Front Cover

Neurotoxicity of Nanomaterials and Nanomedicine

Neurotoxicity of Nanomaterialsand Nanomedicine

Copyright

Contents

List of Contributors

Biography

Xinguo Jiang, BS

Huile Gao, PhD

Preface

Introduction and Overview

HOW DO NANOMATERIALS AND NANOMEDICINES ENTER INTO AND GET EXCRETED FROM BRAIN?

WHAT IS THE NEUROTOXICITY OF NANOMATERIALS?

CONCLUSION

1 - The Medical Applications of Nanomaterials in the Central Nervous System

1. INTRODUCTION

2. SMALL CHEMICAL DRUGS DELIVERY

2.1 Natural Nanomaterials

2.2 Anionic and Neutral Polymers

2.3 Dendrimers

2.4 Metal Nanoparticles

2.5 Carbon-Based Inorganic Nanomaterials

3. PEPTIDE AND PROTEIN DELIVERY

3.1 Natural Nanomaterials

3.2 Polymers

4. GENE DELIVERY

4.1 Lipid Nanomaterials

4.2 Cationic Polymers

4.3 Dendrimers

4.4 Other Materials

5. NANOMATERIALS AS IMAGING PROBE

5.1 Iron Oxide Nanoparticles

5.2 Quantum Dots

5.3 Carbon Dots

6. CONCLUSION AND PERSPECTIVE

REFERENCES

2 - The Route of Nanomaterials Entering Brain

1. INTRODUCTION

2. TRANSPORTER-MEDIATED TRANSCYTOSIS

2.1 Hexose Transporters

2.2 Choline Transporters

2.3 Amino Acid Transporters

3. RECEPTOR-MEDIATED TRANSCYTOSIS

3.1 Transferrin Receptor

3.2 Insulin Receptor

3.3 Low-Density Lipoprotein Receptor-Related Proteins

3.4 Nicotine Acetylcholine Receptor

4. ADSORPTIVE-MEDIATED TRANSCYTOSIS

4.1 Cell-Penetrating Peptides

4.2 Cationic Proteins

4.3 Methods That Improve the Nonselectivity of AMT

5. INTRANASAL DRUG DELIVERY

6. INHIBITING THE FUNCTION OF THE BLOOD–BRAIN BARRIER

6.1 Inhibition of Efflux Pumps

6.2 Disturbing the Structure of the Blood–Brain Barrier

7. NANOMATERIALS ENTERING THE BRAIN UNDER PATHOLOGICAL CONDITIONS

8. SUMMARY AND PROSPECTS

REFERENCES

3 - The Distribution and Elimination of Nanomaterials in Brain

1. BLOOD–BRAIN BARRIER

2. EXISTING PATHWAYS FOR THE BRAIN DELIVERY OF NANOMATERIALS

2.1 Entering the CNS Across the BBB

2.2 Nose-to-Brain Delivery

2.3 Direct Injection or Implantation Into the CNS

3. DISTRIBUTION OF NANOMATERIALS IN BRAIN

3.1 Size

3.2 Surface Charge

3.3 Shape

3.4 Targeting Ligands

3.5 Administration Routes

3.6 Chronobiology

3.7 Disease Conditions

4. ELIMINATION OF NANOMATERIALS IN BRAIN

4.1 Deformability and Biodegradability of the Matrix

4.2 Size and Surface Charge

4.3 Targeting Ligands

4.4 Conscious State

4.5 Disease Conditions

4.6 Brian Regional Distribution

5. CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

4 - Current Perspective on Nanomaterial-Induced Adverse Effects: Neurotoxicity as a Case Example

