Efnisyfirlit

• Front Matter
  • CONTENTS
  • PREFACE
  • ABOUT THE AUTHORS
  • CONTRIBUTORS
• PART I INTRODUCTION AND BASICS OF ADVANCED DRUG DELIVERY
  • 1 PHYSIOLOGICAL BARRIERS IN ADVANCED DRUG DELIVERY: GASTROINTESTINAL BARRIER
    • 1.1 CHAPTER OBJECTIVES
    • 1.2 INTRODUCTION
      • FIGURE 1.1 The intestinal metabolizing enzymes and uptake/efflux transporters [3].
      • 1.2.1 Anatomy of Gastrointestinal Tract
        • 1.2.1.1 Gastrointestinal Anatomy
          • FIGURE 1.2 Gastrointestinal anatomy [8].
        • 1.2.1.2 Pores
        • 1.2.1.3 Tight Junctions
          • FIGURE 1.3 Mechanism of drug transport through epithelial membranes. 1. Paracellular; 2. Transcellular: 2a. Carrier-mediated; 2b. Passive diffusion; 2c. Receptor-mediated endocytosis; 3. Mediated efflux pathway.
      • 1.2.2 Gastrointestinal Physiology
        • 1.2.2.1 Gastrointestinal Components
        • 1.2.2.2 Gastrointestinal Blood Flow
        • 1.2.2.3 Luminal pH
          • TABLE 1.1 Gastrointestinal Physiology in Humans
        • 1.2.2.4 Gastric Emptying and Gastrointestinal Motility
          • TABLE 1.2 Factors Affecting Gastric Emptying
      • 1.2.3 Gastrointestinal Barrier
        • 1.2.3.1 Barrier to Bioavailability
        • 1.2.3.2 Barrier to Immunity
        • 1.2.3.3 Barrier to Microorganisms
      • 1.2.4 Absorption Models
        • FIGURE 1.4 Absorption models and tools for in silico, in vitro, and in vivo experiments/methods to get various parameters influencing human dosage regimen.
    • 1.3 PHYSIOLOGICAL FACTORS INFLUENCING DRUG ABSORPTION
      • 1.3.1 Epithelial Membranes
        • FIGURE 1.5 Illustration of a eukaryotic cell membrane. The cell membrane is a biological membrane that separates the interior of all cells from the outside environment [46].
      • 1.3.2 Absorption Processes
        • TABLE 1.3 Characteristics of Absorption Processes
        • 1.3.2.1 Passive Diffusion
        • 1.3.2.2 Ion Channels
          • FIGURE 1.6 Concentration dependence of membrane transport: linear (A) and saturable (B) transport processes. Simple diffusion and ion channels obey the linear dependency on the substrate concentration. Facilitated transporter and active transporters follow a saturable pattern [48]. (See color figure in color plate section.)
        • 1.3.2.3 Facilitated Diffusion
        • 1.3.2.4 Active Transporters
        • 1.3.2.5 Secondary Active Transporters
        • 1.3.2.6 Macromolecular and Bulk Transport
      • 1.3.3 Food
      • 1.3.4 Age
      • 1.3.5 Disease Status
    • 1.4 PHYSICOCHEMICAL FACTORS INFLUENCING DRUG ABSORPTION
      • 1.4.1 pH-Partition Theory
      • 1.4.2 Drug pKa and Gastrointestinal pH
      • 1.4.3 Lipid Solubility
      • 1.4.4 Unstirred Water Layer
      • 1.4.5 Dissolution
      • 1.4.6 Hydrolysis in the Gastrointestinal Tract
      • 1.4.7 Complexation and Adsorption
      • 1.4.8 Deviation from pH-Partition Hypothesis
    • 1.5 STRATEGIES TO OVERCOME GASTROINTESTINAL BARRIERS IN DRUG DELIVERY
      • 1.5.1 Alternative Formulations
        • FIGURE 1.7 Schematic representation of transporter-targeted prodrug strategy.
      • 1.5.2 Alternative Routes of Administration
    • 1.6 SUMMARY
    • ASSESSMENT QUESTIONS
    • REFERENCES
  • 2 SOLUBILITY AND STABILITY ASPECTS IN ADVANCED DRUG DELIVERY
    • 2.1 CHAPTER OBJECTIVES
    • 2.2 SOLUBILITY
      • 2.2.1 Introduction
        • TABLE 2.1 Potential Characteristics for Lead Substance Selection
        • FIGURE 2.1 Systemic approach for drug discovery and development. Reproduced with permission from Ref. 6.
      • 2.2.2 General Concept
        • TABLE 2.2 Solubility Definition in the USP
      • 2.2.3 Biopharmaceutics Classification System (BCS)
        • TABLE 2.3 BCS Classification of Drugs
    • 2.3 BIOAVAILABILITY IMPROVEMENT
      • 2.3.1 Enhancement of Solubility
        • 2.3.1.1 Prodrugs
          • Solubility Enhancement
            • FIGURE 2.2 A schematic representation of the prodrug concept. Reproduced with permission from Ref. 26.
          • Stability Enhancement
            • FIGURE 2.3 A schematic list of objectives in prodrug research, together with the overlaps. Reproduced with permission from Ref. 27.
        • 2.3.1.2 Salts
          • TABLE 2.4 Potential Counterions Used in Preparation of Pharmaceutical Salts [39]
          • FIGURE 2.4 Schematic representation of the pH-solubility profile of a basic drug. Reproduced with permission from Ref. 41.
          • FIGURE 2.5 Schematic representation of the pH-solubility profile of an acidic drug. Reproduced with permission from Ref. 41.
        • 2.3.1.3 Crystal Engineering
        • 2.3.1.4 Particle Size Reduction
        • 2.3.1.5 Co-solvency
        • 2.3.1.6 Use of Surfactants
        • 2.3.1.7 Complexation
          • FIGURE 2.6 Structure of 1,3,5-triazene dendrimer encapsulating two molecules of methotrexate Reproduced with permission from Ref. 106.
        • 2.3.1.8 Lipid-Based Formulations
        • 2.3.1.9 Drug Dispersions in Formulation Carriers
          • TABLE 2.5 The Most Commonly Used Carriers and Additives in Solid Dispersion
      • 2.3.2 Polarity Modification of Drugs
    • 2.4 STABILITY
      • 2.4.1 Stability of Pharmaceuticals
        • 2.4.1.1 Stability Assessment Methods
        • 2.4.1.2 Modes of Chemical Degradation
          • Hydrolysis
          • Oxidation
          • Photodegradation
        • 2.4.1.3 Factors Affecting Stability
          • Temperature
          • pH
            • FIGURE 2.7 The pH-rate profile for decarboxylation of 4-aminosalicylic acid at 25°C [191].
      • 2.4.2 Preformulation Considerations in Stability
        • 2.4.2.1 Analytical Tools
        • 2.4.2.2 Salt Formation
        • 2.4.2.3 Crystal Engineering
          • Polymorphism
          • Co-crystals
      • 2.4.3 Formulation Considerations in Stability
        • 2.4.3.1 Excipients
        • 2.4.3.2 Stabilization Techniques
    • 2.5 SUMMARY
    • ASSESSMENT QUESTIONS
    • REFERENCES
  • 3 THE ROLE OF TRANSPORTERS AND THE EFFLUX SYSTEM IN DRUG DELIVERY
    • 3.1 CHAPTER OBJECTIVES
    • 3.2 INTRODUCTION
    • 3.3 ABC TRANSPORTERS
      • 3.3.1 ABC Proteins
      • 3.3.2 Efflux Transporters
        • TABLE 3.1 Tissue Distribution of the P-gp, MRP, and BCRP [3, 28, 29]
        • FIGURE 3.1 Localization of selected transporters in four tissues involved in ADME of drugs. Adapted from Ref. 2.
      • 3.3.3 P-Glycoprotein
        • TABLE 3.2 P-gp Substrates and Inhibitors [38]
      • 3.3.4 Multidrug Resistance Associated Proteins (MRPs)
        • FIGURE 3.2 Human MRP gene family.
        • TABLE 3.3 Substrates and Inhibitors for MRP2 [38]
      • 3.3.5 Breast Cancer Resistant Protein (BCRP)
        • FIGURE 3.3 Predicted secondary structures of drug efflux transporters of the ATP-binding cassette family: Four classes are distinguished here, based on predicted structure and amino acid sequence homology. (1) P-glycoprotein consists of two transmembrane domains, each containing six transmembrane segments and two nucleotide-binding domains (NBDs). It is N-glycosylated (branches) at the first extracellular loop. (2) MRP1, 2, and 3 have an additional amino terminal extension containing five transmembrane segments, and they are N-glycosylated near the N-terminus and at the sixth extracellular loop. (3) MRP4 and 5 lack the amino terminal extension of MRP1–3 and are N-glycosylated at the fourth extracellular loop. (4) BCRP is a “half transporter” consisting of one NBD and six transmembrane segments, and it is most likely N-glycosylated at the third extracellular loop. Note that, in contrast to the other transporters, the NBD of BCRP is at the amino terminal end of the polypeptide. The BCRP almost certainly functions as a homodimer. N and C denote amino- and carboxy-terminal ends of the proteins, respectively. Cytoplasmic (IN) and extracellular (OUT) orientation indicated for BCRP applies to all transporters drawn here. Reproduced with permission from Ref. 41.
        • TABLE 3.4 Substrates and Inhibitors for BCRP [38]
      • 3.3.6 Genetic Factors in Drug Response
      • 3.3.7 Substrate Recognition by P-glycoprotein
      • 3.3.8 Substrate and Inhibitor Selectivity
    • 3.4 STRATEGIES TO OVERCOME ACTIVE EFFLUX
      • 3.4.1 Pharmacological Inhibition of Efflux Proteins
        • FIGURE 3.4 Combination therapy approach.
      • 3.4.2 First-Generation MDR Modulators
      • 3.4.3 Second-Generation MDR Modulators
      • 3.4.4 Third-Generation MDR Modulators
      • 3.4.5 Herbal Modulation of MDR Efflux Proteins
      • 3.4.6 Pharmaceutical Excipients as Inhibitors of MDR Efflux Proteins
      • 3.4.7 Prodrug Strategy
        • FIGURE 3.5 Transporter-targeted prodrug strategy: Improved permeability could be achieved by overcoming MDR efflux transporters during chemical modification of the parent drug molecule.
      • 3.4.8 Nanotechnology
        • FIGURE 3.6 Evasion of MDR efflux proteins by surface-decorated nanoparticles: Substrate drug molecules encapsulated in the nanoparticles can evade MDR proteins during endocytosis. Adapted from Ref. 96.
      • 3.4.9 Antibodies Specific to the MDR1 Protein
    • 3.5 INFLUX TRANSPORTERS
      • 3.5.1 Peptide Transporters
        • TABLE 3.5 Distribution of Peptide Transporters in Tissues, Cells, and Subcellular Compartments
        • TABLE 3.6 Example of Various Drugs/Prodrugs Acting as Substrates/Competitive Inhibitors of Peptide Transporters
        • FIGURE 3.7 Model of peptide transport in epithelial cells from intestine and kidney. Reproduced with permission from Ref. 104.
