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 xviiPreface xxi1 Factors that Impact the Developability of Drug Candidates 1Chao Han and Binghe Wang1.1 Challenges Facing the Pharmaceutical Industry 11.2 Factors that Impact Developability 51.2.1 Commercial Goal 51.2.2 The Chemistry Efforts 61.2.3 Biotechnology in the Discovery of Medicine 71.2.4 Target Validation in Animal Models 81.2.5 Drug Metabolism and Pharmacokinetics 91.2.6 Preparation for Pharmaceutical Products 111.3 Remarks on Developability 121.4 Drug Delivery Factors that Impact Developability 13References 152 Physiological, Biochemical, and Chemical Barriers to Oral Drug Delivery 19Paul Kiptoo, Anna M. Calcagno, and Teruna J. Siahaan2.1 Introduction 192.2 Physiological Barriers to Drug Delivery 202.2.1 Paracellular Pathway 222.2.2 Transcellular Pathway 252.3 Biochemical Barriers to Drug Delivery 252.3.1 Metabolizing Enzymes 252.3.2 Transporters and Efflux Pumps 272.4 Chemical Barriers to Drug Delivery 282.4.1 Hydrogen‐Bonding Potential 282.4.2 Other Properties 292.5 Drug Modifications to Enhance Transport Across Biological Barriers 292.5.1 Prodrugs and Structural Modifications 292.5.2 Formulations 302.6 Conclusions 31Acknowledgment 31References 313 Physicochemical Properties, Formulation, and Drug Delivery 35Dewey H. Barich, Mark T. Zell, and Eric J. Munson3.1 Introduction 353.2 Physicochemical Properties 363.2.1 Solubility 373.2.2 Stability 403.3 Formulations 423.3.1 Processing Steps 423.3.2 Influence of Physicochemical Properties on Drugs in Formulations 433.3.3 Other Issues 433.4 Drug Delivery 433.4.1 Duration of Release 443.4.2 Site of Administration 453.4.3 Methods of Administration 463.5 Conclusion 47References 474 Targeted Bioavailability: A Fresh Look at Pharmacokinetic and Pharmacodynamic Issues in Drug Discovery and Development 49Christine Xu4.1 Introduction 494.2 Target Bioavailability 504.3 Drug Delivery Trends and Targets Related to PK and PD 514.4 PK–PD in Drug Discovery and Development 514.5 Source of Variability of Drug Response 554.6 Recent Development and Issues of Bio‐Analytical Methodology 574.7 Mechanistic PK–PD Models 584.8 Summary 60References 605 The Role of Transporters in Drug Delivery and Excretion 62Marilyn E. Morris and Xiaowen Guan5.1 Introduction 625.2 Drug Transport in Absorption and Excretion 635.2.1 Intestinal Transport 635.2.2 Hepatic Transport 645.2.3 Renal Transport 675.2.4 BBB Transport 675.3 ABC (ATP‐Binding Cassette) Transporter Family 675.3.1 P‐Glycoprotein (ABCB1) 675.3.2 Multidrug Resistance‐Associated Proteins (ABCC) 715.3.3 Breast Cancer Resistance Protein (ABCG2) 745.3.4 Other ABC Transporters 765.4 SlC (Solute Carrier) Transporter Family 765.4.1 Organic Anion Transporting Polypeptides (SLCO) 765.4.2 Organic Anion Transporters (SLC22A) 805.4.3 Organic Cation Transporters (SLC22) 815.4.4 Multidrug and Toxin Extrusion Transporters (SLC47A) 835.4.5 Monocarboxylate Transporters (SLC16 and SLC5) 845.4.6 Peptide Transporters (SLC15A) 865.4.7 Other SLC Transporters 885.5 Conclusions 88Acknowledgment 88References 896 Intracellular Delivery and Disposition of Small‐Molecular‐Weight Drugs 103Jeffrey P. Krise6.1 Introduction 1036.2 The Relationship between the Intracellular Distribution of a Drug and its Activity 1046.3 The Relationship between the Intracellular Distribution of a Drug and its Pharmacokinetic Properties 