Drug Delivery to the Brain: Physiological Concepts, Methodologies and Approaches (AAPS Advances in the Pharmaceutical Sciences Series, 33)

✍ Scribed by Elizabeth C.M. de Lange (editor), Margareta Hammarlund-Udenaes (editor), Robert G. Thorne (editor)

• Publisher: Springer
• Year: 2022
• Tongue: English
• Leaves: 810
• Category: Library

✦ Synopsis

The development of new CNS drugs is notoriously difficult. Drugs must reach CNS target sites for action and these sites are protected by a number of barriers, the most important being the blood–brain barrier (BBB). Many factors are therefore critical to consider for CNS drug delivery, e.g. active/passive transport across the BBB, intra-brain distribution, and central/systemic pharmacokinetics, to name a few. Neurological disease and trauma conditions add further complexity because CNS barriers, drug distribution and pharmacokinetics are dynamic and often changed by disease/trauma. Knowledge of all these factors and their interplay in different conditions is of utmost importance for proper CNS drug development and disease treatment. In recent years much information has become available for a better understanding of the many factors important for CNS drug delivery and how they interact to affect drug action. This book describes small and large drug delivery to the brain with an emphasis on the physiology of the BBB and the principles and concepts for drug delivery across the BBB and distribution within the brain. It contains methods descriptions for studying drug delivery, routes and approaches of administering drugs into the brain, the influence of disease, drug industry perspectives, and a primer on neuroanatomy and physiological considerations written specifically for drug delivery scientists. Therewith, it contributes to an in-depth understanding of the interplay between brain (patho)-physiology and drug characteristics. Furthermore, the content is designed to be both cutting-edge and educational, so that the book can be used in high-level training of academic and industry scientists with full references to original publications.

✦ Table of Contents

Preface
Book Structure
References
Acknowledgments
Contents
Contributors
Part I: Physiology and Basic Principles for Drug Handling by the CNS
Chapter 1: Anatomy and Physiology of the Blood-Brain Barriers*
1.1 Neural Signalling and the Importance of CNS Barrier Layers
1.2 The Brain Endothelium and the Neurovascular Unit
1.3 Nature and Organisation of the Membranes of the Barrier Layers
1.4 Tight Junctions in Brain Endothelium and Barrier Epithelia: Structure and Restrictive Properties
1.5 Small Solute Transport at the Barrier Layers
1.6 Vesicular Transport and Transcytosis
1.7 Routes for Permeation Across Barrier Layers and Influence on Drug Delivery
1.8 Development, Induction, Maintenance and Heterogeneity of the BBB
1.9 Beyond the Barrier: The Fluid Compartments of the ISF and CSF
1.10 Changes in BBB and BCSFB in Pathology
1.11 Implications for Drug Delivery
1.12 Points for Discussion
References
Chapter 2: Increasing Brain Exposure of Antibodies
2.1 Introduction
2.2 Overview of Strategies to Increase Brain Exposure of Antibodies
2.3 Brain Transport Mechanisms
2.4 Trojan Horse Approach
