A Historical Review of Brain Drug Delivery
|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|
|7.3. 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|
|8.1.9. 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|
|8.3.3. 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|
|9.1. Nanoparticle Formulations|
|9.2. Polymer-Based Nanoparticles|
|9.2.1. Polymeric Nanoparticles|
|9.2.4. Albumin Nanoparticles|
|9.3. Lipid-Based Nanoparticles|
|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|
|10.1.3. 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|
- Invasive brain drug delivery: the BBB is circumvented by drug injection into either the cerebrospinal fluid (CSF) following intrathecal or trans-nasal administration, or by trans-cranial direct injection of drug into brain tissue by either intra-cerebral implants or convection-enhanced diffusion (CED).
- BBB disruption brain drug delivery: the brain capillary endothelial tight junctions that form the BBB are disrupted by either the intra-arterial infusion of noxious agents, or by the intravenous injection of micro-bubbles followed by sonication of brain.
- Trans-vascular brain drug delivery: the non-disrupted brain capillary endothelial barrier is traversed following the re-engineering of the pharmaceutical so as to gain access to multiple carrier-mediated transporters (CMT) for small molecules, or receptor-mediated transporters (RMT) for biologics. This category also includes the development of co-drugs that inhibit active efflux transporters (AET) at the BBB, such as p-glycoprotein (P-gp), as well as the free diffusion of lipid-soluble small molecules.
1.1. Blood–Brain Barrier and Blood–CSF Barrier
1.2. History of the Blood–Brain Barrier
- “Vital stains possess an affinity for the nervous system, and specially for the ganglion cells. If they are introduced by means of subcutaneous or intravenous injections, they are kept back by the plexus.”
- “From the plexus choroideus the cerebro-spinal fluid receives important metabolic products, which are carried to the nerve substance by the fluid.”
- “Certain dye substances can pass directly from the blood to the brain substance proper without being found in the cerebrospinal fluid, while others fail to penetrate into the brain.”
- Certain substances “do not possess the necessary solubility to allow them to pass from the blood-vessels into the brain substance. Their relative inefficiency has nothing to do with their absence from the cerebrospinal fluid”.
1.3. History of Brain Drug Delivery
- “After intravenous injections of salvarsan and neosalvarsan in man and animals no arsenic can be found in the brain.”
- “This phenomenon is not due to a lack of affinity between the brain and the drugs, but to an inability on the part of the drugs to penetrate into the substance of the brain.”
2. Invasive Drug Delivery to Brain
2.1. CSF Delivery
2.1.1. CSF Macrocirculation and Microcirculation
2.1.2. Drug Transfer from CSF to Blood
- The intrathecal injection of an interferon resulted in drug distribution to the surface of the brain, and to the blood, but not into brain parenchyma .
- The effect of intrathecal cholecystokinin (CCK) on food intake was found to be caused by CCK action in peripheral organs following CCK transfer from CSF to blood .
- Drug was injected into CSF in rats implanted with an intra-cerebral dialysis fiber; however, the drug did not appear in the dialysate of brain following ICV administration .
- Liver glycosaminoglycans (GAG) were reduced in the Type IIIB Mucopolysaccharidosis (MPSIIIB) mouse following the intrathecal injection of N-acetyl-α-glucosaminidase (NAGLU), the enzyme that is mutated in MPSIIIB , owing to enzyme movement from CSF to liver via the blood.
- The rapid movement of a monoclonal antibody (MAb) from CSF to liver, via the blood, was demonstrated by positron emission tomography (PET) in humans following the administration of the [124I]-8H9 MAb via an Ommaya reservoir. Whole body PET scans at 24 h after intrathecal injection showed the antibody was present in liver, but not within the parenchyma of brain .
2.1.3. Lumbar CSF Drug Delivery
2.1.4. Ventricular CSF Drug 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 Following Intravenous Microbubble/Focused Ultrasound
4.3. Miscellaneous Forms of BBBD
4.3.1. BBBD with Tight Junction Modulators
4.3.2. BBBD with Adenosine Analogues
4.3.3. BBBD with Anti-Bacteria 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 BBB Transport
5.1. Stem Cells for Brain Drug Delivery
5.2. Exosomes for Brain Drug Delivery
- Low yield of exosomes from the starting cell line. These yields are generally not provided in exosome publications, but may be on the order of only 5%, as discussed above.
