Nervous System Drug Delivery: Principles and Practice

Cover
NERVOUS
SYSTEM DRUG
DELIVERY:

Principles and Practice
Copyright
Dedications
Contributors
Preface
Acknowledgments
Section I: Physiology of Nervous System Drug Delivery
1
Fundamentals of Brain-Barrier Anatomy and Global Functions
	Barriers of the central nervous system
	The neurovascular unit
		Pericytes
		Neuroglia
		Basement Membrane
	Transport routes across the brain endothelium
		Paracellular Pathway
		Transcellular Pathway
	Junctional complexes of the BBB
		Tight Junctions
			Occludin
			Claudins
		Adherens Junctions
			Junctional Adhesion Molecules
			Scaffolding Proteins
	Opening the BBB for therapeutic considerations
	References
2
Blood-Brain Barrier in Disease States
	Blood-brain barrier research
	Building a BBB for experimental studies
	The BBB as an impediment to therapeutic interventions for neurological disease
	The BBB as a target for therapeutic interventions for neurological diseases
	How does the BBB control neuronal activity?
	Conclusions
	References
3
Pharmacokinetics of Systemic Drug Delivery
	Pharmacokinetics and the blood-brain barrier
	The neurovascular unit and the blood-brain barrier
	Pharmacokinetic analysis methods
		Brain Uptake Index Determination
		In Situ Brain Perfusion
		Microdialysis Method and Improvements Using Cassette Dosing
		Pharmacological Inhibition Assay
		Flux Assay
	Pharmacokinetic methods for overcoming the blood-brain barrier
		Peptide Mimics
		RNA Interference
		Intra-Arterial Hyperosmolar Infusion
		Focused Ultrasound
		Molecular Trojan Horse Drug Delivery Across The BBB
		Insulin Receptors
		Transferrin Receptor
		Lipoprotein Receptors
		Diphtheria Toxin Receptor
		Immunoglobulin G Fusion Proteins and Molecular Trojan Horse Technology
		Avidin-Biotin Technology in Molecular Trojan Horse Technology
		Efflux Transporter Inhibitors
		Viral Vectors
		Liposome Delivery of Therapeutics
	Conclusions
	References
4
Pharmacokinetics of Drug Delivery Past the Blood-Brain Barrier
	Introduction
	Anatomy of the BBB
	Methods of measuring pharmacokinetics across the BBB
	Methods of enhancing drug delivery to the CNS
		Transcytosis
		Carrier- and Receptor-Mediated Transport
		Designer Molecules and Manufactured Delivery Systems
		Iron Particles: Ultrasmall Iron Oxide Particles
	Methods that bypass the BBB
	Methods that open the BBB
	Osmotic disruption of the BBB
	Conclusions
	References
5
Anatomy and Physiology of Cerebrospinal Fluid Dynamics
	Introduction
	Summary of cerebrospinal fluid space anatomy
	Biological significance of CSF
	CSF circulation
	Origins of CSF pulsations
	In vivo assessment of CSF dynamics
	Numerical assessment of CSF dynamics
	Solute transport within the CSF
	Acknowledgment
	Funding statement
	References
6
Pharmacokinetics of Polymeric Drug Delivery
	Drug delivery to the central nervous system
	Brain tumors
	The role of the blood-brain barrier in drug delivery
	Polymeric drug delivery to the brain
		Polymer Degradation in Animal and in Vitro Models
		Release of Carmustine from The Wafer
		Metabolic Processing of Sebacic Acid, p(CPP), and Carmustine in Animal Models
			Sebacic Acid
			1,3-Bis-(p-Carboxyphenoxy)propane (p-CPP)
			Carmustine
		Carmustine Distribution in Animal Models and Humans
		Edema and Bulk-Flow Contribute to Interstitial Drug Delivery
		Additional Variables in Drug Penetration
	Pharmacokinetic model
	Clinical use of local chemotherapy in humans
	Conclusions
	References
7
Pharmacokinetic Models of Convection-Enhanced Drug Delivery
	Introduction
	Major tissue flow and pharmacokinetic parameters
		ϕ (Fluid Volume Fraction)
		K (Hydraulic Conductivity or Permeability)
		D (Diffusivity)
		Ps (Product of Permeability Coefficient and Surface Area Per Unit Volume)
		R (Whole Tissue to Extracellular Space Partitioning Parameter)
		k (Reaction Constant)
	Case models of convection-enhanced delivery
		Case i: Quinolinic Acid
		Case ii: SP-DT Neurotoxin
		Case iii: GDNF
	Overview and additional considerations
	References
8
Mechanisms and Clinical Applications of Stem Cell Therapy
	Stem cell technologies
	Human Pluripotent Stem Cells
		Overview
		Clinical Application and Therapeutic Mechanisms of Human Pluripotent Stem Cells
	Fetal-Derived Neural Progenitor Cells
		Overview
		Therapeutic Mechanisms and Clinical Applications of Fetal-Derived Neural Progenitor Cells
