolism 165

9.2.1 Hepatic Enzymes 166

9.3 Intestinal First‐Pass Metabolism 170

9.3.1 Intestinal Enzymes 170

9.3.2 Interplay of Intestinal Enzymes and Transporters 174

9.4 Prediction of First‐Pass Metabolism 174

9.4.1 In vivo Assessment of First‐Pass Metabolism 174

9.4.2 In vitro Assessment of First‐Pass Metabolism 175

9.4.3 In vitro–in vivo Prediction 177

9.4.4 In Silico Approach 178

9.5 Strategies for Optimization of Oral Bioavailability 178

9.6 Summary 179

References 180

10 Pulmonary Drug Delivery: Pharmaceutical Chemistry and Aerosol Technology 186
Anthony J. Hickey

10.1 Introduction 186

10.2 Aerosol Technology 187

10.2.1 Particle Production 187

10.2.2 Propellant‐Driven Metered‐Dose Inhalers 188

10.2.3 Dry Powder Inhalers 188

10.2.4 Nebulizer 190

10.3 Disease Therapy 190

10.3.1 Asthma 190

10.3.2 Emphysema 193

10.3.3 Cystic Fibrosis 195

10.3.4 Other Locally Acting Agents 195

10.3.5 Systemically Acting Agents 196

10.4 Formulation Variables 196

10.4.1 Excipients 197

10.4.2 Interactions 199

10.4.3 Stability 200

10.5 Regulatory Considerations 200

10.6 Future Developments 201

10.7 Conclusion 201

References 202

11 Transdermal Delivery of Drugs Using Patches and Patchless Delivery Systems 207
Tannaz Ramezanli, Krizia Karry, Zheng Zhang, Kishore Shah, and Bozena Michniak‐Kohn