1. NANOTOXICOLOGY

2. NEUROTOXICOLOGY

3. BRAIN AS THE TARGET OF NPS

4. TOXICITY OF NANOPARTICLES

4.1 Toxicity of Carbon-Based Nanoparticles

4.1.1 Fullerenes

4.1.2 Carbon Nanotubes

4.1.3 Graphene

4.2 Metal-Based Nanoparticles

4.2.1 Silver Nanoparticles

4.2.2 Gold Nanoparticles

4.2.3 Metal Oxide Nanoparticles

4.3 Quantum Dots

4.4 Particulate Matter

5. MECHANISMS OF NANOTOXICITY

6. RELEASE OF NANOPARTICLES INTO ENVIRONMENT

7. FACTORS CONTRIBUTING TO NANOTOXICITY

8. INTERACTION OF NANOPARTICLES WITH OTHER CHEMICALS IN THE ENVIRONMENT

9. SAFETY CONSIDERATIONS

10. REDUCING EXPOSURE AND NEUROTOXICITY

REFERENCES

5 - Toxicity of Titanium Dioxide Nanoparticles on Brain

1. INTRODUCTION

2. APPLICATIONS OF TIO2 NANOPARTICLES

3. MAIN ROUTES OF TIO2 NANOPARTICLES INTO THE BRAIN

3.1 Translocation of TiO2 Nanoparticles From the Blood to the Brain

3.2 Axonal Translocation of TiO2 Nanoparticles From the Nose to the Brain

3.3 Translocation Into the Brain of Offspring Through the Placental Barrier

4. BIODISTRIBUTION AFTER DIFFERENT ADMINISTRATION ROUTES AND ELIMINATION RATE OF TIO2 NANOPARTICLES FROM THE BRAIN

4.1 Biodistribution

4.2 Elimination

5. MAIN MECHANISMS UNDERLYING NEUROTOXICITY OF TIO2 NANOPARTICLES

5.1 Oxidative Stress

5.2 Apoptosis and Autophagy

5.3 Immune Mechanism

5.4 Activated Signaling Pathways

6. MAJOR FACTORS INFLUENCING THE NEUROTOXICITY OF TIO2 NANOPARTICLES

6.1 Crystal Type

6.2 Size of Nanoparticles

6.3 Shape and Surface Modification

6.4 Administration Route

7. SUMMARY

REFERENCES

6 - The Application, Neurotoxicity, and Related Mechanism of Iron Oxide Nanoparticles

1. IRON OXIDE NANOPARTICLES

2. APPLICATIONS OF IRON OXIDE NANOPARTICLES

2.1 Magnetic Resonance Imaging Contrast Agent

2.2 Hyperthermia

2.3 Drug Delivery

3. MECHANISMS OF ION TOXICITY

4. NEUROTOXICITY

4.1 Mechanisms and Pathways of ION Entry to the Brain

4.2 In Vitro Studies on ION Neurotoxicity

4.2.1 Neurons

4.2.2 Astrocytes

4.2.3 Microglia

4.2.4 Oligodendrocytes

4.3 In Vivo Studies on ION Neurotoxicity

5. CONCLUSIONS

REFERENCES

7 - The Application, Neurotoxicity, and Related Mechanisms of Silver Nanoparticles