      • 3.5.2 Organic Anion Transporting Polypeptide (OATP)
        • TABLE 3.7 Characteristics and Selective Substrates of Human OATP Family Members
        • TABLE 3.8 Expression of OATP in Various Cancer Tissues
      • 3.5.3 Organic Anion Transporter (OAT)
        • TABLE 3.9 Tissue expression and Prototypical Substrates of OAT Family Members
      • 3.5.4 Organic Cation Transporter (OCT)
        • TABLE 3.10 Tissue Expression and Substrates of OCT Family Members
      • 3.5.5 Sodium-Dependent Multivitamin Transporter (SMVT)
        • TABLE 3.11 An Overview of Tissue Distribution and Kinetic Parameters of the SMVT on Cellular Accumulation
      • 3.5.6 Sodium-Dependent Vitamin C Transporters (SVCT1 and SVCT2)
    • 3.6 IN VITRO MODELS TO STUDY TRANSPORTERS
      • FIGURE 3.8 In vitro models for oral absorption studies of the MDCK-MDR1-CYP3A4 cell line (MMC) and the hepatic cell line transfected with CYP3A4 (HepG2-CYP3A4).
    • 3.7 CONCLUSION
    • ASSESSMENT QUESTIONS
    • REFERENCES
  • 4 BIOMATERIAL IN ADVANCED DRUG DELIVERY
    • 4.1 CHAPTER OBJECTIVES
    • 4.2 CLASSIFICATION AND BIOCOMPATIBILITY OF BIOMATERIAL
      • 4.2.1 Definition and Classification of Biomaterials
        • TABLE 4.1 Classification of Biomaterials [1, 2, 5, 6]
        • 4.2.1.1 Mechanism of Tissue Interaction to the Material Surface
        • 4.2.1.2 Material Selection
          • TABLE 4.2 Classification of Polymers [19]
      • 4.2.2 Biocompatibility of Biomaterial
        • 4.2.2.1 Biocompatibility Requirements
        • 4.2.2.2 Types of Interactions Between Biomaterial and Host Tissues
      • 4.2.3 Blood Compatibility
        • 4.2.3.1 Mechanism
        • 4.2.3.2 Factor Affecting Blood Compatibility
        • 4.2.3.3 Approaches to Reduce Blood Coagulation Through Surface Modification
    • 4.3 BIORESORBABLE AND BIOERODIBLE MATERIALS
      • 4.3.1 Application of Bioresorbable and Bioerodible Polymers
        • TABLE 4.3 Application of Bioresorbable and Biodegradable Polymers
      • 4.3.2 Implant Response to Tissue Ingrowth, Capsule Formation, and Tissue Adhesion
      • 4.3.3 Biocompatibility Issues
    • 4.4 COMPOSITE MATERIALS
      • 4.4.1 Composite Materials for Biomedical Application
      • 4.4.2 Composite Materials for Drug Delivery
    • 4.5 OTHER MATERIALS
      • 4.5.1 Hydroxyapatite (HA)
      • 4.5.2 Titanium (Ti)
      • 4.5.3 Nitinol
      • 4.5.4 Platinum (Pt)
      • 4.5.5 Magnesium (Mg)-Containing Alloys
      • 4.5.6 Silver (Ag)
      • 4.5.7 Stainless Steel
      • 4.5.8 Cobalt Chrome (CoCr)
      • 4.5.9 Bioceramics
    • 4.6 FUTURE DIRECTIONS
    • ASSESSMENT QUESTIONS
    • REFERENCES
• PART II STRATEGIES FOR ADVANCED DRUG DELIVERY
  • 5 STRATEGIES OF DRUG TARGETING
    • 5.1 CHAPTER OBJECTIVES
    • 5.2 INTRODUCTION
      • FIGURE 5.1 Schematic illustration depicting numerous drug targeting strategies: (a) encapsulation of therapeutic drugs in polymers and (b) conjugation of therapeutic drugs with targeting ligands via a liker.
    • 5.3 DRUG TARGETING MECHANISMS
      • TABLE 5.1 Different Types of Targeted Drug Delivery Systems
      • FIGURE 5.2 Schematic representation of different drug targeting methods. (a) physical targeting: requires external force such as magnetic field to accumulate the drug at the target site; (b) passive targeting: release the drug in the presence of unusual pH/temperature or large fenestration in capillaries; and (c) active targeting; requires ligands such as antibody/fragments, peptides, or small molecules on the surface of cargo to target the diseased tissues.
      • 5.3.1 Physical Targeting
      • 5.3.2 Passive Targeting
      • 5.3.3 Active Targeting
        • TABLE 5.2 Various Targets and Ligands in Active Targeting [33, 36]
        • FIGURE 5.3 Schematic illustration of different pathways of endocytosis mechanisms. Pinocytosis is ubiquitously present in all cells and can be further classified in clatherin-dependent and clatherin-independent endocytosis.
    • 5.4 DELIVERY SYSTEMS FOR DRUG TARGETING
      • 5.4.1 Nanoscale Carriers
        • FIGURE 5.4 Schematic representation of numerous nanocarriers used in targeted drug delivery.
        • 5.4.1.1 Liposomes
          • FIGURE 5.5 Schematic illustration depicting types of liposomes used in targeted drug delivery systems along with their nanoscale sizes.
        • 5.4.1.2 Polymeric Nanoparticles
        • 5.4.1.3 Solid Lipid Nanoparticles
        • 5.4.1.4 Dendrimers
      • 5.4.2 Targeted Prodrugs
      • 5.4.3 Cellular Carriers
    • 5.5 LIGANDS USED IN DRUG TARGETING
      • 5.5.1 Monoclonal Antibodies/Antibody Fragments
        • FIGURE 5.6 Schematic illustration of (a) whole IgG antibody, (b) antibody fragments, and (c) antibody body obtained from several sources.
      • 5.5.2 Aptamers
      • 5.5.3 Peptides
    • 5.6 INTRACELLULAR TARGETING STRATEGIES
      • 5.6.1 Targeting the Cytoplasm
      • 5.6.2 Targeting the Endo-lysosomes
      • 5.6.3 Targeting the Nucleus
      • 5.6.4 Targeting Mitochondria
    • 5.7 SUMMARY AND FUTURE PERSPECTIVES
    • ASSESSMENT QUESTIONS
    • REFERENCES
  • 6 PRODRUG AND BIOCONJUGATION
    • 6.1 CHAPTER OBJECTIVES
    • 6.2 INTRODUCTION AND RATIONALE
      • FIGURE 6.1 A simplified illustration of the prodrug concept. Reproduced with permission from Ref. 2.
      • FIGURE 6.2 BCS classification of drug molecules. Reproduced with permission from Ref. 2.
    • 6.3 FUNCTIONAL GROUPS FOR PRODRUG DESIGN
      • FIGURE 6.3 Common functional groups amenable to prodrug design.
      • 6.3.1 Ester Prodrugs
      • 6.3.2 Phosphate Prodrugs
      • 6.3.3 Carbamate and Carbonate Prodrugs
      • 6.3.4 Amide Prodrugs
      • 6.3.5 Oxime Prodrugs
        • TABLE 6.1 Examples of Prodrugs with Specific Functional Group Modification and Their Advantages
    • 6.4 MAJOR OBJECTIVES OF PRODRUG DESIGN
      • 6.4.1 Increased Bioavailability
        • 6.4.1.1 Increased Solubility
        • 6.4.1.2 Increased Permeability
        • 6.4.1.3 Increased Duration of Action
          • TABLE 6.2 Examples of Prodrugs Designed to Enhance the Bioavailability of Therapeutic Molecules
      • 6.4.2 Site-Specific Drug Delivery
        • 6.4.2.1 Targeting Specific Transporters/Receptors
          • Peptide Transporters
            • FIGURE 6.4 Apparent permeability of SQV, Val–Val–SQV, and Gly–Val–SQV in apical to basolateral direction (A—B) and basolateral to apical direction (B—A) across MDCK-MDR1 (a) and MDCK-MRP2 (b) cells. Reproduced with permission from Ref. 74 and 76.
          • Amino Acid Transporters
            • FIGURE 6.5 (a) Structures of amino acid ester prodrugs of acyclovir (ACV). (b) Plasma concentration vs time profile of total concentration of ACV upon oral administration of ACV, SACV, and VACV. Reproduced with permission from Ref. 80.
          • Vitamin Transporters
            • FIGURE 6.6 (a) Inhibition of uptake of [14C] ascorbic acid in MDCK-MDR1 cells by ascorbic acid (AA) and ascorbate prodrug of SQV (AA-Su-Saq). Reproduced with permission from Ref. 84. (b) Inhibition of uptake of [3H] biotin in MDCK-MDR1 cells by biotin and biotin prodrug of SQV (Bio-Saq). Reproduced with permission from Ref. 85.
        • 6.4.2.2 Targeting Specific Antigens
          • FIGURE 6.7 Structure of antibody-DM1 drug conjugate via SMCC linker.
    • 6.5 PRODRUGS FOR IMPROVED TOPICAL ADMINISTRATION (OPHTHALMIC AND DERMAL)
      • FIGURE 6.8 Cellular accumulation of targeted lipid prodrugs (B-R-ACV and B-12HS-ACV), targeted prodrug (B-ACV), and lipid prodrugs (R-ACV and 12HS-ACV) compared with parent moiety (ACV) on human corneal epithelial cells.
    • 6.6 PRODRUGS FOR IMPROVED DRUG DELIVERY TO THE BRAIN
    • 6.7 FORMULATION APPROACHES FOR SUSTAINED AND CONTROLLED DELIVERY OF PRODRUGS
    • 6.8 PRODRUGS IN CLINICAL TRIALS
      • TABLE 6.3 Some Examples of Prodrugs in Clinical Trials
    • 6.9 CONCLUSIONS AND FUTURE PERSPECTIVES
    • ASSESSMENT QUESTIONS
    • REFERENCES
  • 7 NANOSCALE DRUG DELIVERY SYSTEMS
    • 7.1 CHAPTER OBJECTIVES
    • 7.2 INTRODUCTION
    • 7.3 CELLULAR INTERNALIZATION OF NANOPARTICULATE SYSTEMS
    • 7.4 NANOPARTICLES
      • 7.4.1 Nanoparticle Types
        • 7.4.1.1 Polymeric Nanoparticles
          • FIGURE 7.1 Nanosphere (left) and nanocapsule (right).
