NANOPARTICLESfor

PHARMACEUTICALAPPLICATIONS

Edited by

Abraham J. DombThe Hebrew University of Jerusalem, Jerusalem, Israel

Yasuhiko TabataKyoto University, Kyoto, Japan

M. N. V. Ravi KumarNational Institute of Pharmaceutical Education and Research,Punjab, India

Shimon FarberThe Hebrew University of Jerusalem, Jerusalem, Israel

ASPAMERICAN SCIENTIFIC PUBLISHERS

25650 North Lewis WayStevenson Ranch, California 91381-1439, USA

ContentsPreface vAbout the Editors xxiList of Contributors xxiii

CHAPTER 1. Liposomes for Drug DeliveryPierre Simard, Jean-Christophe Leroux, Christine Allen, and Olivier Meyer

1. General Introduction 22. Lipids and Polymorphisms 3

2.1. Materials 32.1.1. Phospholipids 32.1.2. Sphingolipids 52.1.3. Sterols 62.1.4. Polymer-bearing Lipids 72.1.5. Cationic Lipids 8

2.2. Lipid Selection 82.3. Polymorphisms 9

3. Liposome Preparation Methods 93.1. Nomenclature Used to Describe Liposomes 93.2. Vesicle Preparation 10

3.2.1. Lipid Film Hydration 113.2.2. Sonication 113.2.3. Shearing of Lyotropic Lamellar Phase 113.2.4. Extrusion 113.2.5. Solvent Injection Method 113.2.6. Reverse Phase Evaporation 123.2.7. Microfluidisation 123.2.8. Dehydration-rehydration 133.2.9. Detergent Removal 13

3.3. Drug Loading 133.3.1. Passive loading 133.3.2. Remote Loading 13

3.4. Industrial Manufacturing 134. Analytical Techniques 14

4.1. Photon Correlation Spectroscopy 144.2. Gel Chromatography 144.3. Microscopy 144.4. Fluorescence Spectroscopy 154.5. Nuclear Magnetic Resonance Spectroscopy 154.6. Fourier Transform Infrared Spectroscopy 164.7. Small-angle X-ray and Neutron Scattering 164.8. Other Techniques 17

5. Stability and Stabilization of Liposome Formulations 175.1. Chemical Stability of Liposome Formulations 175.2. Physical or Colloidal Stability of Liposomes 18

5.2.1. Conventional versus Sterically Stabilized Liposomes 185.2.2. Physico-chemical Properties of PEG 195.2.3. Conformation of PEG at the Surface of Lipid Membranes 195.2.4. Effect of PEG on the Material Properties of Lipid Membranes 20

V I I

viii Content

5.2.5. Influence of PEG on the Pharmacokinetic Parameters of Liposomes 215.2.6. Blood Clearance of PEGylated Liposomes on Repeated Injection 21

5.3. Drug Retention Properties of Liposome Formulations 226. Triggered Release 22

6.1. Light 236.2. Temperature 236.3. pH 246.4. Enzymes 25

7. Medical Applications 267.1. Cancer 26

7.1.1. Passive Targeting 287.1.2. By-Passing of P-glycoprotein 327.1.3. Tumor Cells Targeting 337.1.4. Tumor Vasculature Targeting 35

7.2. Infectious Diseases 367.2.1. Parenteral Antifungals 367.2.2. Parenteral Antibiotics and Antivirals 37

7.3. Rheumatoid Arthritis 387.3.1. Corticosteroids 387.3.2. Folic Acid Antagonists 397.3.3. Biophosphonates 397.3.4. Antioxidant Enzymes 39

7.4. Pulmonary Route and Treatment of Respiratory Disorders 407.4.1. Anatomy and Physiology of Lungs 407.4.2. Treatment of Asthma 417.4.3. Pulmonary Route for Systemic Drug Delivery 41

7.5. Topical and Transdermal Drug Delivery 427.5.1. Interaction of Liposomes with the Skin 427.5.2. Treatment of Skin Disease 437.5.3. Transdermal Drug Delivery 44

