Nanotherapy for Brain Tumor Drug Delivery

Preface to the Series
Preface
Contents
Contributors
Chapter 1: Glioblastoma: State of the Art of Treatments and Applications of Polymeric and Lipidic Nanomedicines
1 Brain Tumors
2 Glioblastoma
2.1 Incidence
2.2 Etiology
2.3 Prognosis
2.4 Clinical Subtypes
2.5 Pathogenesis
3 Diagnosis and Treatment Guidelines
3.1 Diagnosis
3.1.1 Clinical Characteristics
3.1.2 Image Instruments
3.1.3 Tumor Samples
3.1.4 Molecular Markers
3.2 Therapy
3.2.1 Neurosurgery
3.2.2 Radiotherapy
3.2.3 Cytotoxic Chemotherapy
4 Critical Issue in Current Managements
4.1 Surgery
4.2 Radiotherapy
4.3 Drug-Delivery Limits
4.4 Life Expectancy and Therapeutic Patterns
5 The Blood-Brain Barrier
5.1 Structure
5.2 Intercellular Junctions of BBB
5.3 Transport across the BBB
5.4 Blood-Brain-Tumor Barrier
6 The Promise of Nanomedicine
6.1 Nanomedicines for Drug Delivery
6.2 Key Features of Nanomedicines
6.3 Targeting Brain Tumors
7 Nanoparticles for Brian Tumor Therapy
7.1 Paclitaxel
7.2 Docetaxel
7.3 Doxorubicin
7.4 Temozolomide and Nitrosoureas Drugs
8 Conclusion and Perspectives
References
Chapter 2: Passive and Active Targeting of Brain Tumors
1 Introduction
1.1 Types of Brain Tumors and Their Molecular Hallmarks
1.2 Blood-Brain Barrier
1.3 Drug Delivery to the Brain
1.4 Intranasal Brain Delivery
2 Materials
3 Methods
3.1 Intranasal Delivery of Doxorubicin (Dox) Using Nanoparticles Loaded into Intranasal Inserts
3.1.1 Preparation of Dox-Loaded Nanoparticles
3.1.2 Loading of Dox Nanoparticles into Intranasal Inserts
3.1.3 Characterization
3.1.4 Notes
3.2 Preparation of Poly(Ethyleneimine) (PEI)-Grafted Magnetic Nanoparticles for Magnetic Targeting of Brain Tumors
3.2.1 Synthesis of Magnetic Nanoparticles (MNP)
3.2.2 Coating of MNP by Gum Arabic
3.2.3 Preparation of Polyethylenimine (PEI)-Coated Nanoparticles
3.2.4 Characterization
3.2.5 Notes
3.3 Actively Targeted Liposomes with Cysteine-Triggered Unmasking of the Targeting Ligands
3.3.1 Synthesis of Cysteine Cleavable Lipid PEG Conjugates
3.3.2 Synthesis of DSPE-PEG2000-Folate Conjugates
3.3.3 Preparation of Targeted and Non-targeted Liposomes
3.3.4 Characterization
3.3.5 Notes
4 Conclusion
References
Chapter 3: Strategies to Modulate the Blood-Brain Barrier for Directed Brain Tumor Targeting
1 Overview: Brain Tumor Therapy (Obstacles and Alternatives)
2 The Blood-Brain Barrier
3 Convection-Enhanced Delivery
3.1 Background
3.2 Materials
3.3 Methods
3.3.1 Preparation of the Infusion Pumps
3.3.2 Pump Loading
3.3.3 Osmotic Pump Implantation
3.3.4 CED Notes
4 MR-Guided Focused Ultrasound
4.1 Background
4.2 Materials
4.3 Methods
4.3.1 Ultrasound and MRI Setup
4.3.2 Animal Prep
4.3.3 Target Selection
4.3.4 Microbubble Prep
4.3.5 Ultrasound Delivery
4.3.6 Flow of MRI Visualized Cavitation
5 MRgFUS Notes
6 Self-Assembling Hydrogels
6.1 Background
6.2 Materials
6.2.1 Peptide Synthesis
6.2.2 Self-Assembling Prodrug (SAPD) Synthesis and Characterization
6.2.3 Calibration of the Concentration
6.3 Techniques for Hydrogel Characterization
6.3.1 Transmission Electron Microscopy (TEM)
6.3.2 Circular Dichroism (CD)
6.3.3 In Vitro Drug Release
6.3.4 Cell Viability in Response to Supramolecular Hydrogels
6.4 Delivery Methods for Hydrogels in Vivo
6.5 Other Types of Peptide Conjugate Systems to Target Brain Tumors
7 Self-Assembling Hydrogels Notes
8 Future Directions
References
Chapter 4: Drug Delivery Approaches and Imaging Techniques for Brain Tumor
1 Introduction
1.1 Types of Brain Tumor
1.2 The Blood-Brain Barrier
2 Strategies for Enhanced Brain Drug Delivery
2.1 Nanotechnology