- Poor PK properties, and rapid exosome removal from blood, similar to non-pegylated liposomes .
- Drug encapsulation in the exosomes requires procedures such as electroporation  or sonication , which is difficult to scale up for manufacturing. Passive loading will work only for hydrophobic small molecules . Many therapeutics may leak out of exosomes on storage, similar to the drug leakage from liposomes .
- Exosomes will generally require a targeting ligand on the surface of the vesicle, so as to promote RMT across the BBB. The incorporation of such ligands will require genetic modification of the cell line used to produce the exosomes.
- The stability of exosomes is unknown. A 2-year shelf life at 4 °C typically needs to be established for biologics, and it is not clear if exosomes, which are composed of multiple membrane elements, have any significant degree of stability on storage. To what extent exosomes can be lyophilized and then re-solubilized with both high drug retention and BBB transport is not known.
6. Brain Drug Delivery of Small Molecules
6.1. Lipid-Mediated Transport of Small Molecules
6.1.1. Approved Small Molecule Drugs 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
- The substrate transporter profile (STP) that characterizes BBB transport in vivo should be replicated by the STP of the cloned transporter that is expressed in vitro. STPs determined with in vitro BBB models should not be used as a primary method, owing to the marked alteration of gene expression within brain endothelial cells grown in cell culture, as discussed in Section 11.7.2. The STP should be determined in vivo with methods discussed in Section 11.4.
- Evidence should be available that the targeted SLC transporter is expressed on both luminal and abluminal endothelial membranes in the human brain. As discussed above, there are species differences in the expression of certain transporters at the human vs. the animal BBB. Some SLC transporters are only expressed on the abluminal endothelial membrane, and these abluminal transporters would not be available to transport drug from blood to brain.
- The BBB CMT systems form trans-membrane cavities, as illustrated for GLUT1 and LAT1 in Figure 9, and these cavities can be sharply stereospecific with low tolerance for bulky structural changes to the substrate. As an example, if the GLUT1 carrier is targeted for brain drug delivery, the drug should be modified, not by conjugation of the drug to D-glucose, but rather by alteration of the drug structure so as to mimic the structure of the endogenous substrate, D-glucose.
- If the lead CNS drug candidate is a ligand for Pgp, or one of the other active efflux transporters at the BBB, then a co-drug needs to be developed that inhibits the BBB efflux transporter.
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
7.3. 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
8.1.9. 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 Delivery of Biologics
8.3.1. Lysosomal Enzymes
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
9.1. Nanoparticle Formulations
- Polymer-based nanoparticles, which include polymeric NPs (PNP), dendrimers, micelles, and protein nanoparticles, such as albumin nanoparticles;
- Lipid-based nanoparticles, which include liposomes, which have an aqueous interior, and solid lipid nanoparticles (SLN), which lack an aqueous interior; exosomes, which are reviewed in Section 5.2, can be considered natural liposomes;
- Non-polymeric nanoparticles, which include carbon nanotubes (CNT), graphene oxide (GO) fullerenes or quantum dots, and metallic nanoparticles produced from metals such as iron, gold, silver, or silica. Iron nanoparticles are magnetic.
9.2. Polymer-Based Nanoparticles
9.2.1. Polymeric Nanoparticles
9.2.4. Albumin Nanoparticles
9.3. Lipid-Based Nanoparticles
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
- Pegylated and non-pegylated liposomes encapsulating cancer chemotherapeutic agents including doxorubicin, cytarabine/daunomycin, vincristine, irinotecan;
- Liposomes encapsulating amphotericin B for fungal infections;
- Liposomes encapsulating verteporfin for macular degeneration;
- Cremophor-free paclitaxel re-formulated as albumin nanoparticles for cancer;
- siRNA in cationic pegylated liposomes for hereditary transthyretin amyloidosis;
- Iron replacement therapies;
- Imaging agents.
