NanoparticulatesDrug Carriers

EDITOR

VLADIMIR P TORCHILINNortheastern University, USA

Imperial College Press

Contents

Contributors v

1. Introduction. Nanocarriers for Drug Delivery: Needs and Requirements 1

Vladimir Torchilin

References 6

2. Nanoparticle Flow: Implications for Drug Delivery 9

Alexander T. Florence

1 Introduction 9

2 Background 113 Studies on Nanoparticle Flow 134 Convection and Diffusion 135 Bifurcations 156 Interaction with Blood Constituents and Endogenous Molecules . . 167 Nanoparticles with Surface Ligands 188 Deposition on Surfaces and Attachment to Receptors in Flow

Conditions 189 Does Shape Matter? 2010 Speculations on Flow and the EPR Effect 2111 Intra-tumoral Injection 2212 Conclusions 23References 24

3. Polymeric Nanoparticles as Drug Carriers and Controlled ReleaseImplant Devices 29

SM Moghimi, E Vega, ML Garcia, OAR Al-Hanbali and KJ Rutt

1 Introduction 29

XIII

xiv Contents

2 Nanoparticle Engineering 302.1 Drug release mechanisms 32

3 Site-specific Targeting with Nanoparticles: Importance of Sizeand Surface Properties 33

4 Conclusions 37References 38

4. Genetic Vaccines: A Role for Liposomes 43

Gregory Gregoriadis, Andrew Bacon, Brenda McCormack and Peter Laing

1 Introduction 432 The DNA Vaccine 443 DNA Vaccination via Liposomes 45

3.1 Procedure for the entrapment of plasmid DNA intoliposomes 46

3.2 DNA immunization studies 473.3 Induction of a cytotoxic T lymphocyte (CTL) response by

liposome-entrapped plasmid DNA 50

4 The Co-delivery Concept 51References 53

5. Polymer Micelles as Drug Carriers 57

Elena V. Batrakova, Tatiana K. Bronich, Joseph A. Vetro and

Alexander V. Kabanov

1 Introduction 57

2 Polymer Micelle Structures 582.1 Self-assembled micelles 582.2 Unimolecular micelles 612.3 Cross-linked micelles 62

3 Drug Loading and Release 633.1 Chemical conjugation 633.2 Physical entrapment 643.3 Polyionic complexation 66

4 Pharmacokinetics and Biodistribution 685 Drug Delivery Applications 72

5.1 Chemotherapy of cancer 725.2 Drug delivery to the brain 765.3 Formulations of antifungal agents 775.4 Delivery of imaging agents 77

5.5 Delivery of polynucleotides 78

Contents xv

6 Clinical Trials 797 Conclusions 79References 80

6. Vesicles Prepared from Synthetic Amphiphiles — Polymeric Vesiclesand Niosomes 95

Ijeoma Florence Uchegbu and Andreas G. Schatzlein

1 Introduction 952 Polymeric Vesicles 96

2.1 Polymer self assembly 972.2 Polymers bearing hydrophobic pendant groups 982.3 Block copolymers 1012.4 Preparing vesicles from self-assembling polymers 1022.5 Self assembling polymerizable monomers 103

3 Polymeric Vesicle Drug Delivery Applications 1043.1 Drug targeting 1043.2 Gene delivery 1053.3 Responsive release 106

3.3.1 pH 1063.3.2 Enzymatic 1063.3.3 Magnetic 1073.3.4 Oxygen 108

4 Non-ionic Surfactant Vesicles (Niosomes) 1084.1 Self assembly 1084.2 Polyhedral vesicles and giant vesicles (Discomes) Ill4.3 Vesicle preparation 113

5 Niosome Delivery Applications 1135.1 Drug targeting 113

5.1.1 Anti cancer drugs 1135.1.2 Anti infectives 1155.1.3 Delivery to the brain 115

5.2 Topical use of niosomes 1165.2.1 Transdermal 1165.2.2 Ocular 116

5.3 Niosomal vaccines 1165.4 Niosomes as imaging agents 117

6 Conclusions 117References 117

xvi Contents

7. Recent Advances in Microemulsions as Drug Delivery Vehicles 125

M Jayne Lawrence and Warankanga Warisnoicharoen

1 Definition 1251.1 Microemulsion versus an emulsion 1251.2 Microemulsion versus a nanoemulsion 1261.3 Microemulsions 1281.4 Microemulsions, swollen micelles, micelles 1291.5 Microemulsions and cosolvent systems 130