7.6. Ophthalmic Disorders 447.7. Other Administration Routes 45

7.7.1. Oral and Buccal Delivery 457.7.2. Nasal Delivery 457.7.3. Vaginal Delivery 46

8. Other Medical Applications 468.1. Diagnostics 468.2. Vaccine 47

9. Nonmedical Applications 479.1. Biomembranes and Membrane Proteins 479.2. Cosmetics 479.3. Food Industry 48

10. Concluding Remarks and Perspectives 49References 51

CHAPTER 2. Polymeric Micelles as NanosizedDrug Carrier SystemsMasayuki Yokoyama

1. Polymeric Micelles as Drug Carriers 631.1. What are Polymeric Micelles for Drug Delivery? 631.2. Advantages of Polymeric Micelle Drug Carriers 64

Content ix

2. Strategies for Tumor Targeting Using Polymeric Micelles 652.1. Passive Targeting 65

2.1.1. Classification of Targeting Methodology 652.1.2. EPR Effect 66

2.2. Thermo-responsive Polymeric Micelles 663. Examples of Drug Targeting with Polymeric Micelles 67

3.1. Adriamycin (Doxorubicin) 673.2. KRN-5500 683.3. Cisplatin 693.4. Taxol 693.5. Amphotericin B 693.6. Methotrexate 693.7. Camptothecin 69References 70

CHAPTER 3. Characterization of Novel Intranasal Sustained-Release Nanoparticles for Delivery of Neuropeptidesto the BrainMichael J. Kubek, Michael Yard, Debomoy K. Lahiri, and Abraham J. Domb

1. Introduction: Neuropeptides, their Delivery and Role in the Central NervousSystem (CNS) 74

2. Nanoparticles: A Novel Way to Deliver Neuropeptides into the Brain 743. Major CNS Terminations of the Olfactory Pathway 75

3.1. Neuroanatomy of the Human Nasal Cavity 753.2. Important Sites of Nanoparticle Uptake in the Nasal Cavity 76

4. Neuronal Pathways of Olfactory Transduction and Transneuronal Transport 764.1. Neuronal Transport 764.2. Transneuronal Transport 77

5. Barriers to Intranasal Neuropeptide Uptake 786. Difficulties in Neuronal and Transneuronal Neuropeptide Delivery 787. Issues Related to Transported Neuropeptide Release 798. Intranasal Delivery of TRH to the Brain as a Neuropeptide Prototype 799. Strategies to Reduce Obstacles in the Intranasal Delivery on Neuropeptides:

Lessons from TRH Studies 7910. Analysis of Capsular Carriers and Delivery Mechanism 8011. Testing the Efficacy and Toxicity of Sustained-Release Carriers in a Cell Culture Model . . . . 8112. Advantages of Surface-eroding Polymeric Formulation on Bioavailability to the

Receptor Neuron for Uptake and Transport Via the Olfactory Pathway 8112.1. Bioavailability and Mucosal Barriers 8112.2. Bioavailability During Neuronal Transport and Release 81

13. Clinical Applications for Intranasal Neuropeptide Delivery Particularly inNeurological Disorders 82

14. Conclusions 83References 83

CHAPTER 4. The Impact of Surface Charge onNanoparticle PerformanceOshrat Harush, Yoram Altschuler, and Simon Benita

1. Introduction 852. ^-Potential Theory and Calculation 86

Content

3. ^-Potential Formulative Aspects 873.1. Nanoparticle Composition 87

3.1.1. Drug Loading 883.1.2. Nanoparticle Surface Modifications 88

3.2. Nanoparticle Preparation Techniques 903.2.1. Polymerization of Monomers 903.2.2. Dispersion of Preformed Polymers 91

4. In Vitro and In Vivo Performance 924.1. Mucoadhesion 934.2. Interaction with MPS 944.3. Implications of Surface Charge in Pulmonary Delivery 95

4.3.1. Modeling the Respiratory Deposition of Charged Nanoparticles 954.3.2. Gene Delivery to the Lungs 96

5. Concluding Remarks 98References 99

CHAPTER 5. Lipid Nanoparticles (SLN and NLC)for Drug Delivery

Eliana B. Souto and Rainer H. Miiller

1. Introduction 1032. Drug Incorporation into SLN and NLC 104

2.1. Models of Drug Incorporation into SLN 1042.2. Models of Drug Incorporation into NLC 106

3. Materials and Methods for Production of SLN and NLC 1063.1. Materials 1063.2. Methods 106

3.2.1. High Pressure Homogenization Technique 1063.2.2. Microemulsion-Based SLN Preparation 1093.2.3. Solvent Emulsification-evaporation Technique 1103.2.4. Solvent Displacement Technique I l l3.2.5. Emulsification-diffusion Technique I l l