1046.4 Overview of Approaches to Study Intracellular Drug Disposition 1056.4.1 Fluorescence Microscopy 1066.4.2 Organelle Isolation 1066.4.3 Indirect Methods 1076.5 The Accumulation of Drugs in Mitochondria, Lysosomes, and Nuclei 1086.5.1 Mitochondrial Accumulation of Drugs 1086.5.2 Lysosomal Accumulation of Drugs 1126.5.3 Nuclear Accumulation of Drugs 1226.6 Summary and Future Directions 123References 1247 Cell Culture Models for Drug Transport Studies 131Irina Kalashnikova, Norah Albekairi, Shariq Ali, Sanaalarab Al Enazy, and Erik Rytting7.1 Introduction 1317.2 General Considerations 1327.3 Intestinal Epithelium 1337.3.1 The Intestinal Epithelial Barrier 1337.3.2 Intestinal Epithelial Cell Culture Models 1347.4 The Blood–Brain Barrier 1357.4.1 The Blood–Brain Endothelial Barrier 1357.4.2 BBB Cell Culture Models 1367.5 Nasal and Pulmonary Epithelium 1377.5.1 The Respiratory Airway Epithelial Barrier 1377.5.2 The Nasal Epithelial Barrier and Cell Culture Models 1387.5.3 The Airway Epithelial Barrier and Cell Culture Models 1397.5.4 The Alveolar Epithelial Barrier and Cell Culture Models 1407.6 The Ocular Epithelial and Endothelial Barriers 1417.6.1 The Corneal and Retinal Barriers 1417.6.2 Cell Culture Models of Ocular Epithelium and Endothelium 1427.7 The Placental Barrier 1427.7.1 The Syncytiotrophoblast Barrier 1427.7.2 Trophoblast Cell Culture Models 1437.8 The Renal Epithelium 1437.8.1 The Renal Epithelial Barrier 1437.8.2 Renal Epithelial Cell Culture Models 1447.9 3D In Vitro Models 1457.10 Conclusions 146References 1468 Intellectual Property and Regulatory Issues in Drug Delivery Research 152Shahnam Sharareh and Wansheng Jerry Liu8.1 Introduction 1528.2 Pharmaceutical Patents 1538.3 Statutory Requirements for Obtaining a Patent 1548.3.1 Patentable Subject Matter 1548.3.2 Novelty 1558.3.3 Nonobviousness 1558.4 Patent Procurement Strategies 1578.5 Regulatory Regime 1588.6 FDA Market Exclusivities 1608.7 Regulatory and Patent Law Linkage 162References 1629 Presystemic and First‐Pass Metabolism 164Qingping Wang and Meng li9.1 Introduction 1649.2 Hepatic First‐Pass Metabolism 1659.2.1 Hepatic Enzymes 1669.3 Intestinal First‐Pass Metabolism 1709.3.1 Intestinal Enzymes 1709.3.2 Interplay of Intestinal Enzymes and Transporters 1749.4 Prediction of First‐Pass Metabolism 1749.4.1 In vivo Assessment of First‐Pass Metabolism 1749.4.2 In vitro Assessment of First‐Pass Metabolism 1759.4.3 In vitro–in vivo Prediction 1779.4.4 In Silico Approach 1789.5 Strategies for Optimization of Oral Bioavailability 1789.6 Summary 179References 18010 Pulmonary Drug Delivery: Pharmaceutical Chemistry and Aerosol Technology 186Anthony J. Hickey10.1 Introduction 18610.2 Aerosol Technology 18710.2.1 Particle Production 18710.2.2 Propellant‐Driven Metered‐Dose Inhalers 18810.2.3 Dry Powder Inhalers 18810.2.4 Nebulizer 19010.3 Disease Therapy 19010.3.1 Asthma 19010.3.2 Emphysema 19310.3.3 Cystic Fibrosis 19510.3.4 Other Locally Acting Agents 19510.3.5 Systemically Acting Agents 19610.4 Formulation Variables 19610.4.1 Excipients 19710.4.2 Interactions 19910.4.3 Stability 20010.5 Regulatory Considerations 20010.6 Future Developments 20110.7 Conclusion 201References 20211 Transdermal Delivery of Drugs Using Patches and Patchless Delivery Systems 207Tannaz Ramezanli, Krizia Karry, Zheng Zhang, Kishore Shah, and Bozena Michniak‐Kohn11.1 