	Mesenchymal Stem Cells
		Overview
		Clinical Application and Therapeutic Mechanisms for Mesenchymal Stem Cells
	Stem cell therapies for indications of the central nervous system
		Traumatic Brain Injury
			Overview
		Stem Cell Therapies for Traumatic Brain Injury
		Traumatic Spinal Cord Injury
			Overview
		Stem Cell Therapies for Traumatic Spinal Cord Injury
		Parkinson Disease
			Overview
		Stem Cell Therapies for Parkinson Disease
		Multiple Sclerosis
			Overview
		Stem Cell Therapies for Multiple Sclerosis
		Amyotrophic Lateral Sclerosis
			Overview
		Stem Cell Therapies for Amyotrophic Lateral Sclerosis
	References
	Further Reading
Section II: Nervous System Drug Delivery Techniques
9
Intravenous and Intravascular Drug Delivery
	Overview of the blood-brain barrier
		Tight Junctions
		Cellular Components of The Blood-Brain Barrier
			Endothelial Cells
			Astrocytes
			Pericytes
		Biochemical Components
	Rational drug design
		Prodrugs
		Lipophilic Analogs
		Chemical Drug Delivery Systems
		Carrier-Mediated Transport
	Physical disruption of the blood-brain barrier
		Osmotic Disruption
		Magnetic Resonance Imaging-Guided Focused Ultrasound
		Bradykinin
		Radiation
	Biochemical circumvention of the blood-brain barrier
		Convection-Enhanced Delivery
		Receptor-Mediated Transport
		Cell-Penetrating Peptides
		Cell-Mediated Drug Delivery
		Oncolytic Viruses
		P-glycoprotein Modulation
	Conclusions
	References
10
Blood-Brain Barrier Disruption
	Introduction
	Delivering agents across the BBB: Factors that impact chemotherapy delivery to brain tumors, from preclinical studies to c ...
	The clinical method of osmotic blood-brain barrier opening
	Clinical results with blood-brain barrier disruption
	Future directions for blood-brain barrier disruption
	Conclusions
	Acknowledgments
	References
11
Ultrasonic Methods
	Introduction
	Focused ultrasound
		Basic Physical Principles
		Biological Effects
	Blood-brain barrier disruption
		Mechanism of BBB Disruption
		Safety
		Factors Affecting Opening and Closure of the BBB
	Therapeutic delivery
		Neuro-oncology
			Breast Cancer Brain Metastasis
			Glioblastoma Multiforme
			Diffuse Intrinsic Pontine Glioma
		Neurodegenerative Disease
			Alzheimer Disease
			Parkinson Disease
		Other Emerging Indications
	Future prospects
	References
12
Nanoparticles for Brain Tumor Delivery
	Nanoparticles for treatment of brain tumors
	Brain tumor physiology and microenvironment
	Physiological barriers to nanoparticle delivery
	Passive accumulation of nanoparticles by the EPR effect
		siRNA Delivery
		Antivascular Effects of Drug-containing Nanoparticles
	Vascular permeability modulation to enhance EPR-mediated delivery
		Molecular Modulation of Barrier Properties
		Mechanical Modulation of Barrier Properties
	Targeted nanoparticles
	Quantitative tools for development of nanoparticle delivery strategies
	Conclusions
	Acknowledgments
	References
13
Solute Transport in the Cerebrospinal Fluid: Physiology and Practical Implications
	Physiological mechanisms of drug delivery to the central nervous system via cerebrospinal fluid and perivascular channels
	Methods
		Research Animals
		Positron Emission Tomography
		Fluorescence Microscopy With in Vivo Labeling of Perivascular Cells
			Monitoring CSF Pressure
	Key results and discussion
		The Initial Translocation of the Intrathecal Bolus
		Acceptance of Large Additional Volume and Hydrostatic Compliance
		Solute Spread in the CSF: Hydrodynamic Factors
		Solute Clearance from the CSF: Clearance Routes and Solute Molecule/Particle Size Dependence
		Perivascular Entrance and Transport of Macromolecules into the CNS
		The State of Perivascular Channels in Disease
		Overall Physiological Pharmacokinetic Scheme
	Conclusions
	Acknowledgments
	References
	Further Reading
14
Drug-Impregnated Polymer Delivery
	Tumors of the central nervous system
	Natural barriers to the central nervous system
		The Neurovascular Unit
		The Extracellular Space
		The Blood-Brain Tumor Barrier
	Delivery of neurooncology therapeutics
		Polymer Development
		The Polyanhydride Wafer
	Carmustine
		Preclinical Carmustine Studies
		Clinical Applications of Carmustine
			Interstitial Chemotherapy for Recurrent GBM
			Interstitial Chemotherapy for Newly Diagnosed GBM