2 Microemulsions as Drug Delivery Systems 1302.1 Self-emulsifying drug delivery systems (SEDDS) 1312.2 Related systems 133

2.2.1 Microemulsion gels 1332.2.2 Double or multiple microemulsions 134

2.3 Processed microemulsion formulations 1342.3.1 Solid state or dry emulsions 134

3 Formulation 1353.1 Surfactants and cosurfactants 1363.2 Oils 1383.3 Characterization 139

4 Routes of Administration 1394.1 Oral 139

4.1.1 Proteins and peptides 1404.1.2 Other hydrophilic molecules 1414.1.3 Hydrophobic drugs 142

4.2 Buccal 1444.3 Parenteral 144

4.3.1 Long circulating microemulsions 1474.3.2 Targeted delivery 148

4.4 Topical delivery 1484.4.1 Dermal and transdermal delivery 148

4.5 Ophthalmic 1544.6 Vaginal 1564.7 Nasal 157

4.8 Pulmonary 1584.8.1 Antibacterials 159

5 Conclusion 160References 160

Contents xvii

8. Lipoproteins as Pharmaceutical Carriers 173

Suwen Liu, Shining Wang and D. Robert Lu

1 Introduction 173

2 The Structure of Lipoproteins 174

3 Chylomicron as Pharmaceutical Carrier 175

4 VLDL as Pharmaceutical Carrier 176

5 LDL as Pharmaceutical Carrier 177

5.1 LDL as anticancer drug carriers 178

5.2 LDL as carriers for other types of bioactive compounds . . . . 179

5.3 LDL for gene delivery 179

6 HDL as Pharmaceutical Carriers 179

7 Cholesterol-rich Emulsions (LDE) as Pharmaceutical Carriers . . . . 180

8 Concluding Remark 181

References 182

9. Solid Lipid Nanoparticles as Drug Carriers 187

Karsten Mader

1 Introduction: History and Concept of SLN 1872 Solid Lipid Nanoparticles (SLN) Ingredients and Production . . . . 188

2.1 General ingredients 188

2.2 SLN preparation 1892.2.1 High shear homogenization and ultrasound 189

2.3 High pressure homogenization (HPH) 1892.4 Hot homogenization 1902.5 Cold homogenization 1W

2.5.1 SLN prepared by solvent emulsification /evaporation 191

2.5.2 SLN preparations by solvent injection 1912.5.3 SLN preparations by dilution of microemulsions or

liquid crystalline phases 1922.6 Further processing ly3

2.6.1 Sterilization 1932.6.2 Drying by lyophilization, nitrogen purging and

spray drying ' q 4

3 SLN Structure and Characterization 1%

4 The "Frozen Emulsion Model" and Alternative SLN Models . . . . 200

5 Nanostructured Lipid Carriers (NLC) 201

6 Drug Localization and Release 202

xviii Contents

7 Administration Routes and In Vivo Data 2038 Summary and Outlook 205References 205

10. Lipidic Core Nanocapsules as New Drug Delivery Systems 213

Patrick Saulnier and Jean-Pierre Benoit

1 Introduction 2132 Lipidic Nanocapsule Formulation and Structure 215

2.1 Process 2152.2 Influence of the medium composition 2162.3 Structure and purification of the LNC by dialysis 2172.4 Imagery techniques 218

3 Electrical and Biological Properties 2193.1 Electro kinetic comportment 2193.2 Evaluation of complement system activation 220

4 Pharmacokinetic Studies and Biodistribution 2205 Drug Encapsulation and Release 222

5.1 Ibuprofene 2225.2 Amiodarone 223

6 Conclusions 223References 224

11. Lipid-Coated Submicron-Sized Particles as Drug Carriers 225

Evan C. linger, Reena Zutshi, Terry O. Matsunaga and Rajan Ramaswami

1 Technology 2252 Ultrasound Contrast Agents 2283 Sonothrombolysis 2324 Clinical Studies 2375 Blood Brain Barrier 2396 Drug Delivery 242