        • 7.4.1.2 Solid Lipid Nanoparticles (SLNs)
        • 7.4.1.3 Inorganic Nanoparticles
      • 7.4.2 Preparation of Polymeric Nanoparticles
        • TABLE 7.1 Advantages and Limitations of Polymeric Nanoparticles Preparation Methods
        • 7.4.2.1 Nanoparticle Preparation from Preformed Polymer
          • Single Emulsion-Solvent Evaporation
          • Double Emulsion-Solvent Evaporation
          • Emulsification/Solvent Diffusion
          • Nanoprecipitation
          • Salting Out
        • 7.4.2.2 Nanoparticle Preparation from Polymerization of Monomer
          • Emulsion Polymerization
          • Interfacial Polycondensation
        • 7.4.2.3 Advantages of Polymeric Nanoparticles
        • 7.4.2.4 Limitations of Polymeric Nanoparticles
      • 7.4.3 Preparation of Solid Lipid Nanoparticles
        • 7.4.3.1 Homogenization
        • 7.4.3.2 Solvent Emulsification/Evaporation
    • 7.5 MICELLES
      • FIGURE 7.2 Structure of amphiphilic monomer (a) and block co-polymers (b).
      • TABLE 7.2 List of Polymers Used in Micelle Formulation Preparation and Their Applications
      • 7.5.1 Micelle Types
        • TABLE 7.3 List of Surfactant Used for Micelle Preparation
      • 7.5.2 Critical Micellar Concentration (CMC)
      • 7.5.3 Methods for Micelle Preparation
        • FIGURE 7.3 Pictorial representation of different methods for micelle preparations: (1) simple equilibrium, (2) dialysis, (3) o/w emulsion method, (4) solvent casting, and (5) freeze-drying method.
        • 7.5.3.1 Simple Equilibrium
        • 7.5.3.2 Dialysis
        • 7.5.3.3 Oil in Water (o/w) Emulsion
        • 7.5.3.4 Solution Casting
        • 7.5.3.5 Freeze Drying
      • 7.5.4 Advantages
      • 7.5.5 Limitations
    • 7.6 LIPOSOMES
      • 7.6.1 Liposomes Types
        • FIGURE 7.4 Classification and pictorial representation of different types of liposomes.
      • 7.6.2 Methods for Liposome Preparation
        • 7.6.2.1 Mechanical Dispersion Methods
          • Thin Film Hydration
          • Membrane Extrusion
        • 7.6.2.2 Solvent Dispersion Methods
          • Solvent (Ether/Ethanol) Injection
          • Reversed Phase Evaporation
        • 7.6.2.3 Detergent Removal Method
      • 7.6.3 Advantages
      • 7.6.4 Limitations
    • 7.7 CONCLUSION
    • ASSESSMENT QUESTIONS
    • REFERENCES
  • 8 STIMULI-RESPONSIVE TARGET STRATEGIES
    • 8.1 CHAPTER OBJECTIVES
    • 8.2 INTRODUCTION
    • 8.3 PHYSIOLOGICAL-FACTOR-BASED TARGETING FORMULATIONS
      • 8.3.1 pH-Sensitive Targeting
        • FIGURE 8.1 p-Aminobenzenesulfonamide (1) and sulfonamide monomers (2).
        • FIGURE 8.2 Dimethyl maleic anhydride.
        • FIGURE 8.3 Polyethylene glycol (PEG).
      • 8.3.2 Temperature-Sensitive Targeting
        • FIGURE 8.4 Conformational changes of polymeric responsive systems with pH and temperature: (a) homopolymers and (b) block co-polymers; solid line, responsive block; dotted line, hydrophilic block [74].
    • 8.4 MAGNETIC TARGETING PARTICLES
      • 8.4.1 Sources of Magnetic Response
      • 8.4.2 Application of Magnetic Targeting Particles
      • 8.4.3 Theranostic Approach of Magnetic Response
      • 8.4.4 QD-Based Formulations for Magnetic Resonance Responsive Theranostic Modalities
    • 8.5 LIGAND-BASED TARGETING FORMULATIONS
      • 8.5.1 Monoclonal Antibodies Coupled Targeting
      • 8.5.2 Pretargeting Approach
      • 8.5.3 Avidin- and Biotin-Mediated Pretargeting
        • FIGURE 8.5 Structures of avidin and biotin (vitamin B6).
      • 8.5.4 Peptide and Protease Coupled Targeting
      • 8.5.5 Peptide Coupled to Cell-Penetrating Peptides (CPPs) for Target Delivery
      • 8.5.6 Cyclic RGD Peptides and Integrin
      • 8.5.7 Formulations Based on Integrin and Cyclic RGD Peptides
      • 8.5.8 Peptide Ligand Targeting for Tumor Angiogenesis and Vascular
        • FIGURE 8.6 Functionalization of novel poly (vinylidene fluoride) (PVDF) nanoparticles conjugated to CBO-P11. Radio-grafting of PAA, coupling with azido spacer arm (mTEG), and “click” conjugation of fluorescent targeting ligand (CBO-P11-CyTE777) [179].
      • 8.5.9 Folate Conjugated Particle
        • FIGURE 8.7 Folic acid.
      • 8.5.10 siRNA Approach for Targeting
      • 8.5.11 Polysaccharide-Anchored Targeting
    • 8.6 FORMULATIONS APPROACH BASED ON HOST RECEPTOR TARGETING
      • 8.6.1 Peptides Targeting the Epidermal Growth Factor Receptor (EGFR)
      • 8.6.2 Peptides Targeting G-Protein–Coupled Receptors (GPCRs)
      • 8.6.3 Targeting Calcium-Sensing Receptor (CaR)
    • 8.7 DESIGN OF A CORE SHELL MICROPARTICLE: AN EXAMPLE OF FORMULATION DEVELOPMENT
      • 8.7.1 Specific Aim
        • FIGURE 8.8 Design of a core shell microparticle (CSM).
      • 8.7.2 Formulation Development
        • FIGURE 8.9 Schematic representation of preparation of chitosan-SLN microparticles.
        • FIGURE 8.10 SEM results of chitosan mean particle sizes (b) and CSM (a).
      • 8.7.3 Preparation of SLN
      • 8.7.4 Preparation of Core Shell Microparticles (CSMs)
      • 8.7.5 Radioactive Ligand Assay
      • 8.7.6 Cellular Uptake
      • 8.7.7 Competitive Inhibition Studies
      • 8.7.8 The Model for Receptor Binding
      • 8.7.9 Results and Conclusions
    • ASSESMENT QUESTIONS
    • REFERENCES
  • 9 IMPLANTS
    • 9.1 CHAPTER OBJECTIVES
    • 9.2 INTRODUCTION
      • FIGURE 9.1 Plasma drug concentration versus time profile of a drug upon oral administration when compared with a sustained release drug delivery system. Reproduced with permission from Ref. 2.
      • 9.2.1 Advantages
      • 9.2.2 Disadvantages
    • 9.3 POLYMERIC IMPLANTABLE SYSTEMS
      • 9.3.1 Nonbiodegradable Implant Systems
        • 9.3.1.1 Reservoir Systems
          • FIGURE 9.2 Schematic diagram of reservoir and matrix nonbiodegradable implant systems.
        • 9.3.1.2 Matrix Systems
      • 9.3.2 Biodegradable Implant Systems
        • FIGURE 9.3 Chemical structures of the most commonly used polymers.
        • FIGURE 9.4 Schematic diagram of a matrix biodegradable implant system.
    • 9.4 CLINICAL AND THERAPEUTIC APPLICATIONS OF POLYMERIC IMPLANT SYSTEMS
      • 9.4.1 Contraceptive Steroids
        • 9.4.1.1 Norplant
        • 9.4.1.2 Implanon
      • 9.4.2 Ocular Therapeutics
        • 9.4.2.1 Ocusert Pilo
        • 9.4.2.2 Vitrasert
        • 9.4.2.3 Retisert
        • 9.4.2.4 Surodex
        • 9.4.2.5 Ozurdex
      • 9.4.3 Cancer Chemotherapy
        • 9.4.3.1 Zoladex
        • 9.4.3.2 Eligard
        • 9.4.3.3 Gliadel
    • 9.5 IMPLANTABLE PUMP (MECHANICAL) SYSTEMS
      • 9.5.1 Infusion Pumps
        • FIGURE 9.5 An implantable propellant-driven infusion pump system while in operation (top) and during refilling (bottom). Reproduced with permission from Ref. 1.
      • 9.5.2 Osmotic Pumps
        • FIGURE 9.6 (a) Schematic representation of an osmotic pump. Reproduced with permission of John Wiley & Sons, Inc. from Ref. 41. (b) Osmotic pump and components. Reproduced with permission from Ref. 39.
      • 9.5.3 Peristaltic Pumps
        • FIGURE 9.7 Cross-sectional view of a peristaltic pump. Reproduced with permission from Ref. 1.
      • 9.5.4 Positive Displacement Pumps
      • 9.5.5 Controlled-Release Micropumps
    • 9.6 CLINICAL AND THERAPEUTIC APPLICATIONS OF IMPLANTABLE PUMP SYSTEMS
      • 9.6.1 ALZET Osmotic Pumps
        • FIGURE 9.8 Cross-sectional view of (a) ALZET and (b) DUROS pumps. Reproduced with permission from ALZET Osmotic Pumps and DURECT Corporation.
      • 9.6.2 DUROS Pumps
    • 9.7 CLINICAL APPLICATION OF IMPLANTS FOR DELIVERY OF NARCOTIC ANALGESICS
    • 9.8 BIOCOMPATIBILITY ISSUES OF IMPLANTABLE DRUG DELIVERY SYSTEMS
      • 9.8.1 Biological Response to an Implant Device
      • 9.8.2 In Vitro Tests
        • In vitro
      • 9.8.3 In Vivo Tests
        • TABLE 9.1 Different Tests Used for Determining In Vitro and In Vivo Biocompatibility
      • 9.8.4 Blood Compatibility Testing
      • 9.8.5 Tissue Compatibility Testing
    • 9.9 CONCLUSION
    • ASSESSMENT QUESTIONS
    • REFERENCES
  • 10 APTAMERS IN ADVANCED DRUG DELIVERY
    • 10.1 CHAPTER OBJECTIVES
    • 10.2 INTRODUCTION
      • FIGURE 10.1 By using X-ray diffraction combined with theoretical analysis, researchers now can look deep into the binding structure of a protein-aptamer complex: (a) the binding pocket of a 40-mer RNA that binds to streptomycin; and (b) crystal structure of Arc 1172 bound to the A1 domain of von Willebrand factor. Figures adapted from Refs. 14, 15, respectively.
    • 10.3 APTAMER DISCOVERY USING SELEX
      • 10.3.1 Conventional SELEX
        • FIGURE 10.2 Scheme of a conventional SELEX cycle: (i) sequence binding, (ii, iii) partitioning, and (iv) amplifying isolated nucleotides.
      • 10.3.2 Cell-SELEX
        • FIGURE 10.3 Scheme of a cell-SELEX cycle: (i) counterselection, (ii) positive selection, and (iii) elution of sequences from targeted cells, and (iv) amplification of selected sequences.
      • 10.3.3 In Vivo SELEX
    • 10.4 CHARACTERISTICS OF APTAMERS AS TARGETING LIGANDS IN DRUG DELIVERY SYSTEMS
      • FIGURE 10.4 Nucleotide structure and positions often modified to enhance stability, including (a) 5-position of pyrimidine, (b) phosphodiester linkage, (c) 2′-position of nucleotide, and (d) 5′-end of nucleotide. Figure adapted from Ref. 28.
