Crossing the blood-brain barrier: emerging therapeutic strategies for neurological disease

Abstract

The blood-brain barrier is a physiological barrier that can prevent both small and complex drugs from reaching the brain to exert a pharmacological effect. For treatment of neurological diseases, drug concentrations at the target site are a fundamental parameter for therapeutic effect; thus, the blood-brain barrier is a major obstacle to overcome. Novel strategies have been developed to circumvent the blood-brain barrier, including CSF delivery, intracranial delivery, ultrasound-based methods, membrane transporters, receptor-mediated transcytosis, and nanotherapeutics. These approaches each have their advantages and disadvantages. CSF delivery and intracranial delivery are direct but invasive techniques that have not yet shown efficacy in clinical trials, although development of novel delivery devices might improve these approaches. Ultrasound-based disruption has shown some efficacy in clinical trials, but it can require invasive procedures. Approaches using membrane transporters and receptor-mediated transcytosis are less invasive than are other techniques, but they can have off-target effects. Nanotherapeutics have shown promise, but these strategies are in early stages of development. Advancements in drug delivery across the blood-brain barrier will require appropriately designed and powered clinical studies, with a focus on the timing of treatment, demographic and genetic considerations, head-to-head comparison with other treatment strategies (rather than a placebo), and relevant primary and secondary outcome measures.

Figure 1:. Structure of the neurovascular unit and blood–brain barrier

Non-fenestrated brain endothelial cells form a strict selective interface of tight junctions along the basement membrane, comprising the blood–brain barrier2^–. Pericytes, astrocytes, microglia, and neurons wrap around this barrier, creating the neurovascular unit. Components of the neurovascular unit can help to maintain the integrity and protective capacity of the blood–brain barrier (astrocytes and pericytes), ^,,, or might release factors to increase the permeability of the barrier (microglia) . Between the brain endothelial cells are tight junctions that comprise various proteins to provide structural stability and signalling, including junctional adhesion molecules (JAM) and membrane-spanning occludin and claudin proteins. These tight junctions restrict paracellular transport, only allowing passive diffusion of lipid-soluble drugs.

Fig. 2:. Methods and measurement strategies for overcoming the BBB.

A) CSF Delivery. Delivery through the CSF-brain barrier has been targeted using antisense oligonucleotide (ASO) therapy in amyotrophic lateral sclerosis (ALS). The SOD1 protein misfolding is responsible for neuronal degradation in ALS. The ASO will bind the mRNA of SOD1 and initiate the mRNA degradation processes thereby leading to an overall reduction in SOD1 PROTEIN^,. B) Intracranial delivery. Convection-enhanced delivery (CED) can be adapted to deliver a range of therapies^,,. A catheter-pump system creates a positive pressure gradient and allows the diffusion of larger molecules to tissues through bulk flow. Intracranial injection will deliver therapies, such as the oncolytic virus, directly to the target site. C) Fluorescent microscopy image of the brain of a glioblastoma patient who underwent intraoperative sonication with intravenous administration of microbubbles, chemotherapy, and fluorescein as part of pharmacokinetic study to study the effect of sonication on the concentration of drugs in the peri-tumoural brain. Cortex regions that underwent sonication exhibit increased fluorescence intensity compared to the surrounding brain. D) Mechanism of action of ultrasound with concomitant intravenous microbubbles. An ultrasound device is used to cavitate circulating microbubbles and increase the permeability of the BBB. This technique uses an implanted ultrasound device to deliver low-intensity pulsed ultrasound for glioblastoma treatment or for the removal of amyloid plaques in Alzheimer’s.

Fig. 3:. Transport mechanisms across the blood-brain barrier.

Three different transport systems can be targeted: receptor-mediated transcytosis, the amino acid transporter LAT1, and the ABC transporter (Pgp substrate system). Receptor-mediated transport uses the vesicular trafficking system within the brain endothelial cells to allow transcytosis. Ligand-receptor complexes facilitate this without disruption to the barrier. Amino acid transporters, such as the LAT1 transporter, make use of the expression on both the abluminal and luminal sides of the membrane. ABC transporters, such as the P-gp transporters, are efflux transporters existing on the luminal side of the membrane.

Fig 4.. Therapeutic delivery of drugs using nanoparticles.

A nanoparticle containing a gold-core, conjugated with a spherical nucleic acid (SNA-NP) will target oncogenes upregulated in glioblastoma. The SNA-NP are administered intravenously (I.V) and will cross the BBB through paracellular pathways.