Table of Contents
Preface xiii
Part I Fundamentals
1 Recent Trends in Nanotechnology for Brain Delivery: A Brief Outlook Carla Vitorino Andreia Jorge Alberto Pais 3
2 Understanding Brain Delivery Joana Bicker Ana Fortuna Gilberto Alves Amílcar Falcão 9
2.1 The Central Nervous System in Drug Discovery and Development 10
2.2 CNS Barriers and Fluids 12
2.3 Efflux Transporters at the BBB 17
2.4 BBB Evolution in Physiological and Pathological States 21
2.5 Conclusions 25
3 Novel Routes to Accessing the Brain: Intranasal Administration Ana Serralheiro Joana Bicker Gilberto Alves Amílcar Falcão Ana Fortuna 39
3.1 Introduction 40
3.2 Nose-to-Brain Drug Delivery 41
3.2.1 Pathways and Mechanisms of Nose-to-Brain Transport 43
3.3 Nose-to-Brain Delivery Assessment: Experimental Issues 47
3.3.1 Experimental Models 47
3.3.2 Study Design 52
3.3.3 Assessment Parameters 57
3.4 Nose-to-Brain Delivery of Central Drugs 60
3.5 Conclusions 63
Part II Nanomedicines
4 Organic Nanocarriers for Brain Drug Delivery Marlene Lúcio Carla M. Lopes Eduarda Fernandes Hugo Gonçalves Maria Elisabete C. D. Real Oliveira 75
4.1 Introduction 76
4.2 Pathways for Nanocarrier Administration to the Brain 79
4.2.1 Administration Routes 80
4.2.2 Transport Routes across the BBB 82
4.3 Self-Assembly Organic Nanocarriers for Brain Drug Delivery 84
4.4 Vesicles: Liposomes, Ethosomes and PoIymersomes 88
4.4.1 Liposomes 88
4.4.1.1 Liposomes in Alzheimer's disease 91
4.4.1.2 Liposomes in Parkinson's disease 94
4.4.1.3 Liposomes in cerebral ischaemia/reperfusion 95
4.4.1.4 Liposomes in brain tumours 97
4.4.2 Ethosomes 99
4.4.3 Polymersomes 100
4.5 Micelles: Polymeric and Lipidic 102
4.6 Nanoparticles: Lipid Nanoparticles and Polymeric Nanoparticles 103
4.6.1 Lipid Nanoparticles 103
4.6.1.1 Solid lipid nanoparticles 105
4.6.1.2 Nanostructured lipid carriers 111
4.6.2 Polymeric Nanoparticles 116
4.7 Micro- and Nanoemulsions 116
4.8 Synthetic Organic Nanocarriers for Brain Drug Delivery 121
4.8.1 Dendrimers 121
4.9 Biodegradation/Bioelimination of Organic Nanocarriers from the Brain 136
4.10 Conclusions and Future Perspectives 139
5 Magnetic and Plasmonic Nanoparticles for Brain Drug Delivery Ana Luísa Daniel-da-Silva 161
5.1 Introduction 162
5.2 Relevant Properties of inorganic Nanoparticles for Brain Drug Delivery 163
5.2.1 Gold Nanoparticles 163
5.2.2 Magnetic Nanoparticles 165
5.3 Synthesis Procedures 168
5.3.1 Gold Nanoparticles 168
5.3.2 Magnetic Nanoparticles 170
5.4 Surface Modification Strategies towards Brain Delivery 172
5.5 Nanoparticles for Brain Delivery 173
5.5.1 Gold Nanoparticles 173
5.5.2 Magnetic Nanoparticles 176
5.6 Concluding Remarks 179
6 Hybrid Nanosystems Pablo Vicente Torres-Ortega Laura Saludas Jon Eneko Idoyaga Carlos Rodríguez-Nogales Elisa Garbayo María José Blanco-Prieto 189
6.1 Introduction 190
6.2 Hybrid Nanosystems for Brain Cancer 192
6.3 Hybrid Nanosystems for Neurodegenerative Disorders 197
6.3.1 Hybrid Nanosystems for Alzheimer's Disease 198
6.3.2 Hybrid Nanosystems for Parkinson's Disease 200
6.4 Hybrid Nanosystems for Cerebral Ischaemia 202
6.5 Conclusions 204
7 Drug Nanocrystals M. Ermelinda S. Eusébio Ricardo A. E. Castro João Canotilho 211
7.1 Introduction 211
7.2 Relevant Nanocrystal Physicochemical Properties 217
7.3 Preparation of Nanocrystals 220
7.3.1 Top-Down Techniques 223
7.3.1.1 Wet media milling 223
7.3.1.2 High-pressure homogenisation 223
7.3.2 Bottom-Up Techniques 224
7.3.2.1 Bottom-up: evaporation methods 225
7.3.2.2 Bottom-up: precipitation methods 225
7.3.3 Combination of Top-Down and Bottom-Up Techniques 229
7.4 Stability of Nanocrystals 229
7.4.1 Aggregation and Ostwald Ripening 229
7.4.2 Solid Forms: Polymorphs, Amorphous Phases and Solvates 230
7.5 Nanocrystals for Brain Drug Delivery 232