- SGT-53 was developed as a treatment for brain cancer . SGT-53 is a plasmid DNA encoding the p53 tumor suppressor gene that is adsorbed to cationic liposomes conjugated with a ScFv antibody against the human TfR . This ScFv was derived from the 5E9 antibody , also known as the HB21 antibody . The ScFv against the human TfR was chemically conjugated to the liposomal lipids with a thio-ether linkage. SGT-53 was administered to patients with recurrent glioblastoma multiforme (GBM) concurrent with temozolomide treatment (NCT02340156). Only one patient was enrolled and the trial was terminated. The SGT-53 formulation is a cationic lipoplex of DNA, and such agents demonstrate aggregation problems, as discussed in Section 10.2.
- MTX-110 is a complex of panobinostat, a histone decarboxylase inhibitor, and hydroxylpropyl β-cyclodextrin . MTX-110 is a soluble form of panobinostat, which is poorly soluble in water. MTX-110 does not cross the BBB, and this formulation has been administered to rats by CED  and to primates by infusion in the fourth ventricle . MTX-110 was administered to patients with a pontine glioma by CED; the phase 1 trial in 7 patients concluded in February 2022, with no advancement to phase 2 (NCT03566199).
- ARCT-810 is a mRNA encoding ornithine transcarbamylase (OTC) formulated in a LNP for the treatment of late onset OTC deficiency. This condition can lead to seizures, brain edema, and death . The ARCT-810 clinical trial was initiated in 2020 and is ongoing (NCT04442347). The details of ARCT-810 manufacturing are not available, and it is not clear if this was formulated as a lipoplex/RNA mixture or if the mRNA was fully encapsulated in the LNPs.
- CNM-Au8 is a preparation of gold nanocrystals which are daily administered orally at a dose of 30 mg, and were tested in a phase 2 trial for ALS . The trial was completed in 2022 and no results were yet reported (NCT04098406). It is not clear how such AuNPs, which are not functionalized, can cross the BBB in ALS. The BBB is intact in ALS .
- ABI-009 is a preparation of albumin NPs complexed with the macrolide antibiotic, rapamycin, an anti-tumor agent, which is administered to patients with newly diagnosed GBM (NCT03463265). The trial was first posted in 2018, and no results have been reported. Since the albumin NPs are not functionalized, no transport across the intact BBB is expected. The BBB may be leaky in the tumor area of GBM to small molecules . However, much of the GBM tumor retains an intact BBB, and tumor eradication is not possible unless all cancer cells within the tumor are exposed to the therapeutic . Therefore, new treatments for GBM need to be formulated or engineered to enable transport across an BBB.
- NU-0129 is an AuNP conjugated with siRNA and designated a spherical nucleic acid (SNA) . The siRNA targets the Bcl1Like12 oncogene . NU-0129 is said to be BBB-penetrating, but the AuNP is not functionalized. Only the gold part of this NU-0219 was tested for brain penetration, not the siRNA part. The siRNA was simply adsorbed to the surface of the AuNP, and there is immediate separation of the AuNP and the siRNA following IV administration . The plasma T1/2 of the siRNA is 5.4 ± 5.1 min, whereas the plasma T1/2 of the gold is 17 ± 6 h . A phase 1 trial in recurrent GBM was initiated for NU-0129 in 2017 with the last posting in 2020 and no study results are available (NCT03020017).
9.7. Nanoparticle Neurotoxicology
10. Gene Therapy of the Brain
10.1. Viral Gene Therapy of Brain
10.1.1. Lentiviral-Transfected Stem Cells
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 In Vivo 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. In Vivo 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 Models of BBB Transport
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
- Drug injected into the CSF enters brain by diffusion, and diffusion decreases exponentially with the diffusion distance. Consequently, following ICV delivery, drug traverses a distance of only 1–2 mm from the CSF surface of the brain (Figure 5), as reviewed in Section 2.1.1.
- An intrathecal injection of drug is akin to a slow intravenous infusion of drug, as noted by Fishman and Christy in 1965 . Therefore, the control group in a clinical trial of a drug administered by ICV injection, e.g., with an Ommaya reservoir, should be a cohort of patients administered the same drug by IV infusion, as suggested by Aird in 1984 , and reviewed in Section 2.1.4.
- Drug enters brain from an intra-cerebral implant by diffusion, which decreases exponentially with the distance from the implant. The maximal distance from the implant covered by the drug is 0.2–2 mm .