4. Therapeutical Applications of SLN and NLC 1124.1. Parenteral Delivery 1124.2. Oral and Peroral Delivery 1134.3. Pulmonary Delivery 1144.4. Ocular Delivery 1154.5. Topical, Dermal and Transdermal Delivery 1154.6. SLN for Gene Therapy 1164.7. SLN as New Adjuvants for Vaccines 117

5. Conclusions 117References 117

CHAPTER 6. Nanoparticles for the Treatment of RestenosisE. Cohen-Sela, M. Chorny, and G. Golomb

1. Introduction 1231.1. Restenosis 1231.2. Nanoparticles (NP) 1241.3. Nanoparticles in the Treatment of Restenosis 125

2. Local Drug Delivery for Restenosis 125

Content

2.1. Antisense 1252.2. Tyrphostins 1262.3. Dexamethason 126

2.4. 2-Aminochromone U-86893 (U86) 1272.5. Effect of Formulation Characteristics and Delivery Conditions on

Arterial Uptake 1283. Systemic Drug Delivery 129

3.1. Doxorubicin 1293.2. Paclitaxel (PXL) 1293.3. Bisphosphonates 130

4. Summary 130References 131

CHAPTER 7. Polysaccharide-Based Nanoparticles as Carriers forDrug and Vaccine DeliveryMaria Jose Alonso, Cecilia Prego, and Marcos Garcia-Fuentes

1. Introduction 1362. The Special Characteristics of Polybiosaccharides 1363. Polysaccharide-based Nanoparticles: Preparation Techniques and

Pharmaceutical Characteristics 1373.1. Nanomatrix-Type Systems 138

3.1.1. Chitosan Nanoparticles 1383.1.2. Nanoparticles made of Chitosan and Other Oligo- and Polysaccharides 139

3.2. Nanocore-Coated-Type Systems 1413.2.1. Chitosan-coated Lipid Nanoparticles 1413.2.2. Chitosan Nanocapsules 142

4. Biopharmaceutical Applications of Polysaccharide-based Nanoparticles 1424.1. Ocular Administration 143

4.1.1. Chitosan Nanoparticles 1434.1.2. Chitosan Nanocapsules 1434.1.3. Mechanism of Action 143

4.2. Nasal Administration 1444.2.1. Chitosan Nanoparticles 1444.2.2. Chitosan Nanocapsules 1444.2.3. Mechanism of Action 144

4.3. Oral Administration 1454.3.1. Chitosan Nanoparticles 1454.3.2. Chitosan-Glucomannan Nanoparticles 1454.3.3. Chitosan Nanocapsules 1454.3.4. Chitosan-Coated Lipid Nanoparticles 1464.3.5. Mechanism of Action 146

5. Conclusions 146References 147

CHAPTER 8. Nanotechnology: Implications For AntitubercularChemotherapyRajesh Pandey and G. K. Khuller

1. Introduction 1512. Tuberculosis: The Need for Antitubercular Drug Delivery Systems 1523. Nanotechnology and Tuberculosis 153

xii Content

3.1. Studies with Oral ATD-PLG-NP 1543.2. Pulmonary Delivery of ATD-PLG-NP 1583.3. Studies with Injectable ATD-PLG-NP 161

4. Alginate-Based Antitubercular Drug Delivery Systems 1615. Solid Lipid Nanoparticles as Antitubercular Drug Delivery Systems 1646. Summary 164

References 165

CHAPTER 9. Lymphatic Absorption of NanoparticlesPavel Gershkovich, Leonid Kagan, and Amnon Hoffman

1. Introduction 1672. Anatomy and Physiology of the Lymphatic System 1673. Lymphatic Uptake of Nanoparticles from Gastrointestinal Tract 168

3.1. Mechanism of the Intestinal Lymphatic Uptake 1683.2. Utilization of Orally Administered Nanoparticles for Diagnostic and