Introduction 20711.2 Transdermal Patch Delivery Systems 20811.2.1 Definition and History of Patches 20811.2.2 Anatomy and Designs of Patches 20911.3 Patchless Transdermal Drug Delivery Systems 21111.3.1 First‐Generation Systems 21211.3.2 Second‐Generation Systems 21211.3.3 Third‐Generation Systems 21411.4 Recent Advances in Transdermal Drug Delivery 21611.4.1 Frontier in Transdermal Drug Delivery: Transcutaneous Immunization via Microneedle Techniques 21611.4.2 Patchless Transdermal Delivery: The PharmaDur “Virtual Patch” 21911.5 Summary 221References 22212 Prodrug Approaches to Drug Delivery 227Longqin Hu12.1 Introduction 22712.2 Basic Concepts: Definition and Applications 22812.2.1 Increasing Lipophilicity to Increase Systemic Bioavailability 22812.2.2 Sustained‐Release Prodrug Systems 23112.2.3 Improving Gastrointestinal Tolerance 23212.2.4 Improving Taste 23212.2.5 Diminishing Gastrointestinal Absorption 23312.2.6 Increasing Water Solubility 23312.2.7 Tissue Targeting and Activation at the Site of Action 23412.3 Prodrug Design Considerations 23812.4 Prodrugs of Various Functional Groups 24112.4.1 Prodrugs of Compounds Containing─COOH or─OH 24112.4.2 Prodrugs of Compounds Containing Amides, Imides, and Other Acidic NH 24612.4.3 Prodrugs of Amines 24912.4.4 Prodrugs for Compounds Containing Carbonyl Groups 25512.5 Drug Release and Activation Mechanisms 25812.5.1 Cascade Release Facilitated by Linear Autodegradation Reactions 26012.5.2 Cascade Release Facilitated by Intramolecular Cyclization Reactions 26212.5.3 Cascade Activation through Intramolecular Cyclization to form Cyclic Drugs 26412.6 Prodrugs and Intellectual Property Rights—Two Court Cases 266References 26813 Liposomes as Drug Delivery Vehicles 272Guijun Wang13.1 Introduction 27213.2 Currently Approved Liposomal Drugs in Clinical Applications 27313.3 Conventional and Stealth Liposomes 27613.4 Stimuli‐Responsive Liposomes or Triggered‐Release Liposomes 27713.4.1 General Mechanism of Triggered Release 27713.4.2 Thermo‐Sensitive Liposomes 27813.4.3 pH‐Sensitive Liposomes 27913.4.4 Photo‐Triggered Liposomes 28213.4.5 Triggered Release Controlled by Enzymes 28713.5 Targeted Liposomal Delivery 28913.6 Hybrid Liposome Drug Delivery System 29113.7 Conclusions and Future Perspectives 293References 29314 Nanoparticles as Drug Delivery Vehicles 299Dan Menasco and Qian Wang14.1 Introduction 29914.1.1 General DDV Properties 30014.1.2 The DDV Core: Therapeutic Loading, Release, and Sensing 30114.1.3 DDV Targeting: Ligand Display 30514.1.4 DDV Size and Surface: Clearance and the EPR Effect 30814.2 Organic DDVs 30814.2.1 Polymer-Based Nanocarriers 30814.2.2 Polymeric Micelles 31014.2.3 Dendrimers 31414.3 Inorganic DDVs: Metal‐ and Silica‐Based Systems 32014.3.1 Inorganic DDVs: Mesoporous Silica Nanoparticles 32214.3.2 Inorganic DDVs: Gold Nanoparticles 32414.4 Conclusion 330References 33015 Evolution of Controlled Drug Delivery Systems 336Krishnaveni Janapareddi, Bhaskara R. Jasti, and Xiaoling li15.1 Introduction 33615.2 Biopharmaceutics and Pharmacokinetics 33715.3 Material Science 34115.4 Proteins, Peptides and Nucleic Acids 34315.5 Discovery of New Molecular Targets—Targeted Drug Delivery 34515.6 Microelectronics and Microfabrication Technologies 34715.7 Conclusion 349References 34916 Pathways for Drug Delivery to the Central Nervous System 353Ngoc H. On, Vinith