2.4.1 Using Antibodies Ligands of Transporter Receptors to Carry Antibodies to the Brain
2.4.1.1 Transferrin Receptor
Affinity/Valency for TfR and Brain Exposure
Cell Trafficking of Anti-TfR Bispecific Antibodies
Target Engagement
Efficacy
Translation to Humans
Safety
Clinics
2.4.1.2 Insulin Receptor
2.4.1.3 CD98
2.4.1.4 TMEM30
2.4.1.5 IGF1R
2.4.2 Using Peptide Ligands of Transporter Receptors to Carry Antibodies to the Brain
2.5 Charge: Adsorptive-Mediated Transcytosis
2.6 Nanotechnologies
2.7 BBB Disruption
2.7.1 Chemical Modulation of the BBB Permeability
2.7.2 Focused Ultrasounds
2.8 Intranasal Administration
2.9 Conclusions and Perspectives
References
Chapter 3: Brain Delivery of Therapeutics via Transcytosis: Types and Mechanisms of Vesicle-Mediated Transport Across the BBB
3.1 Introduction
3.2 Receptor-Mediated Transcytosis
3.2.1 Endocytosis
3.2.2 Sorting Through the Endosomes
3.2.3 Exocytosis to the Abluminal Side
3.3 Antibody Attributes That Favor Transcytosis: Designing more Efficient BBB Carriers
3.4 Conclusions
References
Chapter 4: Blood-Arachnoid Barrier as a Dynamic Physiological and Pharmacological Interface Between Cerebrospinal Fluid and Blood
4.1 Introduction
4.2 Quantitative Protein Expression Profile of Transporters at the BCSFB: Interspecies Difference Between Human and Experimental Animals (Rat, Dog, and Pig) and Regional Difference Among Four Ventricular Choroid Plexus
4.3 Absolute Protein Expression Amounts and CSF/Blood-Side Localizations of Transporters at the BAB: Comparison with BCSFB
4.4 Drug Efflux Transporters P-gp/MDR1 and BCRP/ABCG2
4.5 Species Difference in the Protein Expression Levels of Transporters at the BAB Between Rat and Pig
4.6 In Vivo Contributions of Oat1, Oat3, and Oatp1a4 at the BAB to the Clearance of Organic Anions from CSF
4.7 Protein Expression Levels of Transporters at the BAB in the Spinal Cord Region: Comparison with Brain BAB and BCSFB
4.8 Can the CSF Concentrations of P-gp and BCRP Substrates Reflect the Brain ISF Concentration?
4.9 Perspectives
References
Chapter 5: Quantitative and Targeted Proteomics of the Blood-Brain Barrier: Species and Cell Line Differences
5.1 Introduction
5.2 Profile of Transporter and Receptor Proteins in the Microvessels of the Human Brain
5.2.1 Species-Level Differences in Isolated Brain Microvessels: ABC Transporters
5.2.2 Species-Level Differences in Isolated Brain Microvessels: SLC Transporters
5.2.3 Species-Level Differences in Isolated Brain Microvessels: Receptors
5.3 Necessities of Plasma Membrane Proteome Analysis for BBB Research
5.4 Methodologies of Plasma Membrane Preparation
5.5 Comparison of Plasma Membrane Proteome Between Two BBB Cell Lines
5.6 Conclusion
References
Chapter 6: Drug Metabolism at the Blood-Brain and Blood-CSF Barriers
6.1 Introduction and History of Cerebral Drug Metabolism
6.2 Current Status
6.2.1 The Blood-Brain Barrier
6.2.1.1 Anatomical and Functional Features of the Blood-Brain Barrier
6.2.1.2 Molecular Characterization, Relative Expression, and Functional Significance of Drug Metabolizing Enzymes at the Blood-Brain Barrier
6.2.1.3 Regulation of Drug Metabolizing Enzymes at the Blood-Brain Barrier
6.2.2 The Blood-Cerebrospinal Fluid Barrier and the Ependyma
6.2.2.1 Anatomical and Functional Features of the Choroidal Blood-CSF Barrier