Therapeutic Purposes 1703.3. Oral Nanoparticles for Immunization Purposes 171

4. Intravenous Administration of Nanoparticles for Lymphatic Uptake 1725. Absorption of Nanoparticles into the Lymphatic System Following

Subcutaneous Administration 173References 175

CHAPTER 10. Carbon Nanotubes: Role in Health CareLalit M. Bharadwaj and Vijayender Bhalla

1. Basics of Carbon Nanotubes 1771.1. Structure 1781.2. Synthesis 1781.3. Properties 1791.4. Functionalization and Assembly 180

2. Applications to Health Care 1812.1. Biosensing 181

2.1.1. DNA Detection 1822.1.2. Glucose Sensor 183

2.2. Medical Imaging 1842.3. Nanoprobing 1842.4. Drug Delivery 1852.5. Treatment of Diseases 186

2.5.1. Cancer Treatment 1862.5.2. Healing Broken Bones 187

3. Conclusion 188References 188

CHAPTER 11. Nanoparticles Aiming at Specific Targets—Dermaland Transdermal DeliveryBiana Godin and Elka Touitou

1. Introduction 1922. Skin Structure 1923. Nanoparticulate Systems for Delivery of Active Molecules to the Skin Surface

and Superficial Layers 194

Content

3.1. Liposomes 194

3.1.1. Composition and Characteristics 1943.1.2. Liposomes for Delivery of Active Agents to the Upper Skin Layers 195

3.2. Solid Lipid Nanoparticles (SLN) 1963.2.1. Composition and Characteristics 1963.2.2. SLN for Delivery of the Active Agents to the Upper Skin Layers

or for Prevention of Skin Penetration 1973.3. Polymeric Nanoparticles 197

3.3.1. Composition and Characteristics 1973.3.2. Delivery of the Active Agents to the Upper Skin Layers from

Polymeric Particles 1983.4. Niosomes 198

3.4.1. Composition and Characteristics 1983.4.2. Niosomes for Delivery of Drugs to the Upper Skin Layers 199

4. Nanoparticulate Systems for Enhanced Dermal and Percutaneous Absorption 2004.1. Ethosomes 201

4.1.1. Composition and Characteristics 2014.1.2. Mechanism of Permeation Enhancement by Ethosomes 2024.1.3. Deep Dermal Delivery from Ethosomes 2034.1.4. Ethosomes as Carriers for Enhanced Percutaneous Absorption 206

5. Conclusions 208References 208

CHAPTER 12. Recent Advances in Poly(alkylcyanoacrylate)Nanoparticles for Drug DeliveryElias Fattal, Karine Andrieux, Gillian Barratt, Patrick Couvreur,Denis Labarre, Gilles Ponchel, and Christine Vauthier

1. Introduction 2142. Synthesis of Poly(alkylcyanoacrylate) Derivatives and Copolymers 2143. Toxicity, Biocompatibility, and Biodegradation of Poly( alky Icy anoacrylates) 2154. Preparation of Nanoparticles 216

4.1. Preparation of Nanospheres by Emulsion Polymerization of Alkylcyanoacrylates 2164.2. Preparation of Nanospheres by Precipitation of a Polymer 2164.3. Preparation of Surface-modified Nanoparticles 2174.4. Preparation of Nanocapsules by Interfacial Polymerization 218

5. Applications of Poly(alkycyanoacrylate) Nanoparticles by the Intravenous Route 2205.1. Fate of Nanoparticles and Their Content After Intravenous Administration 2205.2. Application to the Treatment of Intracellular Infections 2205.3. Application to the Treatment of Cancer 2215.4. Application to the Delivery' of Antisense Oligonucleotides (AON) 2235.5. Application to Brain Delivery 224

5.5.1. Coated Nanoparticles 2245.5.2. Pegylated Nanoparticles 226

6. Applications of PACA Nanoparticles by the Oral Route 2266.1. Translocation of Poly(alkylcyanoacrylate) Nanoparticles Through the

Intestinal Mucosa 2276.2. Bioadhesion of Poly(alkylcyanoacrylate) Nanoparticles and Their

Gastro-intestinal Transit 2276.3. Modulation of Drug Absorption and Bioavailability by Poly

(alkylcyanoacrylate) Nanoparticles 2286.4. Targeting of Gut-Associated Lymphoid Tissues and Access to the Lymph 229