1. INTRODUCTION

2. CURRENT AND FUTURE APPLICATIONS OF AGNPS IN MEDICINE

3. BIODISTRIBUTION OF AGNPS IN MAMMALIAN ORGANISMS

4. AGNP-INDUCED NEUROTOXICITY

4.1 Adverse Effects of AgNPs in Brain Cells

4.2 AgNPs Influence Blood–Brain Barrier Function

5. CELLULAR AND MOLECULAR MECHANISMS OF AGNPS NEUROTOXICITY

5.1 Mitochondria, Oxidative Stress, Inflammation, and Cell Death

5.2 Interactions With Cellular Calcium and NMDA Glutamate Receptors

5.3 AgNP-Induced Neurodegeneration

6. PHYSICOCHEMICAL PARAMETERS INFLUENCING THE TOXICITY OF SILVER NANOPARTICLES

6.1 Size

6.2 Shape and Coating

6.3 Release of Ions

7. SUMMARY

ACKNOWLEDGMENTS

REFERENCES

8 - The Applications, Neurotoxicity, and Related Mechanism of Gold Nanoparticles

1. INTRODUCTION

2. SYNTHESIS

3. ADVANTAGES

4. PHARMACOKINETICS

4.1 Absorption

4.2 Distribution

4.3 Metabolism

4.4 Elimination

5. APPLICATIONS

5.1 Electronics

5.2 For Labeling

5.3 Sensors

5.4 As Delivery Vehicle

5.5 Probes

5.6 As Heat Source

5.7 Catalysis

6. MECHANISM OF CELLULAR UPTAKE

6.1 Phagocytosis

6.2 Pinocytosis

6.2.1 Macropinocytosis

6.2.2 Clathrin-Mediated Endocytosis

6.3 Caveolae-Dependent Endocytosis

6.4 Adhesive Interactions

7. GENERAL MECHANISM OF TOXICITY

7.1 Oxidative Stress

7.2 Disruption of Lipid Bilayer

7.3 Necrosis/Apoptosis

7.4 Mitochondrial Dysfunction

7.5 DNA Damage

7.6 Endocrine Disruption

8. FACTORS AFFECTING TOXICITY

8.1 Size

8.2 Shape

8.3 Surface Charge

8.4 Surface Chemistry

9. NEUROTOXICITY

9.1 Neuronal Uptake

9.1.1 Neuronal Uptake via Olfactory Nerves

9.1.2 Neuronal Uptake via Blood–Brain Barrier

9.2 General Neurotoxicity

9.3 Neurological Pathology

9.3.1 Astrogliosis

9.3.2 Generation of Seizure Activity

9.3.3 Cognition Defect

10. CONCLUSION

LIST OF ABBREVIATIONS

REFERENCES

9 - The Applications, Neurotoxicity, and Related Mechanisms of Manganese-Containing Nanoparticles

1. CHEMICAL PROPERTIES AND APPLICATIONS OF MANGANESE

1.1 Chemical Properties of Manganese

1.2 Applications of Manganese in Industrial, Research, and Medical Purposes

2. ENVIRONMENTAL AND OCCUPATIONAL EXPOSURE TO MANGANESE

2.1 Overview

2.2 Environmental Exposure in Industry Concerning Manganese

2.3 Environmental Exposure Caused by MMT Exhaust

3. MANGANESE-ASSOCIATED NEURODISORDERS AND PATHOPHYSIOLOGY OF MANGANESE NEUROTOXICITY

3.1 Manganese and Neurological Disorders

3.2 Mechanisms of Neurological Disorders by Manganese

4. NEUROTOXICITY MECHANISMS OF MANGANESE NANOPARTICLES

4.1 Manganese Nanoparticles

4.2 Transport of Manganese Into Central Nervous System

4.3 Manganese Nanoparticles and Neurotoxicity and Perspectives of Manganese Nanoparticle

5. SUMMARY AND CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

10 - The Application, Neurotoxicity, and Related Mechanism of Silica Nanoparticles