6.2.2.2 Molecular Characterization, Relative Expression, and Function of Drug Metabolizing Enzymes in Choroid Plexuses and Ependyma
6.2.2.3 Expression of Drug Metabolizing Enzymes and Phase III Transporters in the Arachnoid Blood-CSF Barrier
6.2.2.4 Pharmacotoxicological Significance and Regulation of Drug Metabolism at the Blood-CSF Barrier
6.2.2.5 Drug Metabolism Associated with the Blood-CSF Barrier during Development
6.3 Future Challenge
6.4 Conclusions
References
Part II: PK Concepts and Methods for Studying CNS Drug Delivery
Chapter 7: Pharmacokinetic Concepts in Brain Drug Delivery
7.1 Introduction
7.2 Historical Aspects on Studying Brain Drug Delivery
7.3 Parameters Describing Drug Delivery to the Brain
7.3.1 Rate of Brain Drug Delivery
7.3.1.1 What and Why
7.3.1.2 Methods and Relationships
7.3.2 Extent of Brain Drug Delivery
7.3.2.1 What and Why
7.3.2.2 Methods and Relationships
7.3.3 Intra-Brain Distribution
7.3.3.1 What and Why
7.3.3.2 Methods and Relationships
Microdialysis
Brain Homogenate
Brain Slice
7.3.3.3 Interpretations and Caveats
7.3.4 Intracellular Drug Distribution
7.3.5 Combining Rate, Extent, and Intra-Brain Drug Distribution in Brain Pharmacokinetics
7.4 CSF Pharmacokinetics vs Brain ISF Pharmacokinetics
7.5 Drug Interactions at the BBB
7.6 Species Comparisons
7.7 Current Status and Future Challenges
7.8 Conclusions
7.9 Points for Discussion
References
Chapter 8: In Vitro Models of CNS Barriers
8.1 Introduction
8.1.1 Background and Early History
8.1.2 Criteria for Useful In Vitro CNS Barrier Models
8.1.3 The Physical Barrier and Tight Junctions: Monitoring CNS Barrier Tightness In Vitro
8.1.3.1 Methods to Measure Barrier Permeability and TEER
8.1.3.2 TEER Measurement Based on Ohm’s Law: V = IR (Voltage = Current × Resistance)
8.1.3.3 Impedance Spectroscopy Systems
8.1.3.4 Relation Between Permeability and TEER
8.1.4 Barrier Features Related to Transporters, Enzymes, Transcytosis, and Immune Responses
8.2 Current Status: Overview of Current In Vitro BBB Models
8.2.1 Isolated Brain Capillaries
8.2.2 Primary and Low Passage Brain Endothelial Cells
8.2.3 Immortalized Brain Endothelial Cell Lines
8.2.4 Complex BBB Models: 3D Models, Dynamic Flow, and Microfluidics
8.2.5 Application of In Vitro Models for BBB Drug Permeability Assay
8.2.6 In Vitro-In Vivo Correlations (IVIVC)
8.2.6.1 Unstirred Water Layer, Paracellular Permeability, and Intrinsic Permeability Calculation
8.2.6.2 Transcriptomics, Proteomics, and PKPD Modeling
8.2.7 How to Select an Appropriate In Vitro BBB Model
8.2.8 Epithelial CNS Barriers
8.2.8.1 Choroid Plexus Epithelial (CPE) Cells
8.2.8.2 Arachnoid Epithelial Cells
8.3 Future Directions and Challenges
8.4 Conclusions
8.5 Points for Discussion
References
Chapter 9: Human In Vitro Blood-Brain Barrier Models Derived from Stem Cells
9.1 Introduction
9.2 Stem Cell Sources for BBB Modeling
9.3 Differentiation of Stem Cells to BMEC-Like Cells
9.3.1 hPSC-Derived BMECs
9.3.1.1 Co-differentiation with Neural Progenitors
9.3.1.2 Accelerated Co-differentiation
9.3.1.3 Differentiation in Low Osmolarity Medium
9.3.1.4 Directed Differentiation Models
9.3.1.5 Induction of BMEC Properties in Endothelial Progenitors
9.3.2 Genomic Comparison of hPSC-BMECs Using the Various Protocols