			Interstitial Chemotherapy for Brain Metastases
			Future Directions with the Polymeric Wafer
	Polymeric drug delivery: Preclinical models and future applications
		Hydrogels
			PLGA-Based Hydrogels
			Photosensitive Hydrogels
		Polymeric Nanoparticle-Based Systems
		Synthetic Polymers
		Natural Polymers
		Microchips
	Additional techniques
	Conclusions
	References
	Further Reading
15
Immunomodulatory Methods
	Immunotherapy for malignancies of the central nervous system
	Immune biologics: Antibodies for the treatment of diseases of the central nervous system
		Production and History
		Mechanism of Action and Applications
	Naked monoclonal antibodies
		Monoclonal Antibodies in Neuro-Oncology
			Clinical Implementation Limitations
		Immune Checkpoint Inhibitors
		Indoleamine 2,3-Dioxygenase Pathway Approaches
			Clinical Implementation Limitations
		Monoclonal Antibodies for Patients with Multiple Sclerosis
		Monoclonal Antibodies for Patients with Alzheimer Disease
		Monoclonal Antibodies for Patients with Headaches
			Targeting the Trigeminovascular Calcitonin Gene-Related Pain Mediated Pathway
	Conjugated monoclonal antibodies: Bispecific antibodies, antibodies-drug conjugates, recombinant immunotoxin therapy, radio ...
		Bispecific Antibodies
			Clinical Implementation Limitations
		Antibody-Drug Conjugates
			Clinical Implementation Limitations
		Recombinant Immunotoxin Therapy
			Clinical Implementation Limitations
		Radioimmunotherapy
			Clinical Implementation Limitations
		Immunoliposomes
			Clinical Implementation Limitations
	Cytokines for the treatment of diseases of the central nervous system
		Definition and Function
		Cytokines Across the BBB
		Applications of Cytokines in Neurological Disease: Stroke, Alzheimer Disease, Multiple Sclerosis, Tumors
			Clinical Implementation Limitations
	Cell-based therapies for the treatment of diseases of the central nervous system
		Adoptive Cell Therapy
			Clinical Implementation Limitations
	Active immunotherapy for the treatment of diseases of the central nervous system
		Clinical Implementation Limitations
		Virotherapy
			Clinical Implementation Limitations
	Conclusions
	References
16
Convection-Enhanced Drug Delivery in the Central Nervous System
	Introduction
	Biomechanics and properties of CED in the CNS
		General Properties of CED
		CED Bypasses the BBB
		Targeted Delivery
		Homogeneous Distribution
		Reproducible Distribution
		Clinically Relevant Distribution
		Patterns of Infusate Flow
		Effect of Anatomic Regions
	Convective delivery methodology
		Acute Delivery in the Brain
		Infusion Rates
		Process for Chronic Delivery
	Imaging of convective delivery
		Benefits of Intraoperative Imaging
		Imaging Tracers
		Intraoperative MR Imaging
	Reflux-resistant infusion CANNULAE
		Mechanics and Common Causes of Reflux
		Step Design Reflux-Resistant Cannulae
		Shape-Conforming of Infusate Using Controlled Backflow
		Optimized Cannula Placement
		High Reproducibility with Optimized Cannula Placement
	Infusion volume
		Vd to Vi Ratio in AAV Clinical Trials
	Guidance systems
		Shift from Frame-Based to Frameless Systems
		Ball-Joint Guide Array
	Conclusions
	References
17
Stem Cell Transplantation for Neurological Disease: Technical Considerations and Delivery Devices
	Stem cells in neurologic disease
	Selection of the optimal strategy for stem cell delivery
		Technical Considerations for Intraparenchymal Stem Cell Delivery
			Cell Viability
			Avoiding Reflux of Delivered Cells
			Accuracy of Delivery: Frame-based or Frameless Stereotactic Targeting
		Available Stem Cell Delivery Platforms
			The Straight Cannula-syringe Delivery System
				Limitations in scalability
				The need for multiple injections
			Radial Distribution Cannulas
			Intracerebral Microinjection Instrument
			Radially Branched Deployment Device
			Adaptation to Interventional MRI
	Conclusions
	References
18
CRISPR-Cas Gene Editing for Neurological Disease
	Introduction
	CRISPR-Cas gene editing in mammalian systems
	Moving CRISPR-Cas gene editing toward the clinic
	CRISPR-Cas RNA targeting
	CRISPR transcriptional regulation in the mammalian brain
	References
Section III: Clinical Application of Nervous System Drug Delivery
19
Drug- and Disease-Specific Paradigms for Drug Delivery to the Central Nervous System
	Challenges of delivering drugs to the central nervous system