7. Conclusion 229References 229

xiv Content

CHAPTER 13. Dendrimers and Hyperbranched Nanospheres withMedical ApplicationsSonke Svenson and Donald A. Tomalia

1. Introduction 2332. Synthetic Protocols 2343. Dendrimers as Artificial Proteins 2354. Nanoscale Containers 2375. Carrier Properties 239

5.1. Gene Transfection 2395.2. Drug Delivery 242

6. Imaging Agents 2456.1. Magnetic Resonance Imaging 2456.2. In Vivo Oxygen and Computed Tomography Imaging 247

7. Multifunctional Nanoscaffolds 2477.1. Folic Acid Ligands 2477.2. Carbohydrate Ligands 2487.3. Penicillin Ligands 2497.4. Antibodies and Biotin-Avidin Binding 249

8. Dendrimers as Nano-Drugs 2499. Triggered Dendrimer Disassembly 25010. Biocompatibility Studies 25111. Conclusions 252

References 252

CHAPTER 14. Nanoparticles of Biodegradable Polymersfor Cancer ChemotherapySi-Shen Feng, Priscilla Pui Sze Lee, and Khin Yin Win

1. Cancer and Cancer Chemotherapy 2581.1. Cancer and Cancer Treatments 2581.2. Cancer Chemotherapy 258

2. Nanoparticle Technology for Drug Formulation 2592.1. Biodegradable Polymers 2592.2. Nanoparticle Technology 260

2.2.1. Dispersion of Polymers 2602.2.2. Polymerization of Monomers 2612.2.3. Crosslinking of Amphiphilic Macromolecules 261

3. Nanoparticle Characterization 2613.1. Size and Size Distribution 2613.2. Drug Encapsulation Efficiency 2613.3. Surface Morphology 2623.4. Surface Charge 2633.5. Surface Chemistry 2633.6. Physical State of Drug Trapped in Nanoparticles 264

4. In vitro Drug Release 2655. Cell Line Experiments 266

5.1. In Vitro Cellular Uptake of Nanoparticles 2665.2. In Vitro Cell Viability 268

6. Animal Test 2687. Conclusions 269

References 270

Content XV

CHAPTER 15. Oral Drug DeliveryV; Bhardwaj and M. N. V. Ravi Kumar

1. Introduction 2742. Physiology of the Gastrointestinal Tract 274

2.1. Particle Uptake Pathways 2742.2. Mechanisms of Uptake 275

3. Adhesion to Biosurfaces 2754. Surface Characteristics of Nanoparticles 2765. Particle Size 2766. Models to Study Particle Uptake 2777. Detection and Imaging 277

7.1. Radiotracers 2777.2. Microscopy Techniques 2777.3. Spectroscopy 278

8. Formulation Issues 2788.1. Polymers for Nanoparticle Matrix 2788.2. Stabilizers 2798.3. Freeze drying 2798.4. Sterility 2808.5. Dose 2808.6. Dosage Form 2808.7. Drug Release, Stability and Storage 281

8.7.1. Drug Release 2818.7.2. Degradation Studies 2818.7.3. Storage 281

9. Applications 2829.1. Antigen Delivery 2829.2. Targeted Drug Delivery 2829.3. Local Delivery to the Colon 2839.4. Increase in Oral Bioavailability 283

10. Future Directions 284References 284

CHAPTER 16. Polyester Nano- and Microparticles by Polymerizationand by Self-Assembly of MacromoleculesStanislaw Slomkowski

1. Introduction 2882. Poly(e-Caprolactone) and Polylactide Nano- and Microspheres Formed

During Polymerization 2892.1. Design of Particle Synthesis 2892.2. Polymeric Stabilizers Used for Synthesis of Poly(e-Caprolactone) and

Polylactide Particles 2902.3. Examples of Recipes for Synthesis of Poly(B-CaproIactonc) and

Polylactide Particles 2902.3.1. Synthesis of Poly(e-Caprolactone) Particles 2902.3.2. Synthesis of Poly(D.L-lactide) Particles 290

