Drug Delivery: Principles and Applications

Drug Delivery: Principles and Applications

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ISBN-13: 9781118833308
Publisher: Wiley
Publication date: 03/09/2016
Series: Wiley Series in Drug Discovery and Development
Sold by: Barnes & Noble
Format: NOOK Book
Pages: 720
File size: 50 MB
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About the Author

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.

Read an Excerpt

Drug Delivery

Principles and Applications

John Wiley & Sons

Copyright © 2005 John Wiley & Sons, Inc.
All right reserved.

ISBN: 0-471-47489-4

Chapter One


Chao Han GlaxoSmithKline, Collegeville, PA 19426

Binghe Wang Department of Chemistry, Georgia State University, Atlanta, GA 30303

1.1. Issues facing the pharmaceutical industry 1.2. Factors that impact developability 1.2.1. Commercial goal 1.2.2. The chemistry efforts 1.2.3. Target validation in animal models 1.2.4. Pharmacokinetics and drug metabolism 1.2.5. Preparation for pharmaceutical products 1.2.6. Remarks on developability criteria

1.3. Drug delivery factors that impact developability



Drug discovery is a long, arduous, and expensive process. It was estimated that the total expenditure for research and development in the U.S. pharmaceutical industries was over $20 billion a year in the late 1990s,' and this figure has been increasing. The average cost for every new drug (a new chemical entity, NCE) from research laboratory to patients is a staggering number: $400 to $650 million, and the whole process may take up to 14 years! Because of the high cost, there is tremendous pressure to maximize efficiency and minimize the time it takes to discover and bring a drug to the market. In order to do this, it is necessary to analyze the entire drug discovery and development process and identify steps where changes can be made to increase efficiency and save time. Analyzing the entire drug discovery and development process will help reveal where maximal improvements can be expected with some effort.

The entire endeavor of bringing a new drug from idea to market is generally divided into several stages: target/disease identification, hit identification/discovery, hit optimization, lead selection and further optimization, candidate identification, and clinical trials. Each stage has many aspects and components. A target is identified early in the discovery period, when there is sufficient evidence to validate the relationship between this target and a disease of interest. Tens of thousands of new compounds are then synthesized and screened against the target to identify a few compounds (hits) with the desired biological activity. Analogs of these selected compounds are then screened further for better activity and optimized in order to identify a small number of compounds for testing in pharmacological models. These efficacious compounds (leads) are further optimized for their biopharmaceutical properties, and the most drug-like compounds (drug candidate, only one or two) are then selected for further development. The drug discovery and development path, with emphasis on the discovery stages, is schematically illustrated in Figure 1.1.

Of those drug candidates with most drug-like properties, only about 40% make their way to evaluation in humans (Phase I clinical trial). Unfortunately, the historical average reveals an almost 90% overall attrition rate in clinical trials; in another words, only 1 compound makes it to market from among 10 compounds tested in humans. Results from another statistical analysis gave a similar success rates for NCEs for which an IND (investigational new drug) was filed during 1990-1992. This high attrition rate obviously does not produce the long-term success desired by both the pharmaceutical and health care industries.

In order to reduce the failure rate, it is necessary to analyze how and where failures occur. More than 10 years ago, Prentis et al. analyzed the cause of the high attrition rate based on data from seven UK-based pharmaceutical companies from 1964 to 1985. The results revealed that 39% of the failure was due to poor pharmacokinetic properties in humans; 29% was due to a lack of clinical efficacy; 21% was due to toxicity and adverse effects; and about 6% was caused by commercial limitations. Although not enough detailed information was available, it is believed that some of these causes are interrelated. For instance, toxicity or lack of efficacy can be caused by poor or undesired pharmacokinetic properties. With the understanding that most failure was not due to a lack of "biological activities" per se as defined by in vitro testing, there is a drive to incorporate the evaluation of the other major factors that may potentially precipitate developmental failures in the early drug discovery and candidate selection processes. This is intended to reduce the rate of late-stage failures, which is most costly. This point is further substantiated by the studies indicating that the major cost in drug discovery and development occurs at late stages. For example, in a $400 million total R&D cost, preclinical research costs probably account for only tens of million dollars, whereas clinical studies cost hundreds of millions of dollars (Figure 1.2)