9.3.3 Cord Blood Progenitor Cell Models
9.4 Co-culture Models
9.4.1 Neurons
9.4.2 Astrocytes
9.4.3 Pericytes
9.4.4 Multiple Cell Co-culture
9.5 Application of Physiologically Relevant Structures and Forces to Stem Cell-Derived BBB Models
9.6 Stem Cell-Derived Aggregate BBB Models
9.7 Applications of Stem Cell-Derived BBB Models
9.7.1 Drug Permeability
9.7.2 Studying Human BBB Development
9.7.3 Modeling BBB Disease
9.8 Conclusion
9.9 Points for Discussion
References
Chapter 10: Drug Delivery to the Brain: Physiological Concepts, Methodologies, and Approaches
10.1 Introduction
10.2 Current Status
10.2.1 Two Parameters Commonly Used in In Vivo Brain Drug Distribution Experiments
10.2.2 Systemic Administration Method
10.2.3 Free Vs. Total Drug in BBB Kinetic Analyses and Brain Microdialysis
10.2.4 Brain Vascular Correction
10.2.5 Influence of Flow on Initial Brain Uptake and BBB PS
10.2.6 In Situ Brain Perfusion and Brain Efflux Index
10.2.7 Cerebrospinal Fluid
10.3 Case Study: BBB Permeability Measured with Hydrophilic Low Molecular Weight Markers
10.3.1 Introduction
10.3.2 Sodium Fluorescein and the Importance of Protein Binding
10.3.3 Sucrose and Mannitol: The Importance of Highly Specific Analytical Assays
10.3.4 Conclusion
10.4 Going Beyond BBB Permeability to Drug Uptake and Distribution in Brain Metastases
10.4.1 Introduction: BBB Breakdown and Heterogeneity in Brain Tumors
10.4.2 Case Study: Role of the Barrier in Limiting Drug Therapeutic Effect
10.4.3 Case Study: Clinical Measurements of Brain Metastasis Drug Uptake
10.5 Future Challenges/Directions
10.6 Conclusions
10.7 Points for Discussion (Questions)
References
Chapter 11: Principles of PET and Its Role in Understanding Drug Delivery to the Brain
11.1 Introduction
11.1.1 Background
11.1.2 Principles of PET
11.1.3 PET Concepts and Nomenclature
11.1.4 Discovery Process of CNS PET Radiotracers
11.1.5 Study Protocols
11.2 Current Status
11.2.1 Brain Distribution Studies
11.2.2 Drug-Target Interactions
11.2.3 Drug Effects on Cellular or Organ Physiology
11.2.4 Challenges When Using PET for Studies of BBB Transport
11.3 Future
11.3.1 Macromolecules and Biologics
11.3.2 Instrumentation
11.3.3 PET Chemistry
11.4 Conclusions
11.5 Points for Discussion
References
Chapter 12: Approaches Towards Prediction of CNS PK and PD
12.1 Introdction
12.2 Physiology of the Brain
12.3 Physiological Processes Involved in CNS Drug Distribution
12.4 Small Molecules
12.4.1 Physiologically Based Pharmacokinetic (PBPK) Model Characteristics
12.4.2 Current Status
12.4.2.1 The Multi-CNS Compartment CNS PBPK Model for Small Molecules
12.4.2.2 CNS Target Site Distribution and Target Binding Kinetics
12.4.2.3 Translational PKPD Modeling
Preclinically Derived Translational Human PKPD Model for Remoxipride
Multivariate PKPD Analysis with Metabolomics for Systems-Wide Effects
12.5 Antibodies
12.5.1 Introduction
12.5.2 PK Prediction
12.5.2.1 Motivation
12.5.2.2 Preclinical PK Study at the “Site-of-Action”
12.5.2.3 Empirical PK Model
12.5.2.4 PBPK Model
12.5.3 PD Prediction: Case Study
12.5.3.1 PKPD Modeling of Bispecific TfR/BACE1 Antibodies in Mice
12.5.3.2 PKPD Modeling of Anti-TfR antibody and A β Protein Reduction in Monkey
12.6 Future Directions
12.7 Challenges