- Convection-enhanced diffusion (CED) attempts to overcome the limitations of diffusion in brain. A catheter inserted in the brain is connected to a pump . A clinical trial of GDNF delivery to brain with bilateral CED failed in PD . A primate study demonstrated the GDNF concentration in brain decreases exponentially with each mm of distance from the catheter , as illustrated in Figure 6A. Such an exponential decay in drug distribution in brain is indicative of diffusion, not convection.
- There are >1000 publications in PubMed on trans-nasal delivery to brain (Table 1). However, all clinical trials of drug delivery to brain via the nose have failed, as reviewed in Section 3.3.
- The olfactory region covers 50% of the nasal mucosa in the rat, but only 3% in humans .
- Drug delivery to olfactory CSF following nasal administration in preclinical studies is generally performed in rodents wherein large volumes are instilled in the nose, and these large volumes cause local injury to the nasal mucosa. The volume of the nasal mucosa in humans and mice is 20 mL and 0.03 mL, respectively . Instillation of a volume >100 μL in the human naris causes local injury [147,148].
- BBBD has been induced by intra-carotid artery hyperosmolar mannitol (ICAHM), by focused ultrasound with IV microbubbles (FUS-MB), and by a variety of methods such as opening tight junctions with an anti-claudin-5 antibody, or even electromagnetic radiation, as reviewed in Section 4.
- Stem cells do not cross the BBB , nor enter brain parenchyma  as reviewed in Section 5.1.
- Stem cells do invade the meninges of brain , where there is no BBB.
- Stem cells were permanently transfected with lentivirus (LV) and injected into mice, but the LV genome in brain was near the background of the method and log orders lower than in peripheral tissues .
- Exosomes are liposome-like membrane vesicles derived from cultured cells, as reviewed in Section 5.2.
- Similar to liposomes, exosomes do not cross the BBB in the absence of a surface ligand that triggers RMT across the BBB.
- The future translation of exosomes to human neurotherapeutics is limited by low encapsulation of drug in exosomes, drug efflux from exosomes on storage, the lack of stability of exosomes on long-term storage required for commercialization, the low yield of exosomes from cultured cells, and the unfavorable pharmacokinetic profiles of exosomes following IV administration.
- All CNS drugs on the market have a MW < 450 Da and form <8 hydrogen bonds with solvent water. Only about 2% of all small molecules have these molecular properties of MW and hydrogen bonding, and these drugs typically treat only neuropsychiatric conditions or epilepsy, as reviewed in Section 6.1.1.
- The model of MW dependence of small molecule diffusion through biological membranes was developed by Stein decades ago , and is reviewed in Section 6.1.2, and in Figure 8.
- Water-soluble drugs have been conjugated to lipid-soluble carriers, including dihydropyridine, free fatty acid, or docosahexaenoic acid (DHA), but with little success as reviewed in Section 6.1.4.
- The 20th century model of CNS drug development of lipid-soluble small molecules needs to be expanded to include drugs that cross the BBB via carrier-mediated transport.
- Several carrier-mediated transporters (CMT) are expressed at the BBB for transport of nutrients, including GLUT1, LAT1, CAT1, MCT1, CTL1, and CNT2.
- The genes encoding these CMT systems are members of the Solute Carrier (SLC) superfamily, which includes >400 transporters and >60 families .
- There are >10 glucose transporters (GLUT) genes in the SLC superfamily. Therefore, if a given CMT system is being targeted as a conduit for brain drug delivery, it is important to first confirm the Substrate Transporter Profile (STP) of the CMT system that exists in vivo at the BBB correlates with the STP of the cloned transporter expressed in vitro.
- In addition to the CMT systems for nutrients, there are also several SLC transporters that mediate vitamin transport across the BBB, as reviewed in Section 6.2.7 and Table 3.
- The 3D structure of some CMT systems have been elucidated, as shown in Figure 9 for GLUT1 and LAT1. The dimensions of the transporter cavity are only 0.8–1.5 nm . Therefore, drugs, which do not cross the BBB, should not be conjugated to an endogenous CMT substrate, as the transporter cavity will most likely reject the conjugate.