2.2 Focused Ultrasound
2.3 Hyperthermia
3 EPR Effects
4 Cell-Penetrating Peptides
5 Ligand-Mediated Delivery
5.1 Strategy I: Bypassing the BBB
5.2 Strategy II: Disrupting the BBB
5.3 Strategy III: Penetrating the BBB
6 Nanoparticle-Based Drug Delivery and Imaging Techniques to Identify Brain Tumors
7 Other Drug Delivery System
7.1 Stem Cell Therapy
7.2 Vaccines for Glioblastoma
7.3 Photodynamic Therapy
8 Conclusion and Future Perspective
References
Chapter 5: Surface-Modified Nanodrug Carriers for Brain Cancer Treatment
1 Introduction to Brain Cancer and Current Therapies
2 Barriers to Brain Cancer Treatment
3 Drug Nanoparticle Formulations May Overcome Brain Tumor Treatment Barriers
4 Molecular Targets for Brain Cancer Nanotherapeutics
4.1 Epidermal Growth Factor Receptor (EGFR)
4.2 Epidermal Growth Factor Receptor Variant III (EGFRvIII)
4.3 vβ3 Integrin
4.4 Transferrin Receptor (TfR)
4.5 Lipoprotein Receptor-Related Protein (LRP)
4.6 d-Glucose Transporter (GLUT)
4.7 Glial Fibrillary Acidic Protein (GFAP) and Connexin 43 (Cx43)
4.8 Fibroblast Growth Factor-Inducible 14 (Fn14)
5 DART Nanoparticles: Tissue-Penetrating, Fn14-Targeted Nanotherapeutics
6 Future Perspectives
References
Chapter 6: Inorganic Nanostructures for Brain Tumor Management
1 Introduction
1.1 Brain Tumor and Its Occurrence
1.2 Clinical Features
1.3 Diagnosis of the Brain Tumors
1.4 Genetics of Brain Tumors
1.5 Risk Factors
1.6 Treatment Options for the Brain Tumor
1.7 Scope of Further Research in Brain Tumor Treatment
1.8 Known Hurdles in the Treatment of Brain Tumors
2 Potential and Advantages of Nanoformulations in Brain Tumor Therapy
2.1 Nanoparticle-Based System: A Promising Nanomedicine Approach for Brain Tumor
2.2 Therapeutic Inorganic Nanostructures
3 Methodologies for Nanomaterials Synthesis and Characterization
3.1 Synthesis of Inorganic Nanostructures
3.1.1 Lithography
3.1.2 Ball Mill Method
3.1.3 Chemical Vapor Deposition (CVD)
3.1.4 Coprecipitation Method
3.1.5 Sol-Gel
3.1.6 Hydrothermal Synthesis
3.1.7 Microemulsion Method
3.1.8 Reduction Method
3.2 Characterization of Inorganic Nanostructures
4 Biomedical Application of Inorganic Nanostructures
4.1 Application of Nanoparticles as Nanocarrier in Drug Delivery
4.2 Role of Nanoparticles in Brain Tumor Management
4.2.1 Therapeutic Cancer Vaccine
4.2.2 Imaging and Sensing Probes
4.2.3 Cancer Biomarker
4.2.4 Drug Delivery Vehicles
5 Challenges and Future Prospects
6 Conclusion
References
Chapter 7: Strategies to Enhance the Distribution of Therapeutic Nanoparticles in the Brain by Convection Enhanced Delivery
1 Introduction
1.1 Key Challenge to Therapeutic Delivery to the Brain: Limited Therapeutic Distribution
1.2 Convection Enhanced Delivery as a Strategy to Enhance the Therapeutic Distribution in the Brain
1.3 Challenges for Therapeutic Distribution in the Brain by CED
1.4 Strategies to Enhance NP Distribution in the Brain Following CED
1.5 CED in Clinical Trials
2 Materials
2.1 CED Apparatus
2.2 Syringe and Cleaning Solutions
2.3 Preparation of NPs and Infusate Solutions
2.4 Animal Setup
2.5 Tissue Processing and Confocal Microscopy
3 Methods
3.1 CED Device Arrangement
3.2 Determination of Infusion Parameters
3.3 NP Formulation and Characterization
3.4 Animal Preparation and Execution of CED
3.5 Tissue Processing and Imaging Analysis
4 Notes for Troubleshooting
4.1 Cleaning of Needle Sleeve
4.2 Removal of Air Bubbles
5 Conclusion
References
Chapter 8: Focused Ultrasound-Mediated Blood-Brain Barrier Disruption for Enhanced Drug Delivery to Brain Tumors
1 Blood-Brain Barrier and the Central Nervous System