12.8 Conclusions
12.9 Points for Discussion
References
Part III: Industrial Approaches for Investigation of Potential CNS Drugs
Chapter 13: Drug Discovery Methods for Studying Brain Drug Delivery and Distribution
13.1 Introduction
13.2 The Brain Homogenate Method for fu,brain
13.2.1 Equilibrium Dialysis
13.2.1.1 Principles
13.2.1.2 Technical Challenges
Selection of Dialysis Membrane
Preparation of Brain Homogenate
Equilibration Process
Bioanalysis
13.3 The Brain Slice Method for Vu,brain
13.3.1 Section Heading 13.3.1
13.3.1.1 Principles
13.3.1.2 Technical Challenges
Artificial Extracellular Fluid and Formation of Cassettes
Preparation of Brain Slices and Incubation
Bioanalysis
13.4 Intracellular Distribution
13.4.1 Using Kp,uu,cell to Estimate the Extent of Cellular Barrier Transport
13.4.2 Lysosomal Trapping
13.4.2.1 Compensation for pH Partitioning
13.4.3 Intracerebral Distributional Patterns
13.5 Combinatory Mapping Approach
13.6 Translational Aspects of the Methods
13.6.1 Translational Aspects of Brain Tissue Binding Assays
13.6.2 Translational Aspects of Brain Exposure Assessment
13.7 Current Status and Future Directions
13.8 Points for Discussion (Questions)
References
Chapter 14: Prediction of Drug Exposure in the Brain from the Chemical Structure
14.1 Introduction
14.1.1 Various Measurements of Brain Exposure and Availability of Data
14.1.1.1 LogBB
14.1.1.2 Kp,uu,brain
14.1.1.3 BBB Permeability Surface Area Product (PS)
14.1.1.4 Classification Approaches
14.1.2 Modelling Strategies
14.1.2.1 Compound Selection
14.1.2.2 Molecular Descriptors
14.1.2.3 Generation of Experimental Data
14.1.2.4 Relating Experimental Data to Molecular Descriptors
14.1.2.5 Validation of the Model
14.1.3 Overview of BBB Prediction Models
14.2 Current Status
14.2.1 Which Parameter of Drug Exposure in the Brain Should be Used?
14.2.2 Emerging Understanding of Determinants of Unbound Drug Exposure in the Brain, Kp,uu,brain
14.2.3 The Relationship between Prediction Models for LogBB and Kp,uu,brain
14.2.4 Recent Developments in CNS+/CNS− Classification
14.3 Future Directions and Challenges
14.3.1 Improving Predictions of Kp,uu,brain by Integration of Approaches
14.3.2 Drug Design Strategies
14.4 Conclusions
14.5 Topics for Discussion
References
Part IV: Strategies for Improved CNS Drug Delivery
Chapter 15: Intranasal Drug Delivery to the Brain
15.1 Introduction
15.2 Nasal Anatomy and Physiology
15.2.1 General Overview
15.2.2 Blood Supply and Lymphatic Drainage
15.2.3 The Olfactory Region of the Nasal Passage
15.2.4 The Respiratory Region of the Nasal Passage
15.3 Mechanisms and Pathways for Transport Into the CNS From the Nasal Passages
15.3.1 Transport Across the Olfactory and Respiratory Epithelial Barriers
15.3.2 Transport from the Nasal Lamina Propria to Sites of Brain Entry
15.3.3 Transport from Brain Entry Sites to Widespread Areas Within the CNS
15.4 Current Status of the Intranasal Route of Administration for CNS Targeting
15.4.1 Intranasal Delivery of Small Molecules to the CNS
15.4.2 Intranasal Delivery of Peptides/Proteins to the CNS
15.4.3 Intranasal Delivery of Gene Vectors and Oligonucleotides to the CNS
15.4.4 Intranasal Delivery of Cell-Based Therapies to the CNS
15.5 Future Challenges and Directions for Intranasal Drug Delivery to the Brain