6.1 Targeted bubbles 2426.2 Targeted submicron-sized droplets 244

7 Gene Delivery 2458 Oxygen Delivery 2479 Pulmonary Delivery 24810 Conclusion 249References 250

Contents XIX

12. Nanocapsules: Preparation, Characterization and TherapeuticApplications 255

Ruxandra Grefand Patrick Couvreur

1 Introduction 255

2 Preparation 257

2.1 Nanocapsules obtained by interfacial polymerization 257

2.1.1 Oil-containing nanocapsules 257

2.1.2 Nanocapsules containing an acqueous core 259

2.2 Nanocapsules obtained from preformed polymers 261

3 Characterization 263

4 Drug Release 265

5 Applications 266

5.1 Oral route 266

5.2 Parenteral route 267

5.3 Ocular delivery 269

6 Conclusion 270

References 271

13. Dendrimers as Nanoparticulate Drug Carriers 277

Sbnke Svenson and Donald A. Tomalia

1 Introduction 277

2 Nanoscale Containers — Micelles, Dendritic Boxes, Dendrophanes,

and Dendroclefts 279

2.1 Dendritic micelles 279

2.2 Dendritic box (Nano container) 280

2.3 Dendrophanes and dendroclefts 282

3 Dendrimers in Drug Delivery 282

3.1 Cisplatin 283

3.2 Silver salts 285

3.3 Adriamycin, methotrexate, and 5-fluorouracil 285

3.4 Etoposide, mefenamic acid, diclofenac, and venlafaxine . . . . 286

3.5 Ibuprofen, indomethacin, nifedipine, naproxen, paclitaxel,

and methylprednisolone 287

3.6 Doxorubicin and camptothecin — self-immolative dendritic

prodrugs 28^

3.7 Photodynamic therapy (PDT) and boron neutron capture

therapy (BNCT) 2 9 1

xx Contents

4 Nano-Scaffolds for Targeting Ligands 2924.1 Folic acid 2924.2 Carbohydrates 2934.3 Antibodies and biotin-avidin binding 2944.4 Penicillins 295

5 Dendrimers as Nano-Drugs 2956 Routes of Application 2967 Biocompatibility of Dendrimers 2978 Conclusions 299References 299

14. Drug Nanocrystals/Nanosuspensions for the Delivery of PoorlySoluble Drugs 307

Rainer H. Mtiller and Jens-Uwe A. H. Junghanns

1 Introduction 3072 Definitions 3083 Physicochemical Properties of Drug Nanocrystals 309

3.1 Change of dissolution velocity 3093.2 Saturation solubility 3093.3 Does size really matter? 3113.4 Effect of amorphous particle state 312

4 Production Methods 3134.1 Precipitation methods 313

4.1.1 Hydrosols 3134.1.2 Amorphous drug nanoparticles (NanoMorph®) . . . .313

4.2 Homogenization methods 3144.2.1 Microfluidizer technology 3144.2.2 Piston-gap homogenization in water (Dissocubes®) . . 3144.2.3 Nanopure technology 315

4.3 Combination Technologies 3154.3.1 Microprecipitation™ and High Shear Forces

(NANOEDGE™) 3154.3.2 Nanopure® XP technology 316

5 Application Routes and Final Formulations 3175.1 Oral administration 3175.2 Parenteral administration 3195.3 Miscellaneous administration routes 321

6 Nanosuspensions as Intermediate Products 322

Contents xxi

7 Perspectives 324References 324

15. Cells and Cell Ghosts as Drug Carriers 329

Jose M. Lanao and M, Luisa Sayalero

1 Introduction 329

2 Bacterial Ghosts 329

2.1 Application of bacterial ghosts as a delivery system 3313 Erythrocyte Ghosts 333

3.1 Applications of erythrocyte ghosts as a delivery system . . . .335

4 Stem Cells 338

5 Polymorphonuclear Leucocytes 340

6 Apoptopic Cells 340

7 Tumor Cells 340

8 Dendritic Cells 341

9 Conclusions 341

References 342

16. Cochleates as Nanoparticular Drug Carriers 349

Leila Zarif

1 Introduction 3492 Cochleates Nanoparticles in Oral Delivery 350

2.1 Cochleate structure 350

2.2 Cochleate preparation 350

2.2.1 Which phospholipid and which cation to use? 350

2.2.2 Which molecules can be entrapped in cochleates

nanoparticles 352

2.2.3 Multiple ways of preparing cochleates 353

2.3 Cochleates as oral delivery system for antifungal agent,

amphotericin B 35n

2.3.1 In candidiasis animal model 355

2.3.2 In aspergillosis animal model 355

2.3.3 In cryptococcal meningitis animal model 357

2.3.4 Toxicity of amphotericin B cochleates 357

2.3.5 Pharmacokinetics of amphotericin B cochleates . . . . 357

2.4 Other potential applications for cochleates 3592.4.1 Cochleate for the delivery of antibiotics 3592.4.2 Delivery of clofazimine 360