      • FIGURE 10.5 Mirror-design of L-RNA ligands that bind to Dadenosine. High-affinity D-RNA ligands binding to the enantiomeric form of D-adenosine were identified by in vitro selection. Truncated aptamers containing the binding motif were prepared by solid-phase synthesis in the D- and Lforms. While the selected DRNA is able to recognize the unnatural adenosine enantiomer, the mirror-image RNA binds to naturally occurring D-adenosine. Figure adapted from Ref. 50.
    • 10.5 APPLICATIONS OF APTAMERS AS TARGETING LIGANDS IN DRUG DELIVERY
      • FIGURE 10.6 Timeline of nanotechnology-based drug delivery. Here, we highlight some delivery systems that serve as important milestones throughout the history of drug delivery. Figure adapted from Ref. 60.
      • FIGURE 10.7 Passive versus active targeting. Figure adapted from Ref. 61.
      • 10.5.1 Aptamers Targeting the Prostate-Specific Membrane Antigen (PSMA)
      • 10.5.2 Aptamers Targeting PTK7 on Leukemia Cells
      • 10.5.3 Aptamers Targeting Ramos Cells
      • 10.5.4 AS1411, a Guanosine-Rich Aptamer Targeting the Nucleolin
      • 10.5.5 Other Aptamers Used as Targeting Ligands for Drug Delivery
        • TABLE 10.1 Selected Examples of Aptamers Used as Targeting Ligand in Nanoparticle-Based Drug Delivery
    • 10.6 NOVEL APPLICATIONS OF APTAMERS IN ADVANCED DRUG DELIVERY
    • 10.7 SUMMARY
    • ASSESSMENT QUESTIONS
    • ACKNOWLEDGMENTS
    • REFERENCES
  • 11 NANOFIBER
    • 11.1 CHAPTER OBJECTIVES
    • 11.2 INTRODUCTION
    • 11.3 POLYMERS FOR NANOFIBER PREPARATION
      • TABLE 11.1 Commonly Used Polymers for the Development of Nanofibers
      • TABLE 11.2 Polymeric Blends Used for the Preparation of Nanofibers
      • 11.3.1 Synthetic Polymer Blends
      • 11.3.2 Natural Polymer Blends
      • 11.3.3 Natural–Synthetic Polymer Blends
      • 11.3.4 Hydrophilic and Hydrophobic Polymer Blends
    • 11.4 METHODS FOR NANOFIBER FABRICATION
      • 11.4.1 Electrospinning
        • TABLE 11.3 Factor Affecting Electrospinning Process During Nanofiber Preparation [22, 29]
      • 11.4.2 Self-Assembly
      • 11.4.3 Phase Separation
      • 11.4.4 Template Synthesis
    • 11.5 BIOMEDICAL APPLICATIONS
      • 11.5.1 Tissue Engineering
        • FIGURE 11.1 Main aspects of tissue regeneration scaffold system. Reproduced with permission from Ref. 41.
        • 11.5.1.1 Bone Tissue Engineering
          • FIGURE 11.2 Scanning electron micrograph (SEM) of random PCL nanofibers. Reproduced with permission from Ref. 44.
        • 11.5.1.2 Skeletal Muscle Generation
        • 11.5.1.3 Neural Tissue Engineering
          • FIGURE 11.3 Scanning electron micrograph (SEM) of electro-spun PLLA nanofibers. Reproduced with permission from Ref. 47.
        • 11.5.1.4 Blood Vessel Tissue Engineering
          • FIGURE 11.4 Scanning electron micrograph (SEM) of aligned PLLA-CL nanofibers. Reproduced with permission from Ref. 49.
      • 11.5.2 Drug Delivery
        • 11.5.2.1 Small-Molecule Delivery
        • 11.5.2.2 Macromolecule Delivery
          • FIGURE 11.5 Diagrammatic representation of siRNA delivery by nanofibrous scaffold. Reproduced with permission from Ref. 55.
          • DNA Delivery
          • Protein Delivery
            • FIGURE 11.6 (a) Time-dependent release of luciferase from luciferase-loaded PVA nanofibers at 4°C as determined by enzyme activity. (b) The parallel determination of luciferase activity in solution confirms that luciferase activity remained stable under these experimental conditions for at least 4 h. (c) The linearity of the luciferase release is observed also at an extended time scale. (d) Time-dependent release of luciferase from luciferase-loaded PPX-coated PVALuc composite fibers. The figures show the combination of multiple experiments (bars = SD) or the results of one representative experiment. Reproduced with permission from Ref. 57.
      • 11.5.3 Nanofiber-Enzyme Biocatalyst Conjugates
    • ASSESSMENT QUESTIONS
    • REFERENCES
  • 12 BIOMIMETIC SELF-ASSEMBLING NANOPARTICLES
    • 12.1 CHAPTER OBJECTIVES
    • 12.2 INTRODUCTION
    • 12.3 BODY
      • 12.3.1 Native Nanoparticles
      • 12.3.2 Native Nanoparticle Assembly
        • FIGURE 12.1 Native nanoparticles: ribbon diagrams of 423 and 23 ferritin cages (reproduced with permission from Ref. 10) and a cryoelectron image reconstruction of a clathrin cage with three overlapping triskelions shown in different colors (reproduced with permission from Ref. 11).
        • FIGURE 12.2 Virus architecture. (a) Triangulation numbers on a hexagonal p6 net. (0,0) indicates the origin of a fivefold vertex and the placement of a pentamer. T number is calculated from (h, k) and denotes the number of smaller triangles, arranged around local quasi-sixfolds, in one triangular icosahedron facet. (b) cryoelectron image reconstructions of different viruses showing corresponding T numbers with highlighted icosahedral facets. Reproduced with permission from Ref. 21.
      • 12.3.3 Biomimetic Nanoparticles
        • FIGURE 12.3 Polyhedra designs. Schematics of asymmetric building blocks composed of two protein domains (a) and two coiled-coil domains (b) that self-oligomerize into regular nanoparticles, shown both schematically and in electron micrographs. Reproduced with permission from Refs. 26 and 27.
        • FIGURE 12.4 Biomimetic cages. (a) Schematic and electron micrograph of a C3-symetric conjugation of a β-sheet peptide into nanoscale cages. Reproduced with permission from Ref. 28. (b) A helical-wheel representation of a dendrimer-like assembly of a helical block into polynanocages. Electron micrograph of silver nanoparticles formed in one polynanocage after its enzymatic degradation. The mean diameters of individual cavities and nanoparticles are ~5 nm. Reproduced with permission from Ref. 29.
        • FIGURE 12.5 Facile amphiphiles. Schematics and micrographs of vesicular assemblies from a diblock co-polypeptide amphiphile (a) and a cyclic peptide facial amphiphile (b). Reproduced with permission from Refs. 33 and 34.
    • 12.4 OUTLOOK SUMMARY
    • ASSESSMENT QUESTIONS
      • FIGURE 12.6 Folded hexagonal nets of hypothetical viruses.
      • FIGURE 12.7 Hexagonal nets for Avibirnavirus (a) and Sobemovirus (b). Reproduced with permission from Ref. 35.
      • FIGURE 12.8 An even unit comprising 15 monomeric blocks of trimers and pentamers. Reproduced with permission from Ref. 27.
    • REFERENCES
  • 13 PROTEIN AND PEPTIDE DRUG DELIVERY
    • 13.1 CHAPTER OBJECTIVES
    • 13.2 INTRODUCTION
    • 13.3 CHALLENGES FOR PROTEIN AND PEPTIDE DRUG DELIVERY
    • 13.4 MECHANISM OF ABSORPTION
      • FIGURE 13.1 Various protein transport mechanisms.
    • 13.5 STRATEGIES TO ENHANCE PROTEIN AND PEPTIDE ABSORPTION
      • 13.5.1 Absorption Promoters
        • 13.5.1.1 Surfactants
        • 13.5.1.2 Bile Salts
        • 13.5.1.3 Fusidic Acid Derivatives
        • 13.5.1.4 Cyclodextrins
        • 13.5.1.5 Chelating Agents
        • 13.5.1.6 Cell-Penetrating Peptides
      • 13.5.2 Chemical/Structural Modification Approach
        • 13.5.2.1 Simple Modifications
        • 13.5.2.2 Cyclic Prodrugs
        • 13.5.2.3 Lipidation Approach
        • 13.5.2.4 PEGylation
          • TABLE 13.1 PEGylated and Hyperglycosylated Proteins in the Market
        • 13.5.2.5 Hyperglycosylation
        • 13.5.2.6 Transporter-Mediated Targeted Delivery
        • 13.5.2.7 Receptor-Mediated Peptide Delivery
      • 13.5.3 Formulation Technologies
        • 13.5.3.1 Bioadhesive Systems
          • Hydrogels
            • TABLE 13.2 Hydrogels Used for Oral Protein Delivery
          • Mucoadhesive Tablets and Patches
            • TABLE 13.3 Therapeutic Proteins Delivery as Tablet Dosage Form
        • 13.5.3.2 Particulate Carrier Systems
          • Polymeric Particles (Nanoparticles and Microparticles)
            • TABLE 13.4 Oral Administration of Therapeutic Proteins Encapsulated in Polymeric Particles
          • Micelles
            • TABLE 13.5 Micelle Delivery of Protein and Peptides
          • Liposomes
            • TABLE 13.6 Liposomal Delivery of Protein
    • 13.6 CONCLUSION
    • ASSESSMENT QUESTIONS
    • REFERENCES
  • 14 DELIVERY OF NUCLEIC ACIDS
    • 14.1 CHAPTER OBJECTIVES
    • 14.2 INTRODUCTION
      • TABLE 14.1 Characteristics of Different Types of Nucleic Acids
      • FIGURE 14.1 Different types of nucleic acids and their mechanisms. (i) Plasmids must be delivered into the cell nucleus to express encoded transgenes. (ii) Antigene ODNs exhibit activities at the transcriptional level by forming a triplex with genomic DNA in a sequence-specific manner on the polypurine-polypyrimidine tracts. (iii) Aptamers act extracellularly by binding to membrane proteins. (iv) siRNAs induce the breakdown of target mRNAs in the cytoplasm. (v) Antisense ODNs inhibit gene expressions at the posttranscriptional level. (vi) Ribozymes bind to substrate RNAs in the cytoplasm via Watson-Crick base pairing and cleave the target RNA in a nonhydrolytic reaction.
