DRUG DELIVERY: PRINCIPLES AND APPLICATIONS, 2ND EDITION

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 S trategies 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 S ustained ]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 O rganic 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 AerosolAdministration 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

Following its successful predecessor, this book covers the fundamentals, delivery routes and vehicles, and practical applications of drug delivery. In the 2nd edition, almost all chapters from the previous are retained and updated and several new chapters added to make a more complete resource and reference.

• Helps readers understand progress in drug delivery research and applications
• Updates and expands coverage to reflect advances in materials for delivery vehicles, drug delivery approaches, and therapeutics
• Covers recent developments including transdermal and mucosal delivery, lymphatic system delivery, theranostics
• Adds new chapters on nanoparticles, controlled drug release systems, theranostics, protein and peptide drugs, and biologics delivery

Author Information
• 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.