xxii Contents

2.4.3 Delivery of tobramycin 3602.4.4 Cochleate for the delivery of anti-inflammatory

drugs 3612.5 Other uses of cochleates 361

3 Conclusion 361References 362

17. Aerosols as Drug Carriers 367

N. Renee Labiris, Andrew P. Bosco and Myrna B. Dolovich

1 Introduction 3672 Pulmonary Drug Delivery Devices 369

2.1 Nebulizers 3692.2 Metered-dose inhalers 3712.3 Dry powder inhalers 373

3 Aerosol Particle Size 3734 Targeting Drug Delivery in the Lung 3765 Clearance of Particles from the Lung 378

5.1 Airway geometry and humidity 3785.2 Lung clearance mechanisms 379

6 Nanoparticle Formulations for Inhalation 3816.1 Diagnostic imaging 3826.2 Vaccine delivery 3836.3 Anti Tuberculosis therapy 3856.4 Gene therapy 386

7 Conclusion 388References 388

18. Magnetic Nanoparticles as Drug Carriers 397

Urs O. Ha'feli and Mathieu Chastellain

1 Introduction 3972 Definitions 398

2.1 Properties of magnetic materials 3982.2 Nanoparticles 400

3 Magnetic Nanoparticles 4013.1 Iron oxide based magnetic nanoparticles 4013.2 Cobalt based magnetic nanoparticles 4023.3 Iron based magnetic particles 4023.4 Encapsulated magnetic nanoparticles 4033.5 Biocompatibility issues of magnetic nanoparticles 403

Contents \ x i i i

4 Application of Magnetic Nanoparticles as Drug Carriers 4044.1 Magnetic hyperthermia 4054.2 Magnetic chemotherapy 4064.3 Other magnetic treatment approaches 4084.4 Magnetic gene transfer 409

5 Conclusions 410References 411

19. DQAsomes as Mitochondria-Specific Drug and DNA Carriers 419

Volkmar Weissig

1 Introduction 4192 The Self Assembly Behavior of Bis Quinolinium Derivatives 420

2.1 Monte Carlo computer simulations 4202.2 Physico-chemical characterization 4212.3 Structure activity relationship studies 422

3 DQAsomes as Mitochondrial Transfection Vector 4244 DQAsomes as Carriers of Pro-apoptotic Drugs 4295 Summary 432References 432

20. Liposomal Drug Carriers in Cancer Therapy 437

Alberto A. Gabizon

1 Introduction 437

2 The Challenge of Cancer Therapy 4393 The Rationale for the Use of Liposomal Drug Carriers in Cancer . 442

4 Liposome Formulation and Pharmacokinetics — Stealth

Liposomes 44^5 Preclinical Observations with Liposomal Drug Carriers

in Tumor Models 4486 Liposomal Anthracyclines in the Clinic 444

6.1 Doxil ^

6.2 Myocet 4 S 4

6.3 Daunoxome 4->47 Clinical Development of Other Liposome-entrapped

Cytotoxic Agents 4nr>8 The Future of Liposomal Nanocarriers 456

References T>/

xxiv Contents

21. Nanoparticulate Drug Delivery to the Reticuloendothelial Systemand to Associated Disorders 463

Mukul Kumar Basu and Sanchaita Lala

1 Introduction 4632 Reticuloendothelial System and Associated Disorders 4643 Uptake of Nanoparticles by the Reticuloendothelial System 464

3.1 Sites of uptake 4643.2 Mechanism of uptake 4653.3 Factors influencing uptake 4683.4 Role of surface modifications on uptake 469

4 Active Targeting of Nanoparticles by Receptor MediatedEndocytosis 471

5 Application in Chemotherapy 4736 Summary 475References 477

22. Delivery of Nanoparticles to the Cardiovascular System 481

Ban-An Khaw

1 Introduction 481

2 Targeting the Myocardium with Immunoliposomes 4813 Other Nanoparticle-Targeting of the Cardiovascular System 4844 Novel Application of Nano-Immunoliposomes 4855 CSIL as Targeted Gene or Drug Delivery 4926 Conclusion 495References 496