Yathindranath, Zhizhi Sun, and Donald W. Miller16.1 Introduction 35316.1.1 Cellular Barriers to Drug Delivery in the CNS 35416.1.2 General Approaches for Increasing Brain Penetration of Drugs 35616.2 Circumventing the CNS Barriers 35616.2.1 Intracerebroventricular Injection 35716.2.2 Intracerebral Administration 35716.2.3 Intranasal Delivery Route 35816.3 Transient BBB Disruption 35916.3.1 Osmotic BBB Disruption 35916.3.2 Pharmacological Disruption of the BBB 36016.4 Transcellular Delivery Routes 36416.4.1 Solute Carrier Transport Systems in the BBB 36416.4.2 Adenosine Triphosphate‐Binding Cassette Transport Systems in the BBB 36916.4.3 Vesicular Transport in the BBB 37016.5 Conclusions 375References 37517 Metabolic Activation and Drug Targeting 383Xiangming Guan17.1 Introduction 38317.2 Anticancer Prodrugs and their Biochemical Basis 38417.2.1 Tumor‐Activated Anticancer Prodrugs Based on Hypoxia 38517.2.2 Tumor‐Activated Prodrugs Based on Elevated Peptidases or Proteases 40117.2.3 Tumor‐Activated Prodrugs Based on Enzymes with Elevated Activity at Tumor Sites 41317.3 Antibody‐ and Gene‐Directed Enzyme Prodrug Therapy 42017.3.1 Adept 42117.3.2 Gdept 42517.4 Summary 429References 42918 Targeted Delivery of Drugs to the Colon 435Anil K. Philip and Sarah K. Zingales18.1 Introduction 43518.2 Microbially Triggered Release 43718.2.1 Azo‐Linked Compounds 43718.2.2 Amino Acid Conjugates 44018.2.3 Sugar‐Derived Prodrugs 44018.3 pH‐Sensitive Polymers for Time‐Dependent Release 44218.4 Osmotic Release 44318.5 Pressure‐Controlled Delivery 44318.6 Nanoparticle Approaches 44418.7 Conclusion 446Acknowledgment 446References 44719 Receptor‐Mediated Drug Delivery 451Chris V. Galliford and Philip S. Low19.1 Introduction 45119.2 Selection of a Receptor for Drug Delivery 45419.2.1 Specificity 45419.2.2 Receptor Internalization/Recycling 45519.3 Design of a Ligand–Drug Conjugate 45519.3.1 Linker Chemistry 45519.3.2 Selection of Ligands 45719.3.3 Selection of Therapeutic Drug 45719.4 Folate‐Mediated Drug Delivery 45819.4.1 Expression of FRs in Malignant Tissues 45919.4.2 Expression of FRs in Normal Tissues 46019.4.3 Applications of Folate‐Mediated Drug Delivery 46119.5 Conclusions 467Acknowledgments 467References 46720 Protein and Peptide Conjugates for Targeting Therapeutics and Diagnostics to Specific Cells 475Barlas Büyüktimkin, John Stewart, Jr., Kayann Tabanor, Paul Kiptoo, and Teruna J. Siahaan20.1 Introduction 47520.2 Radiolabeled Antibodies for Cancer Treatment 47920.3 Antibody–Drug Conjugate 48020.3.1 Sites of Conjugation on mAbs, Linkers, and Drugs 48120.4 Non‐Antibody‐Based Protein–Drug Conjugates 48620.5 Peptibody 48820.6 Protein Conjugates for Diagnostics 48920.7 Peptide–Drug Conjugates 49120.8 Challenges in Analyzing Conjugates 49420.9 Conclusions 497References 49721 Drug Delivery to the Lymphatic System 503Qiuhong Yang and Laird Forrest21.1 Introduction 50321.2 Anatomy and Physiology of the Lymphatic System 50421.2.1 Lymph 50421.2.2 Lymphatic Vessels 50421.2.3 Lymph Nodes 50621.2.4 Lymph Organs 50821.3 Influence of Physicochemical Characteristics of Drug Carriers on Lymphatic Uptake and Transport 50921.3.1 Size 50921.3.2 Surface Charge 51121.3.3 Hydrophobicity 51321.4 Carriers for Lymphatic Drug Delivery 51321.4.1 Liposomes 51521.4.2 Lipid‐Based Emulsions and Nanoparticles 51921.4.3 Polymer‐Based Carriers 52421.5 Administration Routes