    • 14.3 TYPES OF NUCLEIC ACIDS AND THEIR MECHANISMS
      • 14.3.1 Plasmids
      • 14.3.2 Antisense and Antigene Oligodeoxynucleotides (ODNs)
      • 14.3.3 Small Interfering RNA
      • 14.3.4 Aptamers
      • 14.3.5 Ribozymes
    • 14.4 BARRIERS FOR NUCLEIC ACIDS DELIVERY
      • FIGURE 14.2 Various biological barriers faced by nucleic acids in vivo. (a) Naked nucleic acids are readily degraded by ubiquitous nucleases in the blood stream and tissues. (b) Nucleic acids are taken up by phagocytes of the RES in the liver and spleen. (c) Nucleic acids are rapidly cleared via the kidney. (d) Inefficient transport across the vascular wall. (e) Extracellular matrix hinders the movement of nucleic acids. (f) Inefficient cellular uptake. (g) Inefficient endosomal escape. (h) Inefficient nuclear import.
      • 14.4.1 Barriers to Systemic Delivery In Vivo
      • 14.4.2 Cellular and Subcellular Barriers
    • 14.5 STRATEGIES TO OVERCOME THE BIOLOGICAL BARRIERS
      • 14.5.1 Mode of Administration
      • 14.5.2 Chemical Modification
        • FIGURE 14.3 Chemical modifications of nucleic acids. (a) Unmodified DNA or RNA (R = H, OH), (b) phosphorothioate, (c) boranophosphate, (d) peptide nucleic acid, (e) 2′-O-methyl, (f) 2′-O-fluoro, (g) 2′-O-methoxyethyl (MOE), (h) locked nucleic acid, and (i) morpholino.
    • 14.6 NUCLEIC ACID DELIVERY SYSTEMS
      • 14.6.1 Lipid-Based Delivery System
        • FIGURE 14.4 The structures of commonly used cationic lipids. (i) DOTAP, composed of monoamine, ether linker, two unsaturated fatty acid chains; (ii) DOTMA, composed of monoamine, ester linker, two unsaturated fatty acid chains; (iii) DC-Chol, composed of monoamine, carbamate linker, and cholesterol; (iv) bis-guanidiniumspermidinecholesterol (BGSC), composed of polyamine, carbamate linker, and cholesterol; (v) pyridinium lipid, composed of pyridinium ring, amide linker, and saturated fatty acid chains; (vi) N-methyl-4(dioleyl) methylpyridiniumchloride (SAINT-2), composed of pyridinium ring, aliphatic linker, and two unsaturated fatty acid chains; and (vii) DOGS, composed of polyamine, amide linker, and two saturated fatty acid chains.
      • 14.6.2 Polymer-Based Delivery System
        • FIGURE 14.5 The structure of commonly used cationic polymers: (a) structure of the naturally occurring chitin, (b) chitosan, (c) linear PEI, (d) branched PEI, (e) different generation PAMAM dendrimer, (f) cyclodextrin, and (g) cationic cyclodextrin.
        • 14.6.2.1 Poly-ethyleneimine
        • 14.6.2.2 Chitosan
        • 14.6.2.3 Dendrimers
          • FIGURE 14.6 Carrier systems for nucleic acids: (a) liposome-based carrier, (b) cationic polyplexbased carrier, (c) dendrimer-based carrier, and (d) peptide-based carrier.
        • 14.6.2.4 Cyclodextrin-Containing Cationic Polymers
        • 14.6.2.5 Peptide-Based Delivery Systems
          • TABLE 14.2 Classic CPP Sequences
    • 14.7 VIRAL VECTORS
      • TABLE 14.3 Characteristics of Various Viral Vectors
    • 14.8 CONCLUSION AND FUTURE PERSPECTIVES
    • ASSESSMENT QUESTIONS
    • REFERENCES
  • 15 DELIVERY OF VACCINES
    • LIST OF ABBREVIATIONS
    • 15.1 CHAPTER OBJECTIVES
    • 15.2 INTRODUCTION
    • 15.3 IMMUNOLOGICAL MECHANISMS
      • FIGURE 15.1 (a) During a bacterial infection, immature dendritic cells capture vaccine antigens and migrate from infection sites to afferent lymph nodes to become mature dendritic cells. During dendritic cell maturation, ingested antigen undergoes degradation in acidic endosomes to produce small peptides. As a result of an exchange mechanism in the endoplasmic reticulum, antigenic-peptide fragments bound to MHC molecules are translocated to the dendritic cell surface. These mature dendritic cells differentiate naïve T cells into TH1 and TH2 cells, which further differentiate naïve B cells to plasma (effector) and memory B cells. Distinct classes of cytokines trigger antibody production as well as class switching of antibodies in plasma B cells. (b) Demonstrates cellular immune mechanism. Specific internalized antigens, such as viruses, virus-like antigens, intracellular pathogens, and soluble proteins are retained inside dendritic cell endosomes. The internalized antigens escape endosomes and cross into cytosol. Now, the effector cytotoxic T cells cause lysis of pathogen loaded cells through distinct cell-death mechanisms.
      • 15.3.1 Innate Immunity
      • 15.3.2 Connecting Innate and Adaptive Immune Responses
        • FIGURE 15.2 (a) APC phagocytosed antigens or antigen carriers enter acidic endosomes, where proteases degrade antigens into small peptides. In the endoplasmic reticulum, MHC-II molecules bind to an invariant protein, which directs the transportation of MHC-II-invariant protein from endoplasmic reticulum into endosomes. Inside the endosomes, invariant protein cleaves leaving a peptide fragment termed as CLIP, which still binds to MHC-II molecules. CLIP fragment exchanges with antigenic peptide and binds to MHC-II molecules. The MHC-II-antigenic peptide is translocated to cell surface to present to CD4+ T cells. In general, the MHC-II pathway leads to humoral immunity. (b) APC phagocytosed antigens or antigen carriers can escape from endosomes and slowly hydrolyze in the cytoplasm, releasing encapsulated antigenic proteins. Released proteins are degraded by proteasomes into smaller peptides, which are then transported by TAP into the endoplasmic reticulum, where they bind MHC-I molecules. The MHC-I-antigenic peptides migrate to the cell surface. Multiple forms of exogenous (e.g., apoptotic cells and necrotic cells) and endogenous antigens (self- or virus-derived proteins) access the MHC-I pathway. Alternatively, antigens might be processed into peptides within endosomes, where they can access MHC-I molecules.
      • 15.3.3 Adaptive Immunity
        • 15.3.3.1 Humoral Immunity
          • TABLE 15.1 Classes of Antibodies and Their Functional Role in Immune Responses
        • 15.3.3.2 Cellular Immunity
    • 15.4 TYPES OF VACCINES
      • 15.4.1 Live Vaccines
      • 15.4.2 Inactivated Antigen Vaccines
      • 15.4.3 Recombinant Vaccines
        • 15.4.3.1 Viral Vectors
          • TABLE 15.2 Characteristics of Viral Vectors Used for Design of Recombinant Vaccines
        • 15.4.3.2 Bacterial Vectors
        • 15.4.3.3 Nucleic Acids
          • FIGURE 15.3 DNA fusion gene vaccine design. A DNA fusion gene vaccine has two main structures: plasmid backbone and transcriptional unit. The transcriptional unit contains the promoter and an insert or gene encoding the antigen of interest followed by a transcript termination/polyadenylation sequence. (a) The plasmid backbone (e.g., pVax1, pUC, and Pbr322) contains an origin of replication for amplification of the plasmid in bacteria, as well as an antibiotic resistance gene, conferring resistance to antibiotic, for example, to enable selective growth of the plasmid in bacteria. (b) Viral promoters, such as cytomegalovirus (CMV), simian virus (SV) 40, and sarcoma virus are often used to drive the expression of transgenic antigen in a number of mammal cells. Nonviral promoters, such as MHC-II promoter, chimeric, and other synthetic promoters, are also considered. (c) Transgene facilitates the possibility of encoding multiple proteins in a single gene construct because not only can an antigen be added, but also the sequences encoding adjuvant can be added to enhance vaccine potency. (d) Polyadenylation sequence (poly A) is an essential aspect of gene expression, playing an important role in messenger RNA (mRNA) stability and translation. Most vectors contain SV40 or bovine growth hormone poly A signal.
    • 15.5 PHYSICOCHEMICAL PROPERTIES OF VACCINE DELIVERY SYSTEMS
    • 15.6 VACCINE DELIVERY SYSTEMS
      • 15.6.1 Micelles
        • FIGURE 15.4 Various vaccine delivery systems include: (a) micelles, (b) emulsions, (c) liposomes (Reprinted with permission from Ref. 51), (d) virosomes, (e) virus-like particles, (f) polymeric nanoparticles, and (g) dendrimers. (Left: A G5 PPI (generation 5 poly (propyleneimine) dendrimer; generations (“shells”) are indicated. Right: MAP dendron (basic MAP core based on lysine as the only monomer, indicating core structure and generation dependent increase of amino group numbers, leading to increased crowding of amino groups in shells of higher generation). Reprinted with permission from Ref. 54.
      • 15.6.2 Emulsions
      • 15.6.3 Liposomes
      • 15.6.4 Virosomes
      • 15.6.5 Virus-Like Particles
      • 15.6.6 Polymeric Nanoparticles
      • 15.6.7 Dendrimers
    • 15.7 ADJUVANTS (IMMUNOPOTENTIATORS)
    • 15.8 ROUTE OF ADMINISTRATION AND DEVICES
      • TABLE 15.3 List of Vaccines Licensed for Immunization in the United States
      • 15.8.1 Oral Route
      • 15.8.2 Intranasal Route
      • 15.8.3 Intramuscular/Subcutaneous Route
      • 15.8.4 Intradermal Route
      • 15.8.5 Transdermal Route
    • 15.9 CONCLUSION
    • ASSESSMENT QUESTIONS
    • REFERENCES
• PART III TRANSLATIONAL RESEARCH OF ADVANCED DRUG DELIVERY
  • 16 REGULATORY CONSIDERATIONS AND CLINICAL ISSUES IN ADVANCED DRUG DELIVERY
    • 16.1 CHAPTER OBJECTIVES
    • 16.2 INTRODUCTION
      • 16.2.1 Drug Development
        • FIGURE 16.1 The flowchart for drug development and regulatory approval process.
