Key Points
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The brains of all vertebrates are protected from substances in the blood by the blood–brain barrier (BBB). Although the BBB maintains brain function under normal conditions, it excludes the penetration into the brain of >98% of small-molecule drugs and virtually 100% of large-molecule drugs or gene medicines.
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One solution to the BBB drug- and gene-delivery problem is chimeric peptide technology. In the formulation of a chimeric peptide, a drug that is normally not transported across the BBB is conjugated or fused to a BBB transport vector. The vector is an endogenous peptide or peptidomimetic monoclonal antibody that undergoes receptor-mediated transcytosis (RMT) through the BBB in vivo.
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BBB transport vectors act as molecular Trojan Horses, which ferry the drug or gene across the BBB on the endogenous-peptide RMT system. The drug or gene can be attached to the Trojan Horse by either genetic engineering or avidin–biotin technology.
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Neurotrophins are strongly neuroprotective if injected directly into the brain immediately after brain ischaemia, but are inactive following intravenous administration in the absence of BBB disruption because these large-molecule drugs do not cross the BBB. Neurotrophin chimeric peptides cause complete neuroprotection in the hippocampus after transient global brain ischaemia, and a 70% reduction in stroke volume in regional ischaemia after delayed intravenous administration, because these molecules have been enabled to cross the BBB.
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Peptide radiopharmaceuticals could allow the early detection of brain diseases, such as brain cancer or Alzheimer's disease, should these molecules be made transportable through the BBB. The epidermal growth factor (EGF) receptor is overexpressed in brain cancer. An experimental human brain cancer could not be imaged with an EGF peptide radiopharmaceutical, because the peptide does not cross the BBB. However, the brain cancer was imaged with an EGF chimeric peptide that was able to cross the blood–tumour barrier after intravenous administration.
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The imaging of gene expression in vivo is possible with antisense radiopharmaceuticals if these highly charged agents are able to cross both the BBB and the brain cell membrane in vivo. The conjugation of a sequence-specific antisense radiopharmaceutical to a molecular Trojan Horse has been shown to enable the imaging of a target gene in the brain in vivo after intravenous administration.
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Widespread expression of a therapeutic gene throughout the central nervous system is required to treat many intractable neurological diseases. This is now possible with brain gene-targeting technology, using a combination of molecular Trojan Horses, non-viral gene medicines and tissue-specific gene promoters.
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The BBB is the rate-limiting factor in the translation of progress in the molecular neurosciences into clinically effective neurotherapeutics.
Abstract
Getting drugs and genes into the brain is a tall order. This is because the presence of the blood–brain barrier prevents many molecules from crossing into the brain. Overcoming this problem will have a profound effect on the treatment of many neurological disorders, allowing larger water-soluble molecules to pass into the brain. Transport vectors, such as endogenous peptides, modified proteins or peptidomimetic monoclonal antibodies, are one way of tricking the brain into allowing these molecules to pass. This article will review such molecular Trojan Horses, and the progress that has been made in the delivery of drugs and genes to the brain.
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DATABASES
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Glossary
- PEPTIDOMIMETIC
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A molecule that binds to a blood–brain barrier (BBB) receptor and initiates receptor-mediated transcytosis (RMT) across the BBB. A peptidomimetic monoclonal antibody binds to an extracellular projecting epitope on the receptor to trigger RMT in a manner similar to the endogenous ligand for the receptor.
- ENDOTHELIUM
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Consists of cells of mesenchymal origin that comprise the innermost cellular lining of the capillary.
- TRANSCYTOSIS
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Transport across the endothelial barrier by movement through the endothelial cytoplasm (the transcellular pathway), in contrast to transport across the endothelial barrier by movement through the inter-endothelial junctional spaces (the paracellular pathway).
- PINOCYTOSIS
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Transcytosis across the endothelial cell through endosomal vesicles and/or a tubulovesicular network within the endothelial cell.
- MICROVASCULATURE
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The capillary network that perfuses the brain and delivers to the brain circulating nutrients and oxygen.
- PERICYTE
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A multifunctional cell that shares the basement membrane of the microvasculature with the endothelium, and sits on the brain side of the capillary.
- EXOFACIAL
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Part of a plasma-membrane receptor that projects outwards into the extracellular space.
- NEUROTROPHIN
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A protein produced within the brain that modulates neuronal function and structure.
- CEREBRAL INFARCTION
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Loss of brain tissue subsequent to the transient or permanent loss of circulation and/or oxygen delivery to that region of the brain; also known as a stroke.
- XENOBIOTIC
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A drug or naturally occuring alkaloid that has pharmacological properties.
- EPENDYMAL SURFACE
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The surface of the brain that is lined by the ependymal epithelium, which is in contact with the cerebrospinal fluid.
- AMYLOID
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A silk-like protein aggregate that consists of a peptide that has a high degree of β-pleated-sheet secondary structure, which enables the aggregation of the peptide into plaques that deposit in the extracellular space of the brain.
- RETICULO-ENDOTHELIAL
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A system of phagocytic cells that line the microvasculature of the liver and spleen, and which remove foreign substances or particles from the blood.
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Pardridge, W. Drug and gene targeting to the brain with molecular trojan horses. Nat Rev Drug Discov 1, 131–139 (2002). https://doi.org/10.1038/nrd725
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DOI: https://doi.org/10.1038/nrd725
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