15.5.1 Methods to Enhance CNS Delivery Following Intranasal Administration
15.5.2 Unresolved Questions
15.6 Conclusions
15.7 Points for Discussion
References
Chapter 16: Blood-to-Brain Drug Delivery Using Nanocarriers
16.1 Introduction
16.2 Current Status of Therapeutic Nanocarrier Development
16.2.1 Criteria for Nanocarriers to Move into Clinical Practice
16.2.2 Nanocarriers Suitable for Brain Drug Delivery
16.2.2.1 Liposomes
16.2.2.2 Albumin Nanoparticles
16.2.2.3 Polymeric Nanoparticles
16.2.2.4 Other Nanocarriers
16.2.3 Points to Consider for Regulatory Approval
16.2.3.1 Pharmaceuticals
16.2.3.2 PK/PD
16.2.3.3 Nanotoxicity
16.2.3.4 Therapeutic Index
16.3 Future Challenges/Directions
16.3.1 Preparation and Characterization of Nanocarriers
16.3.2 Delivery and Efficacy of Brain-Targeted Nanocarriers
16.3.3 Safety of Brain-Targeted Nanocarriers
16.3.4 Clinical Research
16.4 Conclusions
16.5 Points for Discussion
References
Chapter 17: Transport of Transferrin Receptor-Targeted Antibodies Through the Blood-Brain Barrier for Drug Delivery to the Brain
17.1 Introduction
17.2 The Transferrin Receptor
17.3 The Significance of the Transferrin Receptor for Iron Uptake and Transport at the Blood-Brain Barrier
17.4 Targeting the Transferrin Receptor for Transport of Anti-transferrin Receptor Antibodies Across the Blood-Brain Barrier
17.5 Pharmacokinetics of Therapeutics Targeting the Transferrin Receptor at the Blood-Brain Barrier
17.6 Does Existing Knowledge on the Expression of the Transferrin Receptor at the BBB Allow for Improved Antibody Transfer Across the BBB?
17.7 The Fate of Transferrin Receptor-Targeted Antibodies Within the Brain
17.8 Side Effects of Transferrin Receptor-Targeted Therapeutics Targeting the Blood-Brain Barrier
17.9 Points for Discussion
References
Chapter 18: Drug Delivery to the CNS in the Treatment of Brain Tumors: The Sherbrooke Experience
18.1 Introduction
18.2 The BBB as an Impediment to the Treatment of Brain Tumors: A Historic View
18.3 The BBB in Clinical Practice Nowadays
18.4 The BBB in Primary Tumors
18.5 The BBB in Metastatic (Secondary) Tumors
18.6 Alternate Drug Delivery
18.7 The Cerebral Intra-arterial Infusion of Chemotherapy (CIAC) and the Blood-Brain Barrier Disruption (BBBD) Adjunct
18.8 Preclinical Data
18.9 Clinical Procedures
18.10 CIAC or CIAC+BBBD?: A Question of Intensity of Delivery
18.11 Clinical Data: Safety
18.12 Vascular Complications
18.13 Seizure Events
18.14 Hematological Complications
18.15 Clinical Results
18.16 Glioblastoma (GBM)
18.17 Future Perspectives in the Treatment of Malignant Gliomas
18.17.1 Heterogeneity of Response: The Impossibility to Predict the Best Regimen for Each Patient
18.17.2 Radio-Chemotherapy
18.17.3 Primary CNS Lymphomas
18.18 Conclusion
References
Chapter 19: Biophysical and Clinical Perspectives on Blood-Brain Barrier Permeability Enhancement by Ultrasound and Microbubbles for Targeted Drug Delivery
19.1 Therapeutic Ultrasound
19.2 Focused Ultrasound
19.3 Focused Ultrasound, Microbubbles, and the Blood-Brain Barrier
19.3.1 Delivery of Therapeutics
19.3.2 Nondrug Delivery Applications
19.4 Biological Responses to Focused Ultrasound and Microbubble Exposures
19.4.1 Magnetic Resonance Imaging