1. INTRODUCTION

2. APPLICATIONS OF SILICA NANOPARTICLES

2.1 Drug Delivery

2.2 Gene Delivery

2.3 Bioimaging

2.4 Cosmetics

3. NEUROTOXICITY OF SILICA NANOPARTICLES

3.1 The Absorption, Distribution, Metabolism, and Excretion of Silica Nanoparticles

3.2 Factors Affecting Neurotoxicity of Silica Nanoparticles

3.3 Possible Mechanism of Neurotoxicity by Silica Nanoparticles

4. CYTOTOXICITY OF SILICA NANOPARTICLES

4.1 Factors Contributing to Cytotoxicity of Silica Nanoparticles

4.2 Possible Mechanism of Cytotoxicity of Silica Nanoparticles

5. SUMMARY

REFERENCES

11 - The Synthesis, Application, and Related Neurotoxicity of Carbon Nanotubes

1. INTRODUCTION

2. STRUCTURE OF CNTS

3. SYNTHESIS

4. MODIFICATION/FUNCTIONALIZATION

4.1 Covalent Functionalization

4.2 Noncovalent Functionalization

5. CARBON NANOTUBE-RELATED APPLICATIONS

5.1 Tissue Engineering

5.1.1 Bone Tissue Engineering

5.1.2 Neural Tissue Engineering

5.2 Cancer Diagnostics and Treatment

5.2.1 Target Recognition

5.2.2 Drug Loading and Release

6. TOXICITY

6.1 Neurotoxicity

6.1.1 In Vivo Studies

6.1.2 In Vitro Studies

6.2 Other Toxicity Studies

7. CONCLUSIONS AND FUTURE DIRECTIONS

REFERENCES

12 - THE APPLICATION, NEUROTOXICITY, AND RELATED MECHANISM OF CATIONIC POLYMERS*

1.1 Chitosan

1.2 Poly(l-lysine)

1.3 Polyethylenimines

1.4 Polypropylenimine

1.5 Poly(lactic-co-glycolic acid)

1.6 Poly(2-(dimethylamino)ethyl methacrylate)

1.7 Poly(ester amine)s

1.8 Poly(amidoamine) Dendrimers

2. APPLICATIONS OF CATIONIC POLYMERS

2.1 Gene Delivery

2.1.1 Chitosan

2.1.2 Poly(l-lysine)

2.1.3 Polyethyleneimine

2.1.4 Polypropylenimine

2.1.5 Poly(lactic-co-glycolic acid)

2.1.6 Poly(2-(dimethylamino)ethyl methacrylate

2.1.7 Poly(ester amine)s

2.1.8 PAMAM Dendrimers

2.2 Drug Delivery

2.2.1 Physical Encapsulation

2.2.2 Chitosan

2.2.3 Poly(lactic-co-glycolic acid)

2.2.4 Polypropylenimine

2.2.5 PAMAM Dendrimers

2.2.6 Chemical Conjugation

2.2.7 Physical Encapsulation Combined With Chemical Conjugation

2.3 Gene Transfer Combined With Drug Delivery

2.4 Diagnostic Imaging

2.4.1 Chitosan

2.4.2 Poly(l-lysine)

2.4.3 Polyethyleneimine

2.4.4 Polypropylenimine

2.4.5 Poly(lactic-co-glycolic acid)

2.4.6 Poly(2-(dimethylamino)ethyl methacrylate)

2.4.7 PAMAM Dendrimers

2.5 Antimicrobial Agents

2.5.1 Chitosan

2.5.2 Poly(l-lysine)

2.5.3 Polyethyleneimine

2.5.4 Polypropylenimine

2.5.5 Poly(lactic-co-glycolic acid)

2.5.6 Poly(2-(dimethylamino)ethyl methacrylate)

2.5.7 Poly(ester amine)s

2.5.8 PAMAM Dendrimers

3. NEUROTOXICITY OF CATIONIC POLYMERS

3.1 Neurotoxicity of Chitosan

3.2 Neurotoxicity of PEI

3.3 Neurotoxicity of PLGA

3.4 Neurotoxicity of Polystyrene

3.5 Neurotoxicity of PAMAM Dendrimers

4. MECHANISMS OF CATIONIC POLYMERS-INDUCED NEUROTOXICITY

4.1 Physicochemical Mechanisms of Cationic Polymers-Induced Neurotoxicity

4.1.1 Charge

4.1.2 Size

4.1.3 Shape

4.2 Biochemical Mechanisms of Cationic Polymers-Induced Neurotoxicity

4.2.1 Apoptosis

4.2.2 Necrosis

4.2.3 Autophagy

4.2.4 Oxidative Stress

4.2.5 Inflammation and Inflammasome

4.2.5.1 Inflammation

4.2.5.2 Inflammasome

5. CONCLUSION

REFERENCES

13 - Perspective on Strategies to Reduce the Neurotoxicity of Nanomaterials and Nanomedicines

1. INTRODUCTION

2. REDUCING BRAIN EXPOSURE

2.1 Reducing Inhalation of Nanomaterials

2.2 Reducing Blood–Brain Barrier Penetration

2.3 Improving Cell Selectivity in Brain

3. REDUCING THE INHERENT TOXICITY OF NANOMATERIALS

3.1 Composition of Nanomaterials

3.2 Size and Shape

3.3 Surface Property of Nanomaterials

4. CONCLUSION

REFERENCES

Index

A

B

C

D

E

F

G

H

I

L

M

N

O

P

Q

R

S

T

U

V

Z

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