Another factor that is fueling the movement for early integration of multiple disciplines in the drug discovery and development processes is the rapid development of chemical and biological sciences. The past decade has seen tremendous advances in both areas. Advances in combinatorial chemistry, molecular and cellular biology, high-throughput screening, and genomic research have provided both great opportunities and challenges to the pharmaceutical industry. With the rapid development in biological sciences, current interests in therapeutic targets are more focused on rational targets such as receptors, enzymes, and hormones with well-characterized structures and functions. New technologies such as combinatorial chemistry, automation in high-throughput screening, and better instrumentation in bioanalysis have also significantly accelerated the lead identification and discovery process for a given target. With these new technologies, large pharmaceutical research organizations are capable of synthesizing and screening several thousand compounds or more in a year or two to find potential drug candidates. These efforts typically result in the discovery of many lead compounds or potential candidates for a target in the drug discovery process. Then there is the question of how to pick a winner and how to minimize failures. This requires a thorough evaluation of all the factors that are known to affect the developability of a NEC at the early stages. These factors may include efficacy, pharmacokinetics, pharmacodynamics, toxicology, and drug-drug interactions based on the metabolism and substrate properties of certain transporters and enzymes, as well as physicochemical properties, many of which are related to drug delivery issues. For this reason, a drug discovery and development program is more like a symphony (not just a cross-functional action) of multiple sciences including chemistry, biology, toxicology, clinical science, and pharmaceutical engineering.

Under the pressure to reduce the cost and shorten the time needed to bring an NCE to the market, many major pharmaceutical organizations have undergone rapid and drastic changes in the past decade, both in terms of organizational structures and fundamental approaches, in order to develop an integrated approach to drug discovery and development. A conference entitled "Opportunities for Integration of Pharmacokinetics, Pharmacodynamics, and Toxicokinetics in Rational Drug Development" was the landmark event in this fundamental change in the pharmaceutical industry. A brand new concept, "ensuring developability," was introduced and well accepted, which employs criteria for drug development throughout the entire drug discovery and development processes. Under the guidance of such criteria, a drug discovery and development team will not only maximize the chance of success by selecting the best developable drug candidate, but will also play off the failures faster and more cheaply.

The paradigm shifts mostly involve the integration of research activities in functional areas such as pharmacokinetics and drug metabolism, pharmaceutical development, safety assessment, and process chemistry into drug discovery and development process in the very early stages of discovery. The inputs from these functional areas, as well as those from clinical, regulatory, commercial, and marketing groups in the early stages, help to minimize costly mistakes in late stages of development and have become more and more important to the success of the drug discovery and development process. Developability is an overall evaluation of the drug-like properties of a NCE. Many of the recent changes in the pharmaceutical industry have been driven by the concept of ensuring developability. These changes, that is, the integration of multifunctional areas in drug discovery and development, ensure that the NCEs of interest will be successful in every step toward the final goal.

Below is a brief introduction to the factors that impact developability and a discussion on why the examination of drug delivery issues is very important in helping to ensure the developability of a drug candidate.


In most pharmaceutical companies, many efforts have been made to create a clear framework for selecting compound(s) with minimal ambiguity for further progression. Such a framework is not a simple list of the factors that impact the quality of a drug-like molecule. This framework, which is more often referred as "developability criteria," is a comprehensive summary of the characteristics, properties, and qualities of the NCE(s) of interest, which normally consist of preferred profiles with a minimally acceptable range. The preferred profile describes the optimal goal for selection and further progression of a candidate, whereas the minimum range gives the acceptable properties for a compound that is not ideal but may succeed. Molecules that do not meet the criteria will not be considered further. Such criteria cover all the functional areas in drug development. Some of the major developability considerations are briefly described in the following subsections.