19.4.2 Histological and Biochemical Assays
19.4.2.1 Vascular Effects
19.4.2.2 Extravascular Effects
19.5 Acoustic Feedback Control
19.6 Clinical Trials
19.6.1 Implanted Ultrasound Device Approach
19.6.2 Transcranial Approach
19.7 Conclusion
References
Chapter 20: Optimization of Blood-Brain Barrier Opening with Focused Ultrasound: The Animal Perspective
20.1 The Blood-Brain Barrier Physiology: Structure and Function
20.2 The BBB and Neurotherapeutics
20.3 Focused Ultrasound (FUS) with Microbubbles
20.4 BBB Opening Using FUS and Microbubbles
20.4.1 Prior BBB Opening Studies Using FUS
20.4.2 Mechanism of BBB Opening
20.4.3 Molecular Delivery Through the Opened BBB
20.4.4 Safety and Reversibility of BBB Opening
20.4.5 Therapeutic Delivery Through FUS-Induced Blood-Brain Barrier Opening
20.4.5.1 An Early-Stage Parkinson’s Model Used
20.4.5.2 Protein Delivery
20.4.5.3 Adenoviral Delivery
20.4.5.4 Behavioral Assessment
20.4.5.5 Brain Preparation and Immunohistochemistry
20.5 Large Animals
20.5.1 Rationale
20.5.2 Methods
20.5.2.1 Primate FUS System
20.5.2.2 Cavitation Detection and Monitoring
20.5.2.3 Neuronavigation
20.5.3 Imaging of BBB Opening
20.5.3.1 MRI
20.5.3.2 DCE-MRI
20.5.4 Drug Delivery Studies
20.5.4.1 Pharmacodynamic Analysis
20.5.4.2 Prediction of Aberration and Targeting Correction
20.5.4.3 Neuronavigation
20.5.4.4 Cavitation Mapping
20.6 Conclusion
References
Chapter 21: Crossing the Blood-Brain Barrier with AAVs: What’s After SMA?
21.1 AAV-mediated CNS Gene Therapy: From Discovery to Clinic in 10 years
21.1.1 The History of AAV-mediated CNS Gene Delivery via Intravenous Administration
21.1.2 CNS Applications of Systemic AAV Administration Beyond SMA
21.1.3 High AAV Doses Can Stimulate Immune Responses That Are Detrimental to Patient Health and Therapy Efficacy
21.1.4 Navigating Immune Responses with Next-generation AAVs, Pharmacological Interventions, and Alternative Delivery Routes
21.2 Factors That Influence the CNS Tropism of AAV9
21.2.1 Age at Delivery
21.2.2 The Relationship Between AAV9 Receptor Binding, Persistence in the Circulation, and Its CNS Tropism
21.2.3 Mechanistic Insights into BBB Crossing from AAV Domain Swapping
21.3 Engineering Capsids for Enhanced Blood-Brain Barrier Crossing
21.3.1 Learning from the Species and Strain Dependency of AAV-PHP.B and AAV-PHP.eB
21.3.2 Other BBB-targeted AAVs
21.3.3 Identifying and Upregulating the AAV Internalization Pathway
21.3.4 AAV Fates: Transduction Versus Transcytosis
21.4 Concluding Remarks
References
Part V: CNS Drug Delivery in Disease Conditions
Chapter 22: Disease Influence on BBB Transport in Neurodegeneration
22.1 Introduction
22.2 Neurodegenerative Processes and Disorders
22.2.1 Neurodegenerative Processes
22.2.2 Alzheimer’s Disease
22.2.3 Parkinson’s Disease
22.2.4 Pharmacoresistant Epilepsy
22.2.5 Traumatic Brain Injury
22.3 Dysfunction of the BBB in Neurodegenerative Diseases
22.3.1 Tight Junctions
22.3.2 Actin
22.3.3 Basal Lamina and Extracellular Matrix
22.3.4 Perivascular Astrocytes
22.3.5 Pericytes
22.3.6 Metabolic Enzymes
22.3.7 Facilitative and Active Transport Systems
22.3.8 Cerebral Blood Flow
22.3.9 Immunological Aspects
22.4 Quantitative Studies on BBB Transport and Effects of Drugs in Neurodegenerative Diseases
22.4.1 Pharmacoresistant Epilepsy