2 Blood-Brain Barrier and the Immunological Landscape of the Central Nervous System
3 Glioblastoma
4 Focused Ultrasound-Induced BBB Disruption for Enhanced Drug Delivery
5 Focused Ultrasound-Induced BBB Disruption for Enhanced Drug Delivery in Preclinical Studies
6 Conclusions
7 Future Perspectives
References
Chapter 9: Neurosurgical Implant-Based Strategy for Brain Cancer Therapy
1 Introduction
2 The Blood-Brain Barrier
3 Development of Polyanhydride Wafers
4 Preclinical Experiments
5 Clinical Trials
6 Meta-Analysis of Safety and Efficacy of Gliadel Use
7 Further Studies
8 Future Perspectives
9 Conclusion
References
Chapter 10: Liposome-Templated Hydrogel Nanoparticles for Targeted Delivery of CRISPR/Cas9 to Brain Tumors
1 Introduction
1.1 Direct Genetic Modification for Cancer Gene Therapy
1.2 CRISPR/Cas9 as a Promising Gene Editing System
1.3 The BBB as a Major Barrier for Delivery of Therapeutics to the Brain
1.4 Overview of LHNPs
1.5 LHNPs for Targeted Delivery of CRISPR/Cas9 to Brain Tumors
2 Materials and Methods
2.1 Generation of Cas9-Expressing Cells
2.2 Cas9 Protein Expression and Purification
2.3 Mini Circle sgRNA Preparation
2.4 LHNP Preparation
2.5 Characterization of Encapsulation Efficiency and Drug Release
2.6 Preparation of LHNPs for Transmission Electron Microscopy (TEM)
3 Results and Discussion
3.1 Characterization of LHNPs
3.2 Gene Knockout in U87MG-GFP Cells
3.3 Gene Knockout in U87MG-GFP Brain Tumor-Bearing Mice
4 Conclusion
References
Chapter 11: Methods to Separate, Characterize, and Encapsulate Drug Molecules into Exosomes for Targeted Delivery and Treatmen...
1 Introduction
2 Methods of Isolation
2.1 Differential Centrifugation
2.1.1 Materials
2.1.2 Method of Isolation
2.2 Sequential Centrifugation
2.2.1 Materials
2.2.2 Method of Isolation
2.3 Precipitation Method
2.3.1 Materials
2.3.2 Method of Isolation
2.4 Density Gradient Method
2.4.1 Materials
2.4.2 Method of Isolation
2.5 Immunoisolation
2.5.1 Materials
2.5.2 Method of Isolation
2.6 Isolation of RNA from Exosomes
2.6.1 Materials
2.6.2 Method of Isolation
3 Characterization of Exosomes
3.1 Nanoparticle Tracking Analysis (NTA)
3.1.1 Materials
3.1.2 Method
3.2 Dynamic Light Scattering Method
3.2.1 Materials
3.2.2 Methods
3.3 Western Blotting Method
3.3.1 Materials
3.3.2 Method
3.4 Flow Cytometry
3.4.1 Materials
3.4.2 Method
4 Transmission Electron
4.1 Copper Grid Method
4.1.1 Materials
4.1.2 Method
4.2 Glutaraldehyde Method
4.2.1 Materials
4.2.2 Method
5 Drug Loading into Exosomes
5.1 Incubation
5.1.1 Materials
5.1.2 Method of Loading
5.2 Sonication
5.2.1 Materials
5.2.2 Method of Loading
6 Electroporation
6.1 Loading of Doxorubicin into Exosomes Using Electroporation
6.1.1 Materials
6.1.2 Method of Loading
6.2 Loading of siRNA into Exosomes Using Electroporation
6.2.1 Materials
6.2.2 Method of Loading
7 Methods of Labeling Exosomes
7.1 Fluorescent Labeling
7.1.1 Materials (Exo-Red or Exo-Green Kit)
7.1.2 Method of Fluorescent Labeling
7.2 PKH Lipophilic Membrane Dyes
7.2.1 Materials
7.2.2 Method
8 Conclusion
References
Chapter 12: Establishing Orthotopic Xenograft Glioblastoma Models for Use in Preclinical Development
1 Introduction
2 Materials
2.1 Cell Suspension Preparation
2.2 Animal Anesthesia
2.3 Animal Placement on the Stereotaxic Instrument
2.4 Surgical Procedure
2.5 Surgery Recovery
2.6 Tumor Imaging with MRI
3 Methods
3.1 Cell Suspension Preparation
3.2 Animal Anesthesia
3.3 Animal Placement on the Stereotaxic Instrument
3.4 Surgical Procedure
3.5 Surgery Recovery
3.6 Tumor Imaging with MRI
4 Notes
5 Conclusions
References
Index