11.1 Introduction 207

11.2 Transdermal Patch Delivery Systems 208

11.2.1 Definition and History of Patches 208

11.2.2 Anatomy and Designs of Patches 209

11.3 Patchless Transdermal Drug Delivery Systems 211

11.3.1 First‐Generation Systems 212

11.3.2 Second‐Generation Systems 212

11.3.3 Third‐Generation Systems 214

11.4 Recent Advances in Transdermal Drug Delivery 216

11.4.1 Frontier in Transdermal Drug Delivery: Transcutaneous Immunization via Microneedle Techniques 216

11.4.2 Patchless Transdermal Delivery: The PharmaDur “Virtual Patch” 219

11.5 Summary 221

References 222

12 Prodrug Approaches to Drug Delivery 227
Longqin Hu

12.1 Introduction 227

12.2 Basic Concepts: Definition and Applications 228

12.2.1 Increasing Lipophilicity to Increase Systemic Bioavailability 228

12.2.2 Sustained‐Release Prodrug Systems 231

12.2.3 Improving Gastrointestinal Tolerance 232

12.2.4 Improving Taste 232

12.2.5 Diminishing Gastrointestinal Absorption 233

12.2.6 Increasing Water Solubility 233

12.2.7 Tissue Targeting and Activation at the Site of Action 234

12.3 Prodrug Design Considerations 238

12.4 Prodrugs of Various Functional Groups 241

12.4.1 Prodrugs of Compounds Containing─COOH or─OH 241

12.4.2 Prodrugs of Compounds Containing Amides, Imides, and Other Acidic NH 246

12.4.3 Prodrugs of Amines 249

12.4.4 Prodrugs for Compounds Containing Carbonyl Groups 255

12.5 Drug Release and Activation Mechanisms 258

12.5.1 Cascade Release Facilitated by Linear Autodegradation Reactions 260

12.5.2 Cascade Release Facilitated by Intramolecular Cyclization Reactions 262

12.5.3 Cascade Activation through Intramolecular Cyclization to form Cyclic Drugs 264

12.6 Prodrugs and Intellectual Property Rights—Two Court Cases 266

References 268

13 Liposomes as Drug Delivery Vehicles 272
Guijun Wang

13.1 Introduction 272

13.2 Currently Approved Liposomal Drugs in Clinical Applications 273

13.3 Conventional and Stealth Liposomes 276

13.4 Stimuli‐Responsive Liposomes or Triggered‐Release Liposomes 277

13.4.1 General Mechanism of Triggered Release 277

13.4.2 Thermo‐Sensitive Liposomes 278

13.4.3 pH‐Sensitive Liposomes 279

13.4.4 Photo‐Triggered Liposomes 282

13.4.5 Triggered Release Controlled by Enzymes 287

13.5 Targeted Liposomal Delivery 289

13.6 Hybrid Liposome Drug Delivery System 291

13.7 Conclusions and Future Perspectives 293

References 293

14 Nanoparticles as Drug Delivery Vehicles 299
Dan Menasco and Qian Wang

14.1 Introduction 299

14.1.1 General DDV Properties 300

14.1.2 The DDV Core: Therapeutic Loading, Release, and Sensing 301

14.1.3 DDV Targeting: Ligand Display 305

14.1.4 DDV Size and Surface: Clearance and the EPR Effect 308

14.2 Organic DDVs 308

14.2.1 Polymer-Based Nanocarriers 308

14.2.2 Polymeric Micelles 310

14.2.3 Dendrimers 314

14.3 Inorganic DDVs: Metal‐ and Silica‐Based Systems 320

14.3.1 Inorganic DDVs: Mesoporous Silica Nanoparticles 322

14.3.2 Inorganic DDVs: Gold Nanoparticles 324

14.4 Conclusion 330

References 330

15 Evolution of Controlled Drug Delivery Systems 336
Krishnaveni Janapareddi, Bhaskara R. Jasti, and Xiaoling li

15.1 Introduction 336

15.2 Biopharmaceutics and Pharmacokinetics 337

15.3 Material Science 341

15.4 Proteins, Peptides and Nucleic Acids 343

15.5 Discovery of New Molecular Targets—Targeted Drug Delivery 345

15.6 Microelectronics and Microfabrication Technologies 347

15.7 Conclusion 349

References 349

16 Pathways for Drug Delivery to the Central Nervous System 353
Ngoc H. On, Vinith Yathindranath, Zhizhi Sun, and Donald W. Miller

16.1 Introduction 353

16.1.1 Cellular Barriers to Drug Delivery in the CNS 354

16.1.2 General Approaches for Increasing Brain Penetration of Drugs 356

16.2 Circumventing the CNS Barriers 356

16.2.1 Intracerebroventricular Injection 357

16.2.2 Intracerebral Administration 357

16.2.3 Intranasal Delivery Route 358

16.3 Transient BBB Disruption 359

16.3.1 Osmotic BBB Disruption 359

16.3.2 Pharmacological Disruption of the BBB 360

16.4 Transcellular Delivery Routes 364

16.4.1 Solute Carrier Transport Systems in the BBB 364

16.4.2 Adenosine Triphosphate‐Binding Cassette Transport Systems in the BBB 369

16.4.3 Vesicular Transport in the BBB 370

16.5 Conclusions 375

References 375

17 Metabolic Activation and Drug Targeting 383
Xiangming Guan

17.1 Introduction 383

17.2 Anticancer Prodrugs and their Biochemical Basis 384

17.2.1 Tumor‐Activated Anticancer Prodrugs Based on Hypoxia 385

17.2.2 Tumor‐Activated Prodrugs Based on Elevated Peptidases or Proteases 401

17.2.3 Tumor‐Activated Prodrugs Based on Enzymes with Elevated Activity at Tumor Sites 413

17.3 Antibody‐ and Gene‐Directed Enzyme Prodrug Therapy 420

17.3.1 Adept 421

17.3.2 Gdept 425

17.4 Summary 429

References 429

18 Targeted Delivery of Drugs to the Colon 435
Anil K. Philip and Sarah K. Zingales

18.1 Introduction 435

18.2 Microbially Triggered Release 437

18.2.1 Azo‐Linked Compounds 437

18.2.2 Amino Acid Conjugates 440

18.2.3 Sugar‐Derived Prodrugs 440

18.3 pH‐Sensitive Polymers for Time‐Dependent Release 442

18.4 Osmotic Release 443

18.5 Pressure‐Controlled Delivery 443

18.6 Nanoparticle Approaches 444

18.7 Conclusion 446

Acknowledgment 446

References 447

19 Receptor‐Mediated Drug Delivery 451
Chris V. Galliford and Philip S. Low

19.1 Introduction 451

19.2 Selection of a Receptor for Drug Delivery 454

19.2.1 Specificity 454

19.2.2 Receptor Internalization/Recycling 455

19.3 Design of a Ligand–Drug Conjugate 455

19.3.1 Linker Chemistry 455

19.3.2 Selection of Ligands 457

19.3.3 Selection of Therapeutic Drug 457

19.4 Folate‐Mediated Drug Delivery 458

19.4.1 Expression of FRs in Malignant Tissues 459

19.4.2 Expression of FRs in Normal Tissues 460

19.4.3 Applications of Folate‐Mediated Drug Delivery 461

19.5 Conclusions 467

Acknowledgments 467

References 467

20 Protein and Peptide Conjugates for Targeting Therapeutics and Diagnostics to Specific Cells 475
Barlas Büyüktimkin, John Stewart, Jr., Kayann Tabanor, Paul Kiptoo, and Teruna J. Siahaan