      • 16.2.2 Regulatory Background
      • 16.2.3 Advanced Drug Delivery Systems
    • 16.3 MODIFIED-RELEASE ORAL DOSAGE FORM
      • TABLE 16.1 Examples of Multiphasic Modified Release Oral Dosage Forms
      • 16.3.1 Regulatory Concerns for Dose-Dumping
      • 16.3.2 Bioequivalence Assessment
    • 16.4 SUSTAINED-RELEASE PARENTERAL DOSAGE FORMS
      • TABLE 16.2 Examples of Micro-/Nanosphere Products Marketed in the United States
      • 16.4.1 Formulation, Processing, and Performance
      • 16.4.2 In Vitro Release Testing and In Vitro–In Vivo Correlation (IVIVC)
      • 16.4.3 Safety Concerns
    • 16.5 LIPID-BASED ORAL DOSAGE FORMS
      • 16.5.1 Lipid Excipients
        • TABLE 16.3 Lipid Excipients/Surfactants that Interact with Enzymes/Transporters In Vivo or In Vitro
      • 16.5.2 In Vitro Dissolution or Release Testing
      • 16.5.3 Bioequivalence Issues
    • 16.6 TRANSDERMAL DELIVERY SYSTEMS
      • TABLE 16.4 Some Characteristics of Drugs for Transdermal Delivery
      • 16.6.1 Dose-Dumping and Residual Drug Issues
      • 16.6.2 Adhesion Performance
        • TABLE 16.5 A scoring System for Evaluation of Patch Adhesion
      • 16.6.3 Skin Irritation and Sensitization
        • TABLE 16.6 An Example Scoring System for the Skin Irritation Test
    • 16.7 RESPIRATORY DRUG DELIVERY SYSTEMS
      • 16.7.1 Device and Formulation Design
        • TABLE 16.7 Examples of DPI Formulations Currently Marketed in the United States
      • 16.7.2 In Vitro Assessment
        • TABLE 16.8 Examples of In Vitro Tests for MDI and DPI Drug Products
      • 16.7.3 In Vivo Assessment
        • TABLE 16.9 In Vitro Tests to Support Bioequivalence of Nasal Aerosols and Nasal Sprays
    • 16.8 DRUG-ELUTING STENTS
      • 16.8.1 Safety Considerations
      • 16.8.2 Drug-Release Profiles
    • 16.9 NANOTECHNOLOGY-DERIVED DRUG DELIVERY SYSTEMS
      • TABLE 16.10 Examples of Approved Nanomaterial-Containing Drug Products in the United States
      • 16.9.1 Product Quality Assessment
      • 16.9.2 Product Safety Assessment
      • 16.9.3 Bioavailability and Bioequivalence
      • 16.9.4 Liposomes
        • TABLE 16.11 Classification of Liposomes
        • 16.9.4.1 Challenges in Chemistry, Manufacturing, and Controls
          • TABLE 16.12 Some Physicochemical Properties of Liposome Drug Products
        • 16.9.4.2 Biopharmaceutics and Therapeutic Equivalence Issues
    • 16.10 NUCLEIC ACID THERAPEUTICS
    • ASSESSMENT QUESTIONS
    • REFERENCES
  • 17 ADVANCED DRUG DELIVERY IN CANCER THERAPY
    • 17.1 CHAPTER OBJECTIVES
    • 17.2 INTRODUCTION
    • 17.3 BIOLOGICAL CHARACTERISTICS OF CANCER
      • 17.3.1 Molecular Characteristics
      • 17.3.2 Tumor Angiogenesis
        • FIGURE 17.1 Tumor microenvironment. The tumor vasculature is structurally different from normal vessels in healthy tissues. In normal vessels, endothelial cells are well aligned along the vessel wall, which is surrounded by pericytes. The walls of tumor vessels have fenestrations and they are not protected by pericytes. The abnormal structure of tumor vasculature leads to the accumulation of macromolecules or particles in tumor tissue, which is called the EPR effect. Tumor cells secrete endothelial growth factors and induce the angiogenesis. Tumor cells also metastasize to other organs through tumor vessels.
      • 17.3.3 Tumor Microenvironment
      • 17.3.4 Cancer Metastasis
    • 17.4 DRUG DELIVERY TO CANCER CELLS BY NANOSCALE CARRIERS
      • 17.4.1 Liposome
        • TABLE 17.1 Liposome Formulations that Have Been Approved by the FDA or Under Clinical Evaluations
      • 17.4.2 Polymeric Micelle
        • TABLE 17.2 Polymeric Micelles in Translational Cancer Research
      • 17.4.3 Other Nanoparticles
    • 17.5 DRUG DELIVERY TO CANCER CELLS BY BIOCONJUGATES
      • 17.5.1 Antibody–Drug Conjugate
        • TABLE 17.3 Antibody–Drug Conjugates in Cancer Clinical Trials
        • FIGURE 17.2 Structures of CMC544, SGN35, IMGN901, and T-DM1.
      • 17.5.2 Peptide–Drug Conjugate
        • TABLE 17.4 Peptide–Drug Conjugates in Translational Cancer Research
      • 17.5.3 Polymer–Drug Conjugate
        • TABLE 17.5 Polymer–Drug Conjugates in Cancer Clinical Trials
      • 17.5.4 Other Conjugates
    • 17.6 DRUG DELIVERY TO CANCER BY GEL SYSTERMS
    • 17.7 CONCLUSION AND FUTURE PERSPECIVES
    • ASSESSMENT QUESTIONS
    • REFERENCES
  • 18 ADVANCED DELIVERY IN CARDIOVASCULAR DISEASES
    • 18.1 CHAPTER OBJECTIVES
    • 18.2 CARDIOVASCULAR SYSTEM
      • 18.2.1 Architecture of the Cardiovascular Systems
        • 18.2.1.1 Heart Anatomy
          • FIGURE 18.1 A cross-section of human heart showing internal chambers and valves. The right chambers, in blue, contain deoxygenated blood. The left heart chambers, in blue, contain oxygenated blood. Reproduced with permission from the Texas Heart Institute.
        • 18.2.1.2 Circulation System
        • 18.2.1.3 Cardiac Cycle and Heartbeat
      • 18.2.2 Diseases of the Cardiovascular System
        • 18.2.2.1 Angina and Heart Attack
        • 18.2.2.2 Congestive Heart Failure
        • 18.2.2.3 Atherosclerosis
        • 18.2.2.4 Hypertension
      • 18.2.3 Major Drug Classes Used to Treat Cardiovascular Diseases
        • 18.2.3.1 Renin-Angiotensin System
          • FIGURE 18.2 Conversion of angiotensinogen into active angiotensin peptides by proteolytic cleavage.
        • 18.2.3.2 Angiotensin Converting Enzyme (ACE) Inhibitors
          • FIGURE 18.3 Chemical structures of selected angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors such as captopril and lisinopril are active drugs. Other ACE inhibitors such as benazepril, enalapril, perindopril, and quinapril are relatively inactive prodrugs until converted into their corresponding diacids. The part of structures drawn in rectangular boxes are removed by cellular esterases and replaced with a hydrogen atom to form the active drug. The brand names of the drugs are in parentheses.
        • 18.2.3.3 Angiotensin II Receptor Blockers (ARBs)
          • FIGURE 18.4 Chemical structures of selected FDA-approved angiotensin II-receptor antagonists (ARBs). The brand names of the drugs are in parentheses.
        • 18.2.3.4 Diuretics
          • FIGURE 18.5 Chemical structures of selected thiazides, loop, and potassium-sparing diuretics. The brand names of the drugs are in parentheses.
        • 18.2.3.5 Nitrovasodilators
          • FIGURE 18.6 Chemical structures of five nitrovasodilator drugs that are clinically used for angina. The brand names of the drugs are in parentheses.
        • 18.2.3.6 Calcium Channel Blockers
          • FIGURE 18.7 Chemical structures of the five major classes of calcium channel blockers. The phenylalkylamines, benzothiazepines, and dihydropyridines are selective calcium channel blockers, while benzimidazole-substituted tetralines and diarylaminopropylamine are nonselective calcium channel blockers. Dihydropyridines are identified by the suffix “-dipine.”
        • 18.2.3.7 Alpha Blockers
          • FIGURE 18.8 Chemical structures of selected alpha blockers. Almost all these agents are competitive antagonists of the alpha adrenergic receptor except for phenoxybenzamine, an irreversible alkylating agent that binds covalently to alpha receptors. The brand names of the drugs are in parentheses.
        • 18.2.3.8 Beta Blockers
          • FIGURE 18.9 Chemical structures of selected beta blockers. There are two main classes of beta adrenergic receptor antagonists: nonselective and β1 selective. The brand names of the drugs are in parentheses.
        • 18.2.3.9 Statins
          • FIGURE 18.10 Scheme showing 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase catalyzed formation of mevalonate, an early rate-limiting reaction in cholesterol biosynthesis.
          • FIGURE 18.11 Chemical structures of selected FDA-approved statin drugs.
    • 18.3 THE FUNCTION OF HEART VALVES
    • 18.4 THE STRUCTURE OF HEART VALVES
    • 18.5 HEART VALVE DYSFUNCTION
      • 18.5.1 Causes
      • 18.5.2 Treatment: Valve Replacement Therapies
        • 18.5.2.1 Autograft Approach: Ross Procedure
        • 18.5.2.2 Allograft and Xenograft Approach: Artificial Heart Valve Replacement
          • Mechanical Valves
            • FIGURE 18.12 A mechanical valve made entirely of artificial components. This is a tilting disc valve made of pyrolitic carbon, stainless steel, and dacron.
          • Bioprosthetic Heart Valves
    • 18.6 BIOPROSTHETIC HEART VALVE FAILURE
      • 18.6.1 Calcification
        • 18.6.1.1 Causes
        • 18.6.1.2 Involved Variables
          • TABLE 18.1 Physiological/Pathological Variables Involved with Bioprosthetic Heart Valve Substitute Calcification
          • Physiological Variables
            • TABLE 18.2 The Positive and Negative Reactants in Plasma Involved in Heart Valve Substitute Calcification
          • Endothelial Regulation
      • 18.6.2 Heart Valve Fatigue
    • 18.7 TISSUE ENGINEERING IN HEART VALVES
      • 18.7.1 Introduction of Tissue-Engineered Scaffolds
      • 18.7.2 Synthetic Scaffolds for Heart Valves
        • FIGURE 18.13 Tissue-engineered heart valve.
      • 18.7.3 Natural and Acellularized Scaffolds for Heart Valves
      • 18.7.4 Future Tissue Engineering in Heart Valves
    • ASSESSMENT QUESTIONS
    • REFERENCES
  • 19 RECENT ADVANCES IN OCULAR DRUG DELIVERY
    • 19.1 CHAPTER OBJECTIVES
    • 19.2 INTRODUCTION
    • 19.3 BARRIERS TO OCULAR DRUG DELIVERY
      • 19.3.1 Anatomical Barriers
        • FIGURE 19.1 Schematic presentation of the ocular structure with the routes of drug kinetics illustrated. The numbers refer to the following processes: 1) transcorneal permeation from the lacrimal fluid into the anterior chamber, 2) noncorneal drug permeation across the conjunctiva and sclera into the anterior uvea, 3) drug distribution from the bloodstream via blood–aqueous barrier into the anterior chamber, 4) elimination of drug from the anterior chamber by the aqueous humor turnover to the trabecular meshwork and Sclemm's canal, 5) drug elimination from the aqueous humor into the systemic circulation across the blood–aqueous barrier, 6) drug distribution from the blood into the posterior eye across the blood–retina barrier, 7) intravitreal drug administration, 8) drug elimination from the vitreous via posterior route across the blood–retina barrier, and 9) drug elimination from the vitreous via anterior route to the posterior chamber. Adapted from Ref. 2.