	The blood-brain barrier
		The Blood-brain Barrier in Disease States
		Blood-brain Barrier Modulation
		High-intensity Focused Ultrasound
	The brain-cerebrospinal fluid barrier
	Drug-delivery routes for the central nervous system
		Intra-arterial Drug Delivery
		Intrathecal/intraventricular Drug Delivery
		Direct Injection
		Convection-enhanced Delivery
		Dissolvable Wafers
		Intranasal Delivery
	Drug-based paradigms
		Chemotherapy
		Immunotherapy
		Drug-coupling Agents
			Nanoparticles
			Liposomes
		Gene Therapy: Systemic and Direct Injection
			Viral Vectors
			Nonviral Gene Therapy
			Cell-based Gene Therapy
	Disease-specific paradigms
		Glioblastoma Multiforme
		Parkinson Disease
		Other Neurodegenerative Conditions
			Huntington Disease
			Spinal Muscular Atrophy
			Friedreich Ataxia
		Genetic Disorders
			Metachromatic Leukodystrophy
			Stroke
			Pain
	Future work
		Stem Cell Therapies
		CRISPR
	Conclusions
	References
20
Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Brain Tumors
	Convection-enhanced delivery of drugs to the brain
	DCE-MRI for tumors
		Indicator-Dilution Methods for Estimating Microvascular Permeability
			The Graphical Patlak Method and its Extension
			MRI Contrast and Contrast Agent Concentration
			An Example Analysis in an Animal Model of Cerebral Tumor
			The Logan Plot in DCE-MRI
		DCE-MRI Measures of Tumor Fluid and Mechanical Properties
		Combined Measures of Tumor Physiology: Acute Changes after High-Dose Radiotherapy
		MRI Estimates of Tissue Fluid Conductivity and TIFP
	Conclusions
	The Crone-Renkin single-capillary model
	Logan Plot Theory
	References
21
Clinical Methods of Nervous System Drug Delivery for Tumors
	Drug delivery for treatment of glioblastoma
	Methods of drug packaging
		Nanovectors
		Polymers
		Hydrogels
		Microchips
	Methods of drug delivery
		Direct Injection
		Convection-Enhanced Delivery
	Matching drugs with methods
	Conclusions
	References
22
Delivery Methods for Treatment of Genetic Disorders
	Gene therapy in the 21st century
	Non-integrating viral vectors
	Integrating viral vectors
	Nonviral gene editing
	Cellular therapy
	Principles of approaches to the CNS
	Conclusions
	References
23
Direct Convective Nervous System Drug Delivery for Patients with Neurodegenerative Disorders
	Intraoperative magnetic resonance imaging-guided convection-enhanced delivery
	The clearpoint system
	iMRI environment
		ClearPoint Workflow
	Other considerations in intracerebral drug delivery
	Conclusions
	References
24
Central Nervous System Drug Delivery After Ischemic or Hemorrhagic Stroke
	Drug delivery after stroke
	Pathophysiology of ischemic stroke
	Barriers to central nervous system drug delivery
		The Blood-Brain Barrier
		Pathologic Changes in Stroke that Alter Drug Delivery
	Systemic delivery
		Chemical Ligand-enhanced Conjugation
		Biological Conjugation
		Colloidal Drug Carriers
	Localized CNS delivery
		Intra-arterial Delivery
		Intraventricular/Intrathecal Delivery
		Intranasal
		Direct Local Injection
	Goals of drug delivery to the CNS after stroke
		Intra-arterial Thrombolytic Therapy
		Intra-arterial Vasodilator Therapy For Cerebral Vasospasm
		Intraventricular Applications in Patients with Hemorrhagic Stroke
		Sonolysis
		Neuroprotection
		Restorative Stem Cell Therapies
	Conclusions
	References
25
Intrathecal Drug Delivery for Cancer Pain
	Pain management in cancer patients
	Initial evaluation
		Intrathecal Drug Delivery Systems
	Drug selection
		Panel Recommendations from the 2017 PACC
		Compounding of Medications
		Drug Flow Rates and Intermittent Bolusing
		Trial Period for Determination of Permanent Intrathecal Therapy
		Adverse Effects and Complications
	Current evidence for intrathecal therapy
		Emerging Intrathecal Pain Control Agents
			Substance P-saporin and Substance P-pseudomonas Exotoxin-35 for Pain Control
				Basic biochemistry
				Preclinical trials with SP-SAP and SP-PE35
				Human clinical trial experience with SP-SAP and SP-PE35
		Resiniferatoxin for Pain Control
			Basic Neurobiology
			Clinical Indications and Administration Routes for Resiniferatoxin
			Preclinical Trials with Resiniferatoxin
			Human Clinical Trial Experience with Resiniferatoxin
		Future Research
	Conclusions
	References
Index
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