20.1 Introduction 475

20.2 Radiolabeled Antibodies for Cancer Treatment 479

20.3 Antibody–Drug Conjugate 480

20.3.1 Sites of Conjugation on mAbs, Linkers, and Drugs 481

20.4 Non‐Antibody‐Based Protein–Drug Conjugates 486

20.5 Peptibody 488

20.6 Protein Conjugates for Diagnostics 489

20.7 Peptide–Drug Conjugates 491

20.8 Challenges in Analyzing Conjugates 494

20.9 Conclusions 497

References 497

21 Drug Delivery to the Lymphatic System 503
Qiuhong Yang and Laird Forrest

21.1 Introduction 503

21.2 Anatomy and Physiology of the Lymphatic System 504

21.2.1 Lymph 504

21.2.2 Lymphatic Vessels 504

21.2.3 Lymph Nodes 506

21.2.4 Lymph Organs 508

21.3 Influence of Physicochemical Characteristics of Drug Carriers on Lymphatic Uptake and Transport 509

21.3.1 Size 509

21.3.2 Surface Charge 511

21.3.3 Hydrophobicity 513

21.4 Carriers for Lymphatic Drug Delivery 513

21.4.1 Liposomes 515

21.4.2 Lipid‐Based Emulsions and Nanoparticles 519

21.4.3 Polymer‐Based Carriers 524

21.5 Administration Routes for Lymphatic Delivery 528

21.5.1 Intestinal 528

21.5.2 Pulmonary 529

21.5.3 Subcutaneous 531

21.5.4 Intraperitoneal 535

21.6 Lymphatic‐Targeting Vaccination 536

21.7 Conclusions 538

References 539

22 The Development of Cancer Theranostics: A New Emerging Tool Toward Personalized Medicine 549
Hongying Su, Yun Zeng, Gang Liu, and Xiaoyuan Chen

22.1 Introduction 549

22.2 Imaging‐Guided Drug Delivery and Therapy 551

22.3 Optical Imaging-Based Theranostics 553

22.3.1 NIR Fluorescence Imaging 553

22.3.2 Bioluminescence Imaging 556

22.3.3 Gold Nanoparticle as a Theranostics Platform 557

22.4 MRI‐Based Theranostics 558

22.5 Nuclear Imaging-Based Theranostics 559

22.6 Ultrasound‐Based Theranostic Platform 563

22.7 Multimodality Imaging-Based Theranostic Platform 564

22.7.1 PET/CT 565

22.7.2 MRI/Optical 566

22.7.3 MRI/PET 566

22.8 Conclusion and Future Perspectives 567

Acknowledgments 569

References 569

23 Intracellular Delivery of Proteins and Peptides 576
Can Sarisozen and Vladimir P. Torchilin

23.1 Introduction 576

23.2 Intracellular Delivery Strategies of Peptides and Proteins 579

23.3 Concepts in Intracellular Peptide and Protein Delivery 580

23.3.1 Longevity in the Blood 580

23.3.2 Cellular Uptake Pathways 582

23.3.3 Endosomal Escape 585

23.4 Peptide and Protein Delivery to Lysosomes 589

23.5 Receptor‐Mediated Intracellular Delivery of Peptides and Proteins 590

23.5.1 Transferrin Receptor–Mediated Delivery 590

23.5.2 Folate Receptor–Mediated Delivery 593

23.6 Transmembrane Delivery of Peptides and Proteins 595

23.6.1 Well Studied Classes of CPPs for Peptide and Protein Delivery 595

23.6.2 Cellular Uptake Mechanisms of CPPs 596

23.6.3 CPP‐Mediated Delivery of Peptides and Proteins 599

23.6.4 CPP‐Modified Carriers for Intracellular Delivery of Peptides and Proteins 601

23.7 Conclusion 602

References 602

24 Vaccine Delivery: Current Routes of Administration and Novel Approaches 623
Neha Sahni, Yuan Cheng, C. Russell Middaugh, and David B. Volkin

24.1 Introduction 623

24.2 Parenteral Administration of Vaccines 625

24.2.1 Currently Available Vaccines and Devices for Intramuscular and Subcutaneous Delivery 625

24.2.2 Currently Available Intradermal Vaccines and Associated Delivery Devices 629

24.2.3 Novel Devices for Parenteral Injection 630

24.2.4 Novel Formulations and Delivery Approaches for Parenteral Injection 632

24.3 Oral Delivery of Vaccines 634

24.3.1 Currently Available Orally Administered Vaccines 634

24.3.2 Novel Formulations and Delivery Approaches for Oral Administration 635

24.4 Nasal and Aerosol Delivery of Vaccines 639

24.4.1 Currently Available Nasally Administered Vaccines 639

24.4.2 Novel Devices and Formulations for Nasal Administration 639

24.4.3 Devices and Delivery Systems for Aerosol Administration of Vaccines 642

24.5 Conclusions 643

References 644

25 Delivery of Genes and Oligonucleotides 655
Charles M. Roth

25.1 Introduction 655

25.2 Systemic Delivery Barriers 656

25.2.1 Viruses: Learning from Nature 657

25.2.2 Materials for Nucleic Acid Delivery 658

25.2.3 Characterization of Nanoparticles 659

25.2.4 Targeted Delivery of Nucleic Acids 662

25.3 Cellular Delivery Barriers 663

25.3.1 Endosomal Escape 663

25.3.2 Vector Unpackaging 665

25.4 Current and Future Approaches to Nucleic Acid Delivery 666

25.4.1 Vectors in the Clinic 666

25.4.2 Combinatorial Chemistry Approaches 667

25.4.3 Polymer–Lipid Nanocomposites 667

25.5 Summary and Future Directions 668

References 668

Index 674