23. Nanocarriers for the Vascular Delivery of Drugs to the Lungs 499

Thomas Dziubla and Vladimir Muzykantov

1 Introduction 500

2 Biomedical Aspects of Drug Delivery to Pulmonary Vasculature . -5002.1 Routes for pulmonary drug delivery: Intratracheal vs

vascular 5012.2 Pulmonary vasculature as a target for drug delivery 501

3 Pulmonary Targeting of Nanocarriers 5033.1 Effects of carrier size on circulation and tissue distribution . .503

Contents x\v

3.2 Passive targeting 505

3.2.1 Mechanical retention 505

3.2.2 Charge-mediated retention and non-viral genedelivery 506

3.2.3 Pulmonary enhanced permeation-retention (EPR)effect 507

3.3 Active targeting 507

4 Carrier Design 509

4.1 Biocompatibility 509

4.2 Material selection (by application) 510

4.2.1 Imaging 510

4.2.2 Gene delivery 510

4.2.3 Delivery of therapeutic enzymes 511

4.2.4 Small molecule drugs 512

4.3 Types of nanocarriers 512

4.4 Mechanisms of drug loading 512

4.5 Drug release mechanisms 515

4.6 Nanocarriers for active targeting 516

5 Conclusion: Safety Issues, Limitations and Perspectives 517

References 518

24. Nanoparticulate Carriers for Drug Delivery to the Brain 527

Jo'rg Kreuter

1 Introduction ^27

2 Nanoparticles ""28

3 Biodistribution 530

3.1 Influence of surfactants on the biodistribution of

nanoparticles ^30

3.2 Influence of PEGylation on the biodistribution of

nanoparticles ""32

4 Pharmacology "^4

5 Brain Tumors ">-̂ 1

6 Toxicology ~^'s

7 Mechanism of the Delivery of Drug Across the Blood-BrainBarrier with Nanoparticles ">34

8 Summary

9 Conclusions

References

xxvi Contents

25. Nanoparticles for Targeting Lymphatics 549

William Phillips

1 Introduction 5491.1 The lymphatic vessels 5501.2 Lymph nodes 551

2 Potential for Nanoparticles for Drug Delivery to Lymphatics . . . . 5533 Importance of Lymph Nodes for Disease Spread and

Potential Applications of Lymph Node Drug Delivery 5543.1 Cancer 5543.2 HIV 5553.3 Filaria 5553.4 Anthrax 5563.5 Tuberculosis 5563.6 Importance of lymph node antigen delivery for development

of an immune response 5574 Factors Influencing Nanoparticle Delivery to Lymph Nodes 559

4.1 Nanoparticle size 5594.2 Nanoparticle surface 5594.3 Effect of massage on lymphatic clearance of subcutaneously

injected liposomes 5604.4 Macrophage phagocytosis 5614.5 Fate of nanoparticles in lymph nodes 561

5 Nanoparticle Diagnostic Imaging Agents for Determining CancerStatus of Lymph Nodes 5615.1 Subcutaneous injection of iodinated nanoparticles for

computed tomography imaging 5615.2 Subcutaneous and intraorgan injection of magnetic

resonance (MRI) contrast agents 5635.3 Intravenous injection of magnetic nanoparticles for

MRI imaging 5635.4 Nanoparticle diagnostic agents for localizing the sentinel

lymph node 5655.5 Radiolabeled nanoparticles for sentinel lymph node

identification 5665.6 99mTc-Colloidal nanoparticles for sentinel node identification . 5665.7 Optical 5685.8 Ultrasound nanobubbles 569

6 Recently Introduced Medical Imaging Devices for MonitoringLymph Node Delivery and Therapeutic Response 569

Contents xxvii

7 Nanoparticle Lymph Node Drug Delivery 571

7.1 Confusion in reporting lymph node delivery 571

7.2 Calculation of lymph node retention efficiency 573

8 Specific Types Nanoparticles for Lymph Node Targeting 573

8.1 PLGA nanoparticles 573

8.2 Micelles 574

8.3 Liposomes 574

9 Avidin Biotin-Liposome Lymph Node Targeting Method 577

10 Massage and the Avidin-Biotin Liposome Targeting Method 578

11 Nanoparticles for Lymph Node Anti-Infectious Agent Delivery . . . 58012 Liposomes for Intraperitoneal Lymph Node Drug Delivery 581