      • 19.3.2 Physiological Constraints
      • 19.3.3 Drug and Dosage Form Related Factors Affecting Bioavailability
        • 19.3.3.1 Solubility
        • 19.3.3.2 Lipophilicity
        • 19.3.3.3 Molecular Weight and Size
    • 19.4 ADVANCES IN OCULAR DRUG DELIVERY
      • 19.4.1 Drug Delivery Through Novel Routes
        • 19.4.1.1 Intravitreal Injection
        • 19.4.1.2 Subconjunctival Route
        • 19.4.1.3 Retrobulbar Route
        • 19.4.1.4 Peribulbar Route
        • 19.4.1.5 Sub-Tenon Route
        • 19.4.1.6 Intracameral Route
    • 19.5 CONTROLED DRUG DELIVERY
      • 19.5.1 Iontophoresis
        • 19.5.1.1 Iontophoretic Device
        • 19.5.1.2 Probes for Iontophoresis
      • 19.5.2 Implants
        • 19.5.2.1 Classification of Implants
          • Nonbiodegradable Solid Implants
        • 19.5.2.2 Biodegradable Solid Implants
      • 19.5.3 Gelifying Systems
        • TABLE 19.1 Application of Implants [47]
        • 19.5.3.1 Hyaluronic Acid (HA)
        • 19.5.3.2 Polyacrylic Acid (PAA) Derivatives
        • 19.5.3.3 Chitosan
      • 19.5.4 Hydrogels
      • 19.5.5 Particulate Formulations
        • 19.5.5.1 Microspheres
        • 19.5.5.2 Nanoparticles
        • 19.5.5.3 Liposomes
        • 19.5.5.4 Niosomes
        • 19.5.5.5 Dendrimers
      • 19.5.6 Transporter Targeted Strategy
        • TABLE 19.2 Influx Transporter-Targeted Prodrug Strategy for Ocular Drug Delivery
        • TABLE 19.3 Expression/Tissue Distribution and Substrates of ABC Family Efflux Transporters
    • 19.6 MACROMOLECULAR DRUG DELIVERY
      • 19.6.1 Challenges for Delivery of Macromolecule
        • TABLE 19.4 Macromolecule/Protein and Peptide Delivery Through Ocular Route
      • 19.6.2 Permeation Enhancers
    • 19.7 STEM-CELL-BASED DRUG DELIVERY SYSTEM
      • 19.7.1 Types of Stem Cells
      • 19.7.2 Stem Cell Delivery to the Eye
    • 19.8 CONCLUSION
    • ASSESSMENT QUESTIONS
    • REFERENCES
  • 20 ADVANCED DRUG DELIVERY AGAINST STD
    • 20.1 CHAPTER OBJECTIVES
    • 20.2 INTRODUCTION
    • 20.3 PHYSIOLOGY OF VAGINA
      • 20.3.1 General Anatomy
      • 20.3.2 Cellular Structure
      • 20.3.3 Vaginal Fluids and Enzymes
      • 20.3.4 The Role of Cervical Mucus
      • 20.3.5 Viscosity of the Cervical Mucus
      • 20.3.6 Transporters in Vagina Cells
    • 20.4 STD AND PREVENTION STRATEGIES
      • 20.4.1 General Facts About STDs
      • 20.4.2 AIDS (HIV: Human Immunodeficiency Virus)
        • 20.4.2.1 Route of HIV Infection
          • FIGURE 20.1 HIV replication cycle. Source: Wikipedia http://en.wikipedia.org/wiki/HIV.
      • 20.4.3 Microbicides Against HIV
        • TABLE 20.1 Antiretroviral Drugs to Treat HIV
        • TABLE 20.2 Clinical Trial Phases Applicable to Microbicides
      • 20.4.4 Immunization Against HIV: Antibody/Vaccination
      • 20.4.5 Small Interfering RNAs (siRNAs) as a Topical Microbicide
      • 20.4.6 Cervical Cancer (HPV; Human Papilloma Virus)
    • 20.5 VAGINAL DELIVERY SYSTEMS AGAINST STDs
      • 20.5.1 Formulation Types
        • TABLE 20.3 Types of Intravagainal Formulations
      • 20.5.2 pH Regulation of Vaginal Device Against STDs
        • TABLE 20.4 pH of Various Reproductive Fluids
      • 20.5.3 Gel Formulations Against HIV
      • 20.5.4 Gel Formulations for Tenofovir
      • 20.5.5 Gel Formulations for Carrageenan
      • 20.5.6 Vagina Ring: Material and Structures
      • 20.5.7 Types of Vaginal Rings
      • 20.5.8 Micro- and Nanoparticles Against HIV
    • 20.6 DRUG RELEASE AND EFFICACY STUDIES OF VAGINAL FORMULATIONS
      • 20.6.1 Prototype Formulations
      • 20.6.2 Experimental Setup: Preparation of Simulated Vaginal System (SVS): Cervical Membrane (SCM) and Artificial Vaginal Fluid (AVF)
        • FIGURE 20.2 Kershary-Chien diffusion cell with the receptor solution (JP-8 stands for the vaginal formualtions).
        • FIGURE 20.3 Simulated vaginal system (SVS) [5].
        • 20.6.2.1 Rationale for the Selection of Biological Variables
          • TABLE 20.5 Factors Affecting the Drug Release Profile and Efficacy of the Intravaginal System
        • 20.6.2.2 In Vitro Drug Release Study from IVF using the Simulated Vaginal System (SVS)
      • 20.6.3 Evaluation of Cellular Uptake of Candidate Nanoparticles
        • FIGURE 20.4 Hypothetical presentation of ES NP delivery to vaginal epithelial cells. Endosome and lysosome's pH is 5–6.5, at which ES NP is not dissolved. Cytosol pH is pH 7.3–7.5, where the drug is released. Therefore, the drug will be released only at cytosol [173].
        • FIGURE 20.5 Cellular uptake profiles of ES nanoparticles in vaginal cells. (a) Nile red solution. Nile red bound on the cell membrane but not crossing the membrane. (b) Nile red-loaded ES nanoparticles. Vaginal cells internalized ES nanoparticles containing nile red and nile red distributed in entire cells, implying that nile red was released from ES nanoparticles in cytosol. Scale bar = 10 μm [173].
        • 20.6.3.1 Permeability and Pharmacokinetic Evaluation
    • 20.7 TESTING OF BIOCOMPATIBILITY OF THE VAGINAL SYSTEMS
      • 20.7.1 Cell Culture Models for Microbicide Evaluation
        • TABLE 20.6 Characteristics of Cervico/Vagina Cell Lines
      • 20.7.2 Cell Culture Studies
      • 20.7.3 Tests for Carcinogenicity
        • Problem with In Vitro Tests for Carcinogenicity
      • 20.7.4 In Vivo Study with the Animal Model
    • 20.8 CONCLUSION
    • ASSESMENT QUESTIONS
    • REFERENCES
  • 21 ADVANCED DRUG DELIVERY TO THE BRAIN
    • 21.1 CHAPTER OBJECTIVES
    • 21.2 INTRODUCTION
    • 21.3 BARRIERS FOR BRAIN DRUG DELIVERY
      • 21.3.1 Blood–Brain Barrier
        • FIGURE 21.1 Schematic representation of the blood–brain barrier.
      • 21.3.2 Blood–Cerebrospinal Fluid Barrier
        • FIGURE 21.2 Schematic representation of the blood–CSF barrier.
    • 21.4 DIRECT SYSTEMIC DELIVERY
      • 21.4.1 Intravenous Delivery
      • 21.4.2 Intra-Arterial Delivery
      • 21.4.3 Transnasal Delivery
    • 21.5 DIRECT CNS DELIVERY
      • TABLE 21.1 Advantages and Limitations of Various Brain Drug Delivery Methods
      • 21.5.1 Intracerebral (Intraparenchymal) Delivery
      • 21.5.2 Intraventricular Delivery (Transcranial Drug Delivery)
      • 21.5.3 Intrathecal Delivery (Intra-CSF Drug Delivery)
    • 21.6 CHEMICAL AND PHYSIOLOGICAL APPROACHES
      • 21.6.1 Lipidation
      • 21.6.2 Modulation of Efflux Proteins
        • FIGURE 21.3 Schematic representation of expression of efflux proteins on brain capillary endothelial cells.
        • 21.6.2.1 Inhibition of Efflux Process
      • 21.6.3 Circumvention of Efflux Process
        • TABLE 21.2 Endogenous Transporter Expressed on Brain Capillary Endothelial Cells
        • 21.6.3.1 GLUT1 Transporter
        • 21.6.3.2 Amino Acid Transporters
      • 21.6.4 Receptor-Mediated Endocytosis
        • 21.6.4.1 Transferrin Receptor
        • 21.6.4.2 Insulin Receptor
        • 21.6.4.3 Low-Density Lipoprotein Receptor-Related Protein 1 and 2
        • 21.6.4.4 Folate Receptor
    • 21.7 CONCLUSION
    • ASSESSMENT QUESTIONS
    • REFERENCES
• PART IV FUTURE APPLICATIONS OF ADVANCED DRUG DELIVERY IN EMERGING RESEARCH AREAS
  • 22 CELL-BASED THERAPEUTICS
    • 22.1 CHAPTER OBJECTIVES
    • 22.2 INTRODUCTION
      • FIGURE 22.1 A flowchart of issues in developing cell-based therapeutics.
    • 22.3 BONE MARROW TRANSPLANTATION AS A PROTOTYPE OF CELL-BASED THERAPEUTICS
    • 22.4 CELLS—ACTIVE PHARMACEUTICAL INGREDIENTS OF CELL-BASED THERAPEUTICS
      • 22.4.1 Dendritic Cells
      • 22.4.2 Endothelial Progenitor Cells
      • 22.4.3 Mesenchymal Stem Cells
      • 22.4.4 Hematopoietic Stem Cells
      • 22.4.5 Embryonic Stem Cells and Induced Pluripotent Stem Cells
      • 22.4.6 Other Tissue-Specific Stem/Progenitor Cells
    • 22.5 TYPICAL EXAMPLES FOR DISEASE-SPECIFIC APPLICATIONS
      • 22.5.1 Vascular Complications
      • 22.5.2 Cancer Therapy
      • 22.5.3 Ischemic Heart Disease
      • 22.5.4 Type I Diabetes Mellitus
        • FIGURE 22.2 Using dendritic cells to treat type I diabetes. Reproduced with permission from Ref. 21.
      • 22.5.5 Central Nervous System Diseases
      • 22.5.6 Human Immunodeficiency Virus Disease
      • 22.5.7 Cartilage Tissue Regeneration
        • FIGURE 22.3 Procedures of autologous chondrocyte implantation. Reproduced with permission from Ref. 128.
    • 22.6 BRIEF OVERVIEW ON HUMAN CASE STUDIES
    • 22.7 PHARMACEUTICAL CONSIDERATIONS ON CELL-BASED THERAPEUTICS
      • 22.7.1 Manufacturing Process
      • 22.7.2 Administration Routes
      • 22.7.3 In Vivo Fates of Therapeutic Cells
      • 22.7.4 Biosafety Issues
      • 22.7.5 Regulations on Cell-Based Therapeutics
        • FIGURE 22.4 Regulatory information for clinical trials of stem cell therapies. Reproduced with permission from Ref. 120.
