1. Introduction

1.1. Blood–Brain Barrier and Blood–CSF Barrier

1.2. History of the Blood–Brain Barrier

1.3. History of Brain Drug Delivery

2. Invasive Drug Delivery to Brain

2.1. CSF Delivery

2.1.1. CSF Microcirculation and Microcirculation

2.1.2. Drug Transfer from CSF to Blood

2.1.3. Lumbar CSF Delivery

2.1.4. Ventricular CSF Delivery

2.2. Intra-Cerebral Delivery

2.2.1. Intra-Cerebral Implants

2.2.2. Convection-Enhanced Diffusion

3. Trans-Nasal Drug Delivery to Brain

3.1. Drainage of CSF from Brain to Nose

3.2. Drug Delivery from Nose to Brain

3.3. Clinical Trials of Trans-Nasal Drug Delivery to Brain

4. Brain Drug Delivery with Blood–Brain Barrier Disruption (BBBD)

4.1. BBBD Following Intra-Carotid Arterial Infusion

4.1.1. BBBD with Intra-Arterial Hyper-Osmolar Solutions

4.1.2. BBBD with Intra-Arterial Bradykinin Analogs

4.2. BBBD with Intravenous Microbubbles/Focused Ultrasound

4.3. Miscellaneous forms of BBBD

4.3.1. BBBD with Tight Junction Modulators

4.3.2. BBBD with Adenosine Analogs

4.3.3. BBBD with Anti-Bacterial Antibodies

4.3.4. BBBD with Intra-Arterial Polycations

4.3.5. BBBD with Intra-Arterial Amphipathic Agents

4.3.6. BBBD and Free Radicals

4.3.7. BBBD and Electromagnetic Radiation

5. Cell-Mediated Transport

5.1. Stem Cells for Brain Drug Delivery

5.2. Exosomes for Brain Drug Delivery

6. Brain Drug Delivery of Small Molecules

6.1. Lipid-Mediated Transport of Small Molecules

6.1.1. Approved Small Molecules for the CNS

6.1.2. Mechanism of Small Molecule Diffusion through the BBB

6.1.3. Lipid-Soluble Pro-Drugs

6.1.4. Conjugation of Hydrophilic Drugs to Hydrophobic Carriers

6.2. Carrier-Mediated Transport of Small Molecules

6.2.1. GLUT1 Glucose Carrier

6.2.2. LAT1 Large Neutral Amino Acid Carrier

6.2.3. CAT1 Cationic Amino Acid Carrier

6.2.4. MCT1 Monocarboxylic Acid Carrier

6.2.5. CNT2 Purine Nucleoside Carrier and Adenine Carrier

6.2.6. CTL1 Choline Carrier

6.2.7. Vitamin Carriers

6.2.8. Thyroid Hormone Carriers

6.2.9. Organic Cation Carrier

6.3. Active Efflux Transport of Small Molecules

6.3.1. Brain-to-Blood Efflux

6.3.2. ABC Efflux Transporters

6.3.3. SLC Efflux Transporters

7. Absorptive-Mediated Transport of Cationic Proteins or Lectins

7.1. Cationic Proteins

7.1.1. Cationized Proteins

7.1.2. Endogenous Cationic Proteins

7.1.3. Cell-Penetrating Peptides

7.2. Lectins

7.3. Toxicity of Cationic Proteins and Lectins

7.3.1. Toxicity of Cationic Proteins

7.3.2. Toxicity of Lectins

8. Receptor-Mediated Transport of Peptides and Monoclonal Antibodies

8.1. Receptor-Mediated Transporters at the Blood–Brain Barrier

8.1.1. Insulin Receptor

8.1.2. Transferrin Receptor

8.1.3. IGF Receptor

8.1.4. Leptin Receptor

8.1.5. LRP1 Receptor

8.1.6. LDL Receptor

8.1.7. Nicotinic Acetylcholine Receptor

8.1.8. Basigin/CD147

8.1.9. Miscellaneous Receptors

8.2. Trojan Horse Delivery Via Blood–Brain Barrier Receptor-Mediated Transport (RMT)

8.2.1. Peptide-Based RMT Trojan Horses

8.2.2. Monoclonal Antibody-Based RMT Trojan Horses

8.3. IgG Fusion Proteins for Blood–Brain Barrier Delivery of Biologics

8.3.1. Lysosomal Enzymes

8.3.2. Neurotrophins

8.3.3. Decoy Receptors

8.3.4. Bispecific Antibodies

8.4. Avidin-Biotin Technology

8.4.1. Peptide Radiopharmaceuticals for Brain Imaging

8.4.2. Antisense Radiopharmaceuticals for Brain Imaging

8.4.3. IgG–Avidin Fusion Proteins

9. Nanoparticles

9.1. Nanoparticle Formulations

9.2. Polymer-Based Nanoparticles

9.2.1. Polymeric Nanoparticles

9.2.2. Dendrimers

9.2.3. Micelles

9.2.4. Albumin Nanoparticles

9.3. Lipid-Based Nanoparticles

9.3.1. Liposomes

9.3.2. Solid Lipid Nanoparticles

9.4. Non-Polymeric Nanoparticles

9.4.1. Carbon Nanotubes

9.4.2. Graphene Oxide, Fullerenes, and Quantum Dots

9.4.3. Metallic Nanoparticles

9.5. Mediated Blood–Brain Barrier Delivery of Functionalized Nanoparticles

9.5.1. Carrier-Mediated Transport of Nanoparticles

9.5.2. Absorptive-Mediated Transport of Nanoparticles

9.5.3. Receptor-Mediated Transport of Nanoparticles

9.5.4. Brain Delivery of Nanoparticles with BBB Avoidance Strategies

9.6. Nanoparticle Clinical Trials for the Brain

9.7. Nanoparticle Neurotoxicology

10. Gene Therapy of the Brain

10.1. Viral Gene Therapy

10.1.1. Lentivirus-Transfected Stem Cells

10.1.2. Adenovirus

10.1.3. Herpes Simplex Virus

10.1.4. Adeno-Associated Virus

10.2. Non-Viral Gene Therapy of Brain

10.2.1. Cationic Liposomes and Cationic Polyplexes

10.2.2. Pegylated Liposomes

10.2.3. Trojan Horse Liposomes

11. Blood–Brain Barrier Transport Methodology

11.1. Physiologic Model of Free Drug in Brain and Plasma

11.2. Free Drug in Plasma and Role of Plasma Protein Binding

11.3. Measurement of Free Drug in Brain

11.3.1. CSF as a Measure of Free Drug in Brain

11.3.2. Free Drug in Brain with Cerebral Microdialysis

11.3.3. Free Drug in Brain In Vitro with Brain Slices or Homogenates

11.4. Measurement of PSinflux

11.4.1. Brain Uptake index Method

11.4.2. Internal Carotid Artery Perfusion Method

11.4.3. Capillary Depletion Method

11.4.4. Intravenous Injection Methods

11.5. Measurement of PSefflux

11.5.1. Brain Uptake index Method

11.5.2. Brain Efflux index Method

11.6. Measurement of Drug Sequestration in Brain In Vivo

11.7. In Vitro BBB Models

11.7.1. Isolated Brain Microvessels

11.7.2. In Vitro Models of BBB Transport in Cell Culture

11.8. BBB Transport Methods from Perspective of Pharmaceutical Industry

12. Summary

13. Perspective

Abbreviations

References