2.4. Initiators Used in Dispersion Polymerization of r-Caprolactonc and Lactides 2922.5. Mechanism of Particle Formation in Dispersion Polymerization of

e-Caprolactone and Lactides 2922.6. Kinetics of Dispersion Polymerization of e-Caprolactone 2932.7. Diameters of Particles Formed During Dispersion Polymerization 294

xvi Content

2.8. Diameter Distributions of Particles Formed During Dispersion Polymerization 2952.9. Poly(L,L-lactide) Particles With Controlled Crystallinity 2952.10. Transfer of Polyester Particles from Hydrocarbons to the Water-based Media 296

3. Nanoparticles Formed by Self-Assembly of Copolymers With Polyester Blocks 298

4. Nano- and Microparticles with Bioactive Compounds 3004.1. Adsorption of Bioactive Compounds onto Surface of Synthesized Particles 3004.2. Swelling of Particles with Bioactive Compounds 3004.3. Particles with Bioactive Compounds Bound Covalently to Polymers

During Particle Synthesis 3014.4. Physical Incorporation of Bioactive Compounds onto Growing Particles

During Particle Synthesis 3014.5. Self-Assembly of Copolymer Macromolecules and Bioactive Compounds

into Nanoparticles 302

References 302

CHAPTER 17. Nanostructured Polycation Materials forGene Delivery/. Yudovin-Farber and A. J. Domb

1. Introduction 3062. Gene Delivery Systems 3063. DNA Condensation 3064. Cellular Trafficking 306

5. Cationic Nonviral Vectors 3075.1. Polylysine 3075.2. Polyethyleneimine 3075.3. Polyamidoamines 3095.4. Polyaminomethacrylates 3105.5. Chitosan 310

5.5.1. Chitosan Derivatives 3116. Diethylaminoethyl-Dextran 3117. Polysaccharide-Oligoamine Based Conjugates 312

7.1. Synthesis of Dextran-Spermine Based Conjugates 312

7.2. In Vitro Transfection of Dextran-Spermine Based Conjugates 3127.3. In Vivo Mediated Transfection Applying Dextran-Spermine Vector as Gene Carrier . . . . 314References 316

CHAPTER 18. Toxicity Issues Related to Nanoparticulate SystemsRajendra P. Pawar, Sudhakar R. Bhusare, Ravikumar M. Borade, YeshwantB. Vibhute, and Abraham J. Domb

1. Introduction 320

1.1. Effects of Nanoparticle Exposure 3211.1.1. Respiratory Exposure 321

1.1.2. Exposure Through Ingestion 3211.1.3. Dermal Exposure 321

1.2. Effects of Envirnomental Exposure 3211.3. Significance of Nanoscale 321

1.4. Different Nature of Nanoparticles 3221.4.1. Carbon nanotubes 3221.4.2. Fullerenes 322

Content x v j j

1.4.3. Nanodots 122

1.4.4. Carbon nanofoam 3221.4.5. Carbon Nanoshells 322

2. Effects on Human Health 3222.1. Inhalation Effects on the Respiratory Tract 322

2.1.1. Systemic Effects 3232.1.2. Toxicity to the Respiratory Tract Exposure 323

2.2. Dermal Local Effects 3252.2.1. Dermal Uptake 3252.2.2. Systemic Effects 3252.2.3. Irritation of Skin 326

2.3. Blood-Brain Barrier Effects 3262.3.1. Systemic Effects 3262.3.2. Toxicity to Blood Brain Barriers Exposure 327

3. Differences or Similarities in Nanoparticles Toxicity 3283.1. Inhalation Exposure 328

3.1.1. Different Particle Surface Activities 3283.1.2. Differences in Disagglomeration 3283.1.3. Systemic Effects 329

3.2. Dermal Exposure 3294. Other Novel Nanoparticles 329

4.1. Effect of Nanoparticles on Endothelial Cells 3294.2. Effect of Solid-Lipid Naoparticles 3304.3. Effect of CdSe and CdSe/ZnS Nanoparticles 3304.4. Effect of Magnetic Nanoparticles 3304.5. Effect of Magnetic Fluids 330

5. Conclusions 3316. Recommendations 331

References 331

CHAPTER 19. Nanoparticles for Respiratory Drug DeliveryR. Banerjee

1. Introduction 3362. Aerodynamic Diameter and Lung Deposition 336

2.1. Airway Anatomy 3372.2. Mass Median Aerodynamic Diameter 3372.3. Patient and Device Factors 337

3. Advantages of Nanoparticles for Respiratory Drug Delivery 3384. Effect of Inhalation Devices on Nanoparticle Aggregation 338