for Lymphatic Delivery 52821.5.1 Intestinal 52821.5.2 Pulmonary 52921.5.3 Subcutaneous 53121.5.4 Intraperitoneal 53521.6 Lymphatic‐Targeting Vaccination 53621.7 Conclusions 538References 53922 The Development of Cancer Theranostics: A New Emerging Tool Toward Personalized Medicine 549Hongying Su, Yun Zeng, Gang Liu, and Xiaoyuan Chen22.1 Introduction 54922.2 Imaging‐Guided Drug Delivery and Therapy 55122.3 Optical Imaging-Based Theranostics 55322.3.1 NIR Fluorescence Imaging 55322.3.2 Bioluminescence Imaging 55622.3.3 Gold Nanoparticle as a Theranostics Platform 55722.4 MRI‐Based Theranostics 55822.5 Nuclear Imaging-Based Theranostics 55922.6 Ultrasound‐Based Theranostic Platform 56322.7 Multimodality Imaging-Based Theranostic Platform 56422.7.1 PET/CT 56522.7.2 MRI/Optical 56622.7.3 MRI/PET 56622.8 Conclusion and Future Perspectives 567Acknowledgments 569References 56923 Intracellular Delivery of Proteins and Peptides 576Can Sarisozen and Vladimir P. Torchilin23.1 Introduction 57623.2 Intracellular Delivery Strategies of Peptides and Proteins 57923.3 Concepts in Intracellular Peptide and Protein Delivery 58023.3.1 Longevity in the Blood 58023.3.2 Cellular Uptake Pathways 58223.3.3 Endosomal Escape 58523.4 Peptide and Protein Delivery to Lysosomes 58923.5 Receptor‐Mediated Intracellular Delivery of Peptides and Proteins 59023.5.1 Transferrin Receptor–Mediated Delivery 59023.5.2 Folate Receptor–Mediated Delivery 59323.6 Transmembrane Delivery of Peptides and Proteins 59523.6.1 Well Studied Classes of CPPs for Peptide and Protein Delivery 59523.6.2 Cellular Uptake Mechanisms of CPPs 59623.6.3 CPP‐Mediated Delivery of Peptides and Proteins 59923.6.4 CPP‐Modified Carriers for Intracellular Delivery of Peptides and Proteins 60123.7 Conclusion 602References 60224 Vaccine Delivery: Current Routes of Administration and Novel Approaches 623Neha Sahni, Yuan Cheng, C. Russell Middaugh, and David B. Volkin24.1 Introduction 62324.2 Parenteral Administration of Vaccines 62524.2.1 Currently Available Vaccines and Devices for Intramuscular and Subcutaneous Delivery 62524.2.2 Currently Available Intradermal Vaccines and Associated Delivery Devices 62924.2.3 Novel Devices for Parenteral Injection 63024.2.4 Novel Formulations and Delivery Approaches for Parenteral Injection 63224.3 Oral Delivery of Vaccines 63424.3.1 Currently Available Orally Administered Vaccines 63424.3.2 Novel Formulations and Delivery Approaches for Oral Administration 63524.4 Nasal and Aerosol Delivery of Vaccines 63924.4.1 Currently Available Nasally Administered Vaccines 63924.4.2 Novel Devices and Formulations for Nasal Administration 63924.4.3 Devices and Delivery Systems for Aerosol Administration of Vaccines 64224.5 Conclusions 643References 64425 Delivery of Genes and Oligonucleotides 655Charles M. Roth25.1 Introduction 65525.2 Systemic Delivery Barriers 65625.2.1 Viruses: Learning from Nature 65725.2.2 Materials for Nucleic Acid Delivery 65825.2.3 Characterization of Nanoparticles 65925.2.4 Targeted Delivery of Nucleic Acids 66225.3 Cellular Delivery Barriers 66325.3.1 Endosomal Escape 66325.3.2 Vector Unpackaging 66525.4 Current and Future Approaches to Nucleic Acid Delivery 66625.4.1 Vectors in the Clinic 66625.4.2 Combinatorial Chemistry Approaches 66725.4.3 Polymer–Lipid Nanocomposites 66725.5 Summary and Future Directions 668References 668Index 674