22.4.2 Parkinson’s Disease
22.4.3 Alzheimers Disease
22.4.4 Traumatic Brain Injury
22.4.5 Role of Pericytes
22.5 Conclusions
22.5.1 Points for Discussion
22.5.2 Future Directions
References
Chapter 23: The Blood-Brain Barrier in Stroke and Trauma and How to Enhance Drug Delivery
23.1 Introduction
23.2 The Blood-Brain Barrier During Stroke and Trauma
23.2.1 Blood-Brain Barrier and Neurovascular Unit (NVU) Changes
23.2.2 Blood Supply
23.2.3 Endothelial Tight Junctions
23.2.4 Endocytosis/Transcytosis
23.2.5 Cell Trafficking
23.2.6 Transport
23.2.7 Metabolic Barrier
23.3 Enhancing Brain Delivery of Potential Therapeutics in Stroke and Trauma
23.3.1 Highly Lipophilic Compounds with No or Limited Efflux Transport
23.3.2 Highly Lipophilic Compounds with Efflux Transport
23.3.3 Hydrophilic Compounds
23.3.3.1 Increasing Paracellular Diffusion
23.3.3.2 Increasing Transcellular Movement
23.3.3.3 Circumventing the Blood-Brain Barrier
23.3.4 Cell-Based Therapies
23.4 The Blood-Brain Barrier as Therapeutic Targeting
23.5 Future Directions and Challenges
23.6 Conclusion
23.7 Points for Discussion
References
Chapter 24: Drug Delivery to Primary and Metastatic Brain Tumors: Challenges and Opportunities
24.1 Tumors of the CNS: The Disease
24.1.1 Primary Brain Tumors
24.1.2 Metastatic Brain Tumors
24.2 Standard of Care for Primary Brain Tumors
24.3 Standard of Care for Metastatic Brain Tumors
24.4 Challenges in the Treatment of Brain Tumors
24.5 Transporter Expression in Brain Tumors
24.6 Transporter Regulation
24.6.1 Transcriptional Regulation
24.6.1.1 Transporter Regulation Through p53
24.6.1.2 Transporter Regulation by Nuclear Receptors
24.6.2 Growth Factors
24.6.3 PI3K/Akt Signaling
24.6.4 Adenosine Signaling
24.6.5 Temozolomide
24.7 Strategies to Improve Treatment of Brain Tumors
24.7.1 Designing Molecules with Increased Brain Penetration and Reduced Efflux Liability
24.7.2 Inhibition of Efflux Transporters at the BBB
24.7.3 Utilizing Influx Transporters at the BBB
24.7.4 Targeting Receptor-Mediated Transport Systems at the BBB
24.7.5 Antibody Drug Conjugates (ADCs)
24.7.6 Immunotherapy
24.7.7 Development of Radiosensitization Strategies with Current Standard of Care
24.7.8 Modification of Tight Junctions at the BBB
24.7.8.1 Osmotic Disruption of the BBB
24.7.8.2 Focused Ultrasound
24.7.8.3 Photodynamic Therapy Approaches
24.7.9 Local Delivery Methods
24.7.9.1 Biodegradable Wafers
24.7.9.2 Convection-Enhanced Delivery
24.7.9.3 Intrathecal Delivery
24.8 How Much Is Enough? Drug Pharmacokinetic-Pharmacodynamic (PK-PD) Relationships in Brain Tumors
24.8.1 Drug in Plasma Versus Drug in the Brain Versus Drug in Tumor
24.8.2 Utilizing Appropriate Preclinical Models to Determine Effective Drug Concentration
24.8.3 Impact of Drug Binding in Brain Tumor Treatment
24.8.4 Dosage Regimen Design for Achieving Target Drug Concentration and Desired Pharmacodynamic (PD) Effect
24.9 Conclusions
24.10 Points for Discussion
References
Appendix:: Central Nervous System Anatomy and Physiology: Structure-Function Relationships, Blood Supply, Ventricles, and Brain Fluids
A.1 Introduction to Neuroanatomy
A.2 Central Nervous System Functions
A.3 Cerebrovasculature
A.4 Ventricular System and Brain Fluids
A.5 Conclusions
References
Index