4.1. Inhalation Devices 3384.2. Nanoparticle Aggregation 339

5. Preventing Nanoparticle Aggregation: Role of Surfactants 339

6. Pulmonary Surfactant Nanoparticles 339

6.1. Role of Pulmonary Surfactant 3396.2. Anatomy of Type II Alveolar Cells and Surfactant Secretion 3406.3. Need for Nanoparticulate Forms of Surfactant 340

7. Drug Loaded Surfactant Nanoparticles 341

8. Cellular Uptake of Nanoparticles 3429. Nonviral Respiratory Gene Delivery 342

9.1. Need for Respiratory Gene Delivery 3429.2. Barriers for Respiratory Gene Delivery 342

xviii Content

10. Nanoparticulate Respiratory Vaccines 34310.1. Anatomy of Nasal Lymphoid Tissue 34310.2. Nanoparticulate Respiratory Vaccines 343

11. Mucoadhesive Nanoparticles for Tracheobronchial Deposition 34311.1. Mucociliary Clearance 34311.2. Biochemistry of Respiratory Mucus 34311.3. Mucoadhesive Nanoparticles 344

12. Cytoadhesive Nanoparticles for Alveolar Drug Delivery 34413. Nanoparticles for Systemic Delivery through the Respiratory Route 344

13.1. Alveolo-Capillary Membrane Anatomy 34413.2. Alveolar Clearance Via Macrophages 34513.3. Enzymatic Degradation in the Lungs 34513.4. Nanoparticles for Inhalable Peptide Delivery 345

14. Safety Concerns 34615. Summary and Future Scope 346

References 346

CHAPTER 20. Surface Modification of NanoparticulateDrug CarriersVladimir P. Torchilin

1. Why Do We Need Carrier Surface Modification? 3492. Attaching Various Ligands to the Surface of Pharmaceutical Nanocarriers 3503. Polymers for Longevity 351

3.1. Long-Circulating Liposomes 3523.2. Alternative Polymers for Steric Protection 3523.3. Polymer-Modified Nanoparticles 353

4. Ligands for Targeting: Combination with Protecting Polymers 3554.1. Polymer-Protected Targeted Nanocarriers 3554.2. Antibody-Mediated Targeting 3564.3. Transferrin-Mediated Targeting 3574.4. Folate-Mediated Targeting 3574.5. Other Ligands 357

5. Ligands for Intracellular Delivery of Nanocarriers 3586. Labels for Visualization 359

References 361

CHAPTER 21. Nanoparticles in Ocular Drug DeliveryEsther Eljarrat-Binstock and Abraham J. Domb

1. Introduction 3671.1. Conventional Dosage Forms and Festrictions 3671.2. New Ocular Drug Delivery Systems 3681.3. Nanoparticles: Definition and Advantages 368

2. Penetration and Distribution of Nanoparticles in the Eye 3693. Polymers Used in Particulate Ocular Delivery 3694. Ocular Applications of Drug-Loaded Nanoparticles 371

4.1. Glaucoma 3714.2. Ocular Inflammation 3724.3. Ocular Infections 3724.4. Immunotherapy 373

Content xix

5. Biodegradation and Toxicity 1736. Conclusions 374

References 374

CHAPTER 22. Gelatin-based NanomicellesToshihiro Kushibiki and Yasuhiko Tabata

1. Introduction 3771.1. Polyethylene glycol (PEG) for Drug Delivery 3771.2. Feasibility of Gelatin for Drug Delivery 378

2. PEG Grafting of Gelatin for a Micelle Formulation 3782.1. Preparation and Characterization of PEG-gelatin Micelle 3782.2. Body Distribution Studies of PEG-gelatin and the Pharmacokinetics

Analysis 3803. PEG-Cationized Gelatin as a Nonviral Gene Carrier 380

3.1. Preparation and Characterization of PEG-Cationized Gelatin 3803.2. In vivo Assessment of Gene Expression Following Injection of

PEG-Cationized Gelatin-Plasmid DNA Complexes 381References 382

Index 3S5