12.1 Intraperitoneal liposome encapsulated drugs 582

12.2 Effect of liposome size on intraperitoneal clearance 583

12.3 Avidin/Biotin-liposome system for intraperitoneal andlymph node drug delivery 584

12.4 Mediastinal lymph node drug delivery with avidin-biotinsystem by intrapleural injection 585

12.5 Avidin biotin for diaphragm and mediastinal lymph nodetargeting 586

13 Nanoparticles for Cancer Therapy 587

13.1 Intralymphatic drug delivery to lymph nodes 587

13.2 Nanoparticles for treatment of metastatic lymph nodes ofupper GI malignacies 584

13.3 Lessons from endolymphatic radioisotope therapy 591

14 Advantages of Nanoparticles for Lymphatic Radiotherapy 592

15 Intraoperative Radiotherapy for Positive Tumor Margins

and for Treatment of Lymph Nodes 593

16 Potential of Using Radiolabeled Nanoparticles for Intratumoral

Radionuclide Therapy 593

17 Liposome Pharmacokinetics after Intratumoral Administration . . . 5^5

18 Rhenium-Labeled Liposomes for Tumor Therapy S95

19 Nanoparticles for Immune Modulation S97

20 Conclusions S4<s

References "''*'

26. Polymeric Nanoparticles for Delivery in the Gastro-Intestinal Tract 609

Mayank D. Bhavsar, Dinesh B. Shenoy and Maiwor M. Amiji

1 Oral Drug Delivery

xxviii Contents

2 Anatomical and Physiological Considerations of Gastro-intestinal

Tract (GIT) for Delivery 610

3 Introduction to Polymeric Nanoparticles as Carriers 614

4 Preparation of Polymeric Nanoparticles 615

5 Design Consideration for Nanoparticle-based Delivery Systems . . 619

5.1 Polymer characteristics 619

5.2 Drug characteristics 620

5.3 Application characteristics 621

6 Nanoparticles in Experimental and Clinical Medicine 621

6.1 Drug delivery in the oral cavity 621

6.2 Gastric mucosa as a target for oral nanoparticle-mediated

therapy 625

6.3 Nanoparticles for delivery of drugs and vaccines in the small

intestine 626

6.4 Nanoparticles for colon-specific delivery 632

7 Integrating Polymeric Nanoparticles and Dosage Forms 634

8 Toxicology and Regulatory Aspects 636

8.1 Safety 637

8.2 Quality of material/characterization 638

8.3 Environmental considerations 638

9 Conclusion and Outlook 639

References 640

27. Nanoparticular Carriers for Ocular Drug Delivery 649

Alejandro Sanchez and Maria J. Alonso

1 Biopharmaceutical Barriers in Ocular Drug Delivery. Classification

of Nanoparticulate Carriers for Ocular Drug Delivery 650

2 Nanoparticulate Polymer Compositions as Topical Ocular DrugDelivery Systems 651

2.1 First generation: Polymer nanoparticles and nanocapsulesfor topical ocular drug delivery 652

2.1.1 Acrylic polymers-based nanoparticles 654

2.1.2 Polyester-based nanoparticles and nanocapsules . • .655

2.1.3 Polysaccharide-based nanoparticles 657

2.2 Second nanoparticles generation: The coating approach . . . . 659

2.2.1 Polyacrylic coating 659

2.2.2 Polysaccharide coating 660

2.2.3 Polyethyleneglycol (PEG) coating 662

Contents xxix

2.3 Third nanoparticles generation: Towards functionalizednanocarriers 663

3 Nanoparticulate Polymer Compositions as Subconjuctival DrugDelivery Systems 665

4 Nanoparticulate Polymer Compositions as Intravitreal DrugDelivery Systems 665

5 Conclusions and Outlook 667References 668

28. Nanoparticles and Microparticles as Vaccine Adjuvants 675

Janet R. Wendorf, Manmohan Singh and Derek T. O'Hagan

1 Introduction 675

2 Nanopart icle and Microparticle Preparation Methods 678

2.1 Nanoparticles and microparticles made from polyesters . . . . 678

2.2 Nanoparticles and microparticles made with chitosan 681

2.3 Other nanoparticles and microparticles 681

3 Adjuvant Effect of Nanoparticles and Microparticles 681

3.1 Nanoparticles and microparticles as mucosal adjuvants . . . . 682

3.2 Nanoparticles and microparticles as systemic adjuvants . . . . 686

4 Delivery of DNA Using Nanoparticles and Microparticles 688

5 Conclusions 690

References 691

29. Pharmaceutical Nanocarriers in Treatment and Imaging of Infection 697

Raymond M. Schiffelers, Gert Storm and Irma A. J. M. Bakker-Woudenberg

1 Introduction 6972 Carriers that are Easily Recognized as Foreign Materials 6983 Carriers that Avoid Recognition as Foreign Materials 701

4 Local Application of Carriers 705

5 Concluding Remarks 706

References 707

Index 713