1.2.1. Commercial Goal

It does not need to be emphasized that we are in a business world. Generally speaking, a product needs to be profitable to be viable. Therefore, early inputs from commercial, marketing, and medical outcome professionals are very important for setting up a projective product profile, which profoundly affects the creation of the developability criteria for the intended therapeutics. In general, this portfolio documents the best possible properties of the product and the minimum acceptable ones that may succeed based on the studies of market desires. These studies should be based on the results of professional analyses of the medical care needs, potential market, and existing leading products for the same, similar, or related indications. The following aspects need to be well thought out and fully justified before the commencement of a project: (1) therapeutic strategy; (2) dose form and regimen; and (3) the best possible safety profile, such as the therapeutic window, potential drug interactions, and any other potentially adverse effects. Using the development of an anticancer agent as an example for therapeutic strategy selection, one may consider the choice of developing a chemotherapeutic (directly attacking the cancer cells) versus an antiangiogenic agent (depriving cancer cells of their nutrients), or combined or stand-alone therapy. In deciding the optimal dose form and regimen, one may consider whether an oral or intravenous (iv) formulation, or both, should be developed, and whether the drug should be given once daily or in multiple doses. The results of such an analysis form the framework for developing the developability criteria and become the guideline in setting up the criterion for each desired property. For example, pharmacokinetic properties such as the half-life and oral bioavailability of a drug candidate will have a direct impact on developing a drug that is to be administered orally once a day.

1.2.2. The Chemistry Efforts

Medicinal chemistry is always the starting point and driver of drug discovery programs. In a large pharmaceutical R&D organization, early discovery of bioactive compounds (hits) can be carried out either by random, high-throughput screening of compound libraries, by rational design, or both. Medicinal chemists will then use the structural information of the pharmacophore thus identified to optimize the structures. Chemical tractability needs to be examined carefully at the very beginning when a new chemical series is identified. Functional modifications around the core structure are carefully analysed. After the examination of a small number of compounds, the initial exploratory structure-activity relationship (SAR) or quantitative SAR (QSAR) should be developed. Blackie et al. described how the establishment of exploratory SAR helped the discovery of a potent oral bioavailable phospholipase [A.sub.2] inhibitor. In this example, numerous substructural changes were made, leading to the most active compounds; this is normally done in parallel with several different chemical series. For medicinal chemists, it is important that many different SARs are considered, developed, and integrated into their efforts at the same time, providing more opportunities to avoid undesirable properties unrelated to their intended biological activities. Such factors, again, may include potential P450 inhibition, permeability, selectivity, stability, solubility, etc.

Structural novelty of the compounds (i.e., can this product be patented?), complexity of synthetic routes, scalability (can the syntheses be scaled up in an industrial way?) and the cost of starting materials (cost of goods at the end of the game), and potential environmental and toxicity issues will all need to be closely examined at early stages of the drug discovery and development processes. It is never too early to put these thoughts into action.

1.2.3. Target Validation in Animal Models

Although drug discovery efforts almost always start with in vitro testing, it is well recognized that promising results of such testing do not always translate into efficacy. There are numerous reasons for this to happen, some of which are well understood and others that are not. Therefore, target validation in animal models before clinical trials in humans is a critical step. Before a drug candidate is fully assessed for its safety and brought to a clinical test, demonstration of the efficacy of a biologically active compound (e.g., active in an enzyme binding assay) in pharmacological models (in vivo, if available) is considered a milestone in the process of discovering a drug candidate. Many cases exemplify the challenges and importance of pharmacological models. For example, inhibitors of the integrin receptor [[alpha].sub.v][ss.sub.3] have been shown to inhibit endothelial cell growth, which implies their potential as clinically useful antiangiogenic agents for cancer treatment. However, the proposed mechanism did not work in animal models, although compounds were found to be very active in vitro. What has been recognized is that the integrin receptor [[alpha].sub.v][ss.sub.3] may not be the exclusive pathway on which cell growth depends. Its inhibition may induce a compensatory pathway for angiogenesis.

Ideally, an in vivo model should comprise all biochemical, cellular, and physiological complexities, as in a real-life system, which may predict the behavior of a potential drug candidate in human much more accurately than an in vitro system. In order to have a biological hypothesis tested in the system with validity, a compound has to be evaluated in many other regards. Knowing the pharmacokinetic parameters such as absorption, distribution, and metabolism in the animal species that is used in the pharmacological model is critical. Showing successful drug delivery in an animal model serves as an important milestone.

The pharmacokinetics/pharmacodynamics relationship, systemic and tissue levels of drug exposure, frequency of dosing following which the drug may demonstrate efficacy, and the strength of efficacy are very important factors that may affect further development of an NEC. They are all directly or indirectly related to drug delivery.


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Table of Contents

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 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

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