- Medicinal chemistry can be used to create a dual-purpose pharmaceutical that has affinity for both the CMT cavity as well as for the drug receptor in brain.
- Active efflux transporters (AET) mediate the transport of molecules in the brain-to-blood direction and include members of both the SLC and the ATP-binding cassette (ABC) gene families. There are ~50 genes and 7 families in the ATP superfamily, and many of these AET systems are expressed at the BBB, as reviewed in Section 6.3.
- The model AET system is P-glycoprotein (ABCB1), but there are multiple other ABC transporters expressed at the BBB.
- Drug efflux via either ABC or SLC transporters can be assessed with the Brain Efflux Index (BEI) method, as reviewed in Section 11.5.2.
- Cationic proteins or lectins traverse the BBB via absorptive-mediated transport (AMT), as reviewed in Section 7.
- Cationic proteins include cationized proteins, endogenous cationic proteins, e.g., protamine or histone, and cell-penetrating peptides (CPP), such as the tat or penetratin peptides. Wheat germ agglutinin (WGA) is the model lectin that undergoes AMT at the BBB.
- AMT ligands are not preferred delivery systems, as these tend to have low affinity for BBB binding sites, are largely sequestered within the brain endothelium, and have unacceptable toxicity profiles.
- Receptor-mediated transporters at the BBB include the endogenous receptors for insulin, transferrin, leptin, and the IGFs, as reviewed in Section 8.1.
- Localization of a putative BBB RMT system should be confirmed by brain immunohistochemistry (IHC), as exemplified by Figure 11A. Brain IHC for several receptors targeted for RMT shows these receptors are localized at brain cells, not at the capillary endothelium, including LRP1, LDLR, nAChR, and the NMDAR (Figure 11B).
- Receptor-specific MAbs act as molecular Trojan horses to ferry across the BBB a biologic drug that is genetically fused to the MAb. IgG fusion proteins for biologics drug delivery to brain have been engineered and validated in vivo for lysosomal enzymes, neurotrophins, decoy receptors, and therapeutic antibodies (Figure 12, Table 4).
- Avidin-biotin technology, and the engineering of IgG–avidin fusion proteins, allows for the BBB delivery of peptide or antisense radiopharmaceuticals for neuro-imaging as shown in Figure 14.
- Nanoparticles (NP) are reviewed in Section 9, and they include polymer-based nanoparticles (polymeric NPs, dendrimers, micelles, and protein NPs, such as albumin NPs), lipid NPs (solid lipid NPs, liposomes), and non-polymeric NPs (magnetic NPs, carbon nanotubes).
- NPs do not cross the BBB without surface functionalization of the NP with a ligand that triggers RMT across the BBB.
- NPs have been functionalized with ligands that target CMT systems, but the narrow cavities of the CMT systems do not allow for transport of the 100 nm NP, as reviewed in Section 9.5.1.
- Apart from vaccines, NP have been slow to enter clinical trials, and no successful CNS clinical trials have been performed to date with NP formulations, as reviewed in Section 9.6.
- NPs have significant toxicity profiles, particularly for magnetic NPs, carbon nanotubes, and PBCA polymeric NPs, as reviewed in Section 9.7. Detailed safety pharmacology and toxicology studies of the effects of long-term NP administration are lacking. Such 6-month GLP toxicology studies are required for an IND application, but few IND applications have been submitted for CNS clinical trials with NPs.
- Viral gene therapy and non-viral gene therapy of the brain are reviewed in Section 10.1 and Section 10.2, respectively.
- Zolgensma®® is an intravenous AAV gene therapeutic, and was FDA approved in 2019 as a single-dose treatment for spinal muscular atrophy (SMA) at an IV dose of 1.1 × 1014 vg/kg . Zolgensma is a self-complementary (sc) form of adeno-associated virus (AAV)-9, which undergoes BBB transport following IV administration .
- Non-viral gene therapy of brain is possible with Trojan horse liposomes (THLs) as described in Figure 17. THLs are produced by conjugation of a receptor-specific MAb to the tips of polyethyleneglycol strands on the surface of 100–150 nm pegylated liposomes. Both reporter genes and therapeutic genes have been delivered to mice, rats, and monkeys with antibodies that target either the insulin receptor or the transferrin receptor at the BBB.
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
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