    • 22.8 CONCLUSION AND FUTURE PERSPECTIVES
    • ASSESSMENT QUESTIONS
    • REFERENCES
  • 23 BIOMEDICAL APPLICATIONS AND TISSUE ENGINEERING OF COLLAGEN
    • 23.1 CHAPTER OBJECTIVES
    • 23.2 INTRODUCTION
    • 23.3 CHARACTERIZATION OF COLLAGEN AS A BIOMATERIAL
      • FIGURE 23.1 Schematic of collagen molecule. Reproduced from Ref. 36.
      • TABLE 23.1 Advantages and Disadvantages of Collagen as a Biomaterial
    • 23.4 COLLAGEN-BASED DRUG DELIVERY SYSTEMS
      • 23.4.1 Film/Sheet/Disc
      • 23.4.2 Collagen Shields
        • TABLE 23.2 Application of Collagen Shields for Various Topical Agents
      • 23.4.3 Collagen Sponges
      • 23.4.4 Gels/Hydrogels
      • 23.4.5 A Coupling of Liposomes to Hydrogels
      • 23.4.6 Pellet/Tablet
      • 23.4.7 Nanoparticles/Microparticles
    • 23.5 COLLAGEN-BASED SYSTEMS FOR GENE DELIVERY
      • 23.5.1 Collagen Film/Matrix
      • 23.5.2 Collagen Shield
      • 23.5.3 Collagen Sponges
      • 23.5.4 Hydrogels
      • 23.5.5 Pellet
      • 23.5.6 Particles
      • 23.5.7 Scaffold
      • 23.5.8 A Coupling of Liposomes to Collagen
    • 23.6 COLLAGEN-BASED SYSTEMS FOR TISSUE ENGINEERING
      • FIGURE 23.2 Tissue engineering in biomedical applications (cited from Wikipedia).
      • 23.6.1 Collagen as Skin Replacement and Skin Wounds
        • 23.6.1.1 Collagen-Based Implants
        • 23.6.1.2 The Mixture of Collagen and Other Physiological Substrates
      • 23.6.2 Collagen as Bone Substitutes
      • 23.6.3 Collagen as Bioengineered Tissues
      • 23.6.4 Collagen Constructs and Synthetic Collagenous Peptide Polymers
      • 23.6.5 Computational Model for Collagen in Tissue Engineering
    • 23.7 COLLAGEN FILM AS A CALCIFIABLE MATRIX SYSTEM: AN EXAMPLE OF THE FORMULATION DEVELOPMENT
      • FIGURE 23.3 The effect of elastin and ethanol (80%) pretreatment on the calcification rate of CEM and porcine aortic walls implanted in the rat subcutaneous model for 7 days (N = 6) [235].
      • TABLE 23.3 The Tensile Strength of the Collagen Elastin Matrix (CEM) Containing Various Combinations of Collagen and Elastin [235]
    • 23.8 CONCLUSION
    • ASSESMENT QUESTIONS
    • REFERENCES
  • 24 MOLECULAR IMAGING OF DRUG DELIVERY
    • 24.1 CHAPTER OBJECTIVES
    • 24.2 INTRODUCTION
      • TABLE 24.1 Characteristics and Applications of Commonly Used Imaging Modalities
    • 24.3 IMAGING MODALITIES
      • 24.3.1 Ultrasound Imaging
      • 24.3.2 Magnetic Resonance Imaging
      • 24.3.3 Optical Imaging
      • 24.3.4 X-Ray Computed Tomography
      • 24.3.5 Single-Photon Emission Computed Tomography
      • 24.3.6 Positron Emission Tomography
    • 24.4 MOLECULAR IMAGING OF DRUG DELIVERY
      • 24.4.1 Molecular Imaging of Intracellular Drug Delivery
        • FIGURE 24.1 The binding of the OV-TL16 antibody to the cell surface of human ovarian carcinoma OVCAR-3 cells. Fluorescence images show the upper cell surface (a) and an optical section through the bottom part (b) of a cluster of cells, and an optical section through the lower middle region of mitotic cells (c). Bar: 5 μm. Adapted from Ref. 75.
        • FIGURE 24.2 Confocal images of Hep G2 cells at 15 min (left), 60 (middle) min, and 24 h (right) after cytoplasmic injection of fluorescein-labeled HPMA co-polymers. Adapted from Ref. 76.
        • FIGURE 24.3 Confocal fluorescence images of OVCAR-3 human ovarian cancer cells after 6 h of incubation at 37°C with the OV-TL16 antibody Fab′ fragment targeted pHPMA-Mce6 conjugate (left) and pHPMA-Mce6 conjugate (right) based on the intrinsic fluorescence of Mce6.
      • 24.4.2 Molecular Imaging of In Vivo Drug Delivery
        • FIGURE 24.4 Three-dimensional MIP MR images of mice bearing MDA-MB-231 human breast carcinoma xenografts injected with pHPMA-GFLG-(Gd-DOTA monoamide) conjugates with molecular weights of 28, 60, and 121 kDa before contrast and at various time points after the injection of the conjugates at a dose of 0.03 mmol-Gd/kg. Arrows are pointing to the liver (1), heart (2), and tumor (3). Bright signal in the blood and the fluid of the urinary bladder indicates a high concentration of the conjugate. The bright signal from the stomach and intestine is from the food and fluid. Adapted from Ref. 27.
        • FIGURE 24.5 Color-coded 2D axial spin-echo MR images of mice injected with pHPMA-GFLG (Gd-DOTA monoamide) conjugates with molecular weights of 28, 60, and 121 kDa before contrast and at various time points after the injection of the conjugates at a dose of 0.03 mmol-Gd/kg. The color distribution represents the accumulation and distribution of the conjugates. Adapted from Ref. 27.
        • FIGURE 24.6 Whole body SPECT images of 123I-labeled galactosamine targeted pHPMA-DOX conjugate (PK2) of a patient acquired at 4 h (posterior view) and 4, 24, and 48 h (anterior view) after the end of infusion. The bright signal indicates the concentration of the conjugate. Adapted from Ref. 79.
    • 24.5 IMAGING THERAPEUTIC EFFICACY OF DRUG DELIVERY SYSTEMS
      • 24.5.1 Bioluminescence Imaging of In Vivo Transfection Efficiency of Nucleic Acids
        • FIGURE 24.7 Dynamic bioluminescence images of an A/J mouse bearing Neuro2a tumor xenograft at different days after intravenous injection of pCpG-hCMV-Luc/PAMAM G5 polyplexes. Blue color represents the lowest intensity and red for the highest intensity. Adapted from Ref. 115.
        • FIGURE 24.8 Color-coded bioluminescence images of a group of mice with constitutive expression of luciferase in the liver before and after the treatment with a lipid nanoparticle of antiluciferase siRNA at 3 mg/kg. Blue color represents the lowest intensity and red for the highest intensity. Adapted from Ref. 123.
      • 24.5.2 Therapeutic Efficacy Evaluation with PET
      • 24.5.3 Therapeutic Efficacy Evaluation with Dynamic Contrast Enhanced (DCE) MRI
        • FIGURE 24.9 Tumor volume and normalized tumor growth percentage relative to the tumor size of the day 20 (inset) before and after treatment with Avastin (a) and dynamic signal changes in the tumor before and after the treatment measured by DCE-MRI with (Gd-DTPA)-cystamine co-polymers (40 kDa, b) and Gd(DTPA-BMA) (c). Treatment was started on the day 22 by intraperitoneal administration of Avastin at a dose of 200 μg/mouse every 2 days in 6 days. 1: First treatment; 2: second treatment; 3: third treatment. Tumor growth was temporarily arrested by initial administration of Avastin and then resumed at a slower rate even after the second and third administrations. Adapted from Ref. 102.
        • FIGURE 24.10 The vascular parameters Ktrans (a) and fPV (b) for GDCC-40 and Gd(DTPA-BMA) before and after Avastin administration calculated from the DCE-MRI data in Figure 24.9b and c. *p < 0.05. Ktrans = endothelial transfer coefficient (mL of plasma/mL of tissue/min), fPV = fractional vascular volume (mL of plasma/mL of tissue). Adapted from Ref. 102.
    • 24.6 THERANOSTICS
      • FIGURE 24.11 Structure of PEG-PGA-(Gd-DOTA monoamide)-Mce6 conjugate.
      • FIGURE 24.12 Three-dimensional MIP MR images of the mice bearing MDA-MB-231 breast tumor xenografts showing the biodistribution of PEG-PGA-(Gd-DO3A)-Mce6 (top panel), PGA (Gd-DO3A)-Mce6 (middle panel), and PGA-(Gd-DO3A) (bottom panel) before (a) and at 2 min (b), 5 min (c), 15 min (d), 30 min (e), 2 h (f), and 18 h (g) postinjection at a dose of 0.05 mmol-Gd/kg. Bright signal in the blood and the fluid of the urinary bladder indicates a high concentration of the conjugate. The bright signal from the stomach and intestine is from the food and fluid. Adapted from Ref. 153.
      • FIGURE 24.13 The signal-to-noise ratio (SNR) in the tumor of the mice bearing MDA-MB-231 breast tumor xenografts indicating the tumor concentration of PEG-PGA-(Gd-DO3A)-Mce6, PGA (Gd-DO3A)-Mce6, and PGA-(Gd-DO3A) after the IV injection of the conjugates at a dose of 0.05 mmol-Gd/kg. Adapted from Ref. 153.
      • FIGURE 24.14 (a) Tumor growth curve, the percentage increase in relative tumor size, for the mice bearing MDA-MB-231 breast tumor xenografts after photodynamic treatments at 18 and 24 h postinjection of PEG-PGA-(Gd-DO3A)-Mce6, PGA-(Gd-DO3A)-Mce6 at a Mce6 equivalent dose of 6.0 mg/kg, and PGA-(Gd-DO3A), at a dose of 0.045 mmol-Gd/kg. (b) Relative signal intensity plots of the DCE-MRI data showing the dynamic uptake of (Gd-DTPA)-cystine co-polymers in tumor periphery, which is rich of angiogenic blood vessels, of tumor bearing mice after PDT with the conjugates. Adapted from Ref. 153.
    • 24.7 SUMMARY
    • ASSESSMENT QUESTIONS
    • REFERENCES
• Back Mattter
  • ANSWERS
    • CHAPTER 1
    • CHAPTER 2
    • CHAPTER 3
    • CHAPTER 4
    • CHAPTER 5
    • CHAPTER 6
    • CHAPTER 7
    • CHAPTER 8
    • CHAPTER 9
    • CHAPTER 10
    • CHAPTER 11
    • CHAPTER 12
    • CHAPTER 13
    • CHAPTER 14
    • CHAPTER 15
    • CHAPTER 16
    • CHAPTER 17
    • CHAPTER 18
    • CHAPTER 19
    • CHAPTER 20
    • CHAPTER 21
    • CHAPTER 22
    • CHAPTER 23
    • CHAPTER 24
  • INDEX

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