7.5.1 Oral Administration 232
7.5.2 Parenteral Administration 237
7.5.3 Nasal Administration 239
7.6 Concluding Remarks 240
8 Lipid Nanocarriers for Oligonucleotide Delivery to the Brain Andreia F. Jorge Santiago Grijalvo Alberto Pais Ramón Eritja 257
8.1 Introduction 258
8.2 Oligonucleotide-Based Therapeutics 260
8.2.1 Antisense Oligonucleotides 260
8.2.2 RNA Interference 262
8.2.3 Anti-miRNA oligonucleotides 263
8.2.4 Aptamers 264
8.2.5 Antiproliferative Oligonucleotides 266
8.3 Lipid-Based Nanocarriers for Brain Delivery 266
8.3.1 Oligonucleotide-Lipid Conjugates 266
8.4 Vesicular Systems: Liposomes and Niosomes 270
8.5 Natural Vesicular Systems: Exosomes 274
8.6 Solid Lipid-Based Nanocarriers 274
8.7 Conclusions 276
9 Carriers for Nucleic Acid Delivery to the Brain Sören Reinhard Ernst Wagner 289
9.1 Introduction 290
9.2 Nonviral Nucleic Acid Carriers 291
9.3 Brain-Targeted Nucleic Acid Delivery 293
9.3.1 Transport across the Blood-Brain Barrier 294
9.3.1.1 Protein ligands 294
9.3.1.2 Peptide ligands 295
9.3.1.3 Carrier-mediated transport 298
9.3.2 Blood-Brain Barrier Disruption 299
9.3.3 Intracranial Delivery 299
9.4 Glioma-Targeted Nucleic Acid Delivery 300
9.5 Conclusions 301
10 Advances in Nanotheranostics with Plasmonic and Magnetic Nanoparticles Sérgio R. S. Veloso Paula M. T. Ferreira J. A. Martins Paulo J. G. Coutinho Elisabete M. S. Castanheira 317
10.1 Nanomedicine in Brain Therapy 318
10.2 Nanotheranostics: Concepts and Strategies 320
10.2.1 Plasmonic Nanoparticles 324
10.2.2 Brain Theranostics with Plasmonic Nanoparticles 327
10.2.3 Magnetic Nanoparticles 330
10.2.4 Brain Theranostics with Magnetic Nanoparticles 331
10.2.5 Advances in Brain Theranostics Using Magnetoliposomes 334
10.3 Conclusion and Future Perspectives 338
Part III Development and Translation
11 Quality by Design for Nanocarriers Branca M. A. Silva Cláudia Silva 351
11.1 Introduction 351
11.2 The QbD Approach 353
11.2.1 QTPP 354
11.2.2 CQAs 355
11.2.3 Risk Assessment 355
11.3 Design of Experiments, Design Space and Control Strategy 373
11.3.1 Continuous Monitoring and Improvement 377
11.4 Conclusion 377
12 Recent in vitro Models for the Blood-Brain Barrier João Basso Maria Mendes Maria Ferreira João Sousa Alberto Pais Carlo Vitorino 383
12.1 Introduction to Blood-Brain Barrier Models 384
12.2 Microfluidic BBB Models 387
12.3 Cell Cultures 396
12.4 Model Assessment 398
12.4.1 Shear Stress 398
12.4.2 Barrier Permeability 399
12.4.3 Transepithelial Electrical Resistance 399
12.5 Concluding Remarks 400
13 Current in vivo Models for Brain Disorders Marta Guerra-Rebollo Cristina Garrido 407
13.1 Introduction to Animal Models 408
13.2 Neurological Disease Animal Models 408
13.2.1 Neurodegenerative Diseases 410
13.2.2 Brain Tumours 411
13.2.3 Ischaemic Stroke 412
13.3 Animal Trials in the Development of Nanoparticles for CNS Disorders 413
13.4 Imaging Techniques for Nanoparticles: Diagnosis and Treatment 417
14 Modelling and Simulation of Nanosystems for Delivering Drugs to the Brain Tânia F. G. G. Cova Sandra C.C. Nunes 427
14.1 Impact of Computational Approaches in the Design and Optimisation of Nanocarriers 428
14.2 Understanding BBB Permeability 431
14.3 Predicting Treatment Efficacy 438
14.4 Optimising Drug Delivery to the Brain 443
14.5 Concluding Remarks 445
15 Translational Challenges Bárbara Rocha Nelson Pacheco Rocha Bruno Gago 453
15.1 Introduction 454
15.2 Translationai Medicine 455
15.3 Nanoparticles as Carriers of Drugs 457
15.4 Nanotechnology: From the Diagnosis to the Treatment of Neurological Disorders 458
15.5 Clinical Applications of Nanoparticles in the Management of Brain Tumours 460
15.6 Challenges of Clinical Applications of Nanoparticles 461
15.7 The Importance of the Regulatory Pathway 463
Index 473
