Receptor-mediated transcytosis for brain delivery of therapeutics: receptor classes and criteria

The delivery of therapeutics into the brain is highly limited by the blood-brain barrier (BBB). Although this is essential to protect the brain from potentially harmful material found in the blood, it poses a great challenge for the treatment of diseases affecting the central nervous system (CNS). S...

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Published inFrontiers in Drug Delivery Vol. 4
Main Authors Haqqani, Arsalan S., Bélanger, Kasandra, Stanimirovic, Danica B.
Format Journal Article
LanguageEnglish
Published Frontiers Media SA 12.03.2024
Frontiers Media S.A
Subjects
blood-brain barrier
Drug Delivery
receptor-mediated transcytosis
RM1-950
RMT receptors
Therapeutics. Pharmacology
trafficking
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Abstract The delivery of therapeutics into the brain is highly limited by the blood-brain barrier (BBB). Although this is essential to protect the brain from potentially harmful material found in the blood, it poses a great challenge for the treatment of diseases affecting the central nervous system (CNS). Substances from the periphery that are required for the function of the brain must rely on active mechanisms of entry. One such physiological pathway is called receptor-mediated transcytosis (RMT). In this process, ligands bind to specific receptors expressed at the luminal membrane of endothelial cells composing the BBB leading to the internalization of the receptor-ligand complex into intracellular vesicles, their trafficking through various intracellular compartments and finally their fusion with the abluminal membrane to release the cargo into the brain. Targeting such RMT receptors for BBB crossing represents an emerging and clinically validated strategy to increase the brain permeability of biologicals. However, the choice of an appropriate receptor is critical to achieve the best selectivity and efficacy of the delivery method. Whereas the majority of work has been focused on transferrin (Tf) receptor (TfR), the search for novel receptors expressed in brain endothelial cells (BECs) that can deliver protein or viral vector cargos across the BBB has yielded several novel targets with diverse molecular/structural properties and biological functions, and mechanisms of transcytosis. In this review, we summarize well-studied RMT pathways, and explore mechanisms engaged in BBB transport by various RMT receptors. We then discuss key criteria that would be desired for an optimal RMT target, based on lessons-learned from studies on TfR and accumulating experimental evidence on emerging RMT receptors and their ligands.
AbstractList The delivery of therapeutics into the brain is highly limited by the blood-brain barrier (BBB). Although this is essential to protect the brain from potentially harmful material found in the blood, it poses a great challenge for the treatment of diseases affecting the central nervous system (CNS). Substances from the periphery that are required for the function of the brain must rely on active mechanisms of entry. One such physiological pathway is called receptor-mediated transcytosis (RMT). In this process, ligands bind to specific receptors expressed at the luminal membrane of endothelial cells composing the BBB leading to the internalization of the receptor-ligand complex into intracellular vesicles, their trafficking through various intracellular compartments and finally their fusion with the abluminal membrane to release the cargo into the brain. Targeting such RMT receptors for BBB crossing represents an emerging and clinically validated strategy to increase the brain permeability of biologicals. However, the choice of an appropriate receptor is critical to achieve the best selectivity and efficacy of the delivery method. Whereas the majority of work has been focused on transferrin (Tf) receptor (TfR), the search for novel receptors expressed in brain endothelial cells (BECs) that can deliver protein or viral vector cargos across the BBB has yielded several novel targets with diverse molecular/structural properties and biological functions, and mechanisms of transcytosis. In this review, we summarize well-studied RMT pathways, and explore mechanisms engaged in BBB transport by various RMT receptors. We then discuss key criteria that would be desired for an optimal RMT target, based on lessons-learned from studies on TfR and accumulating experimental evidence on emerging RMT receptors and their ligands.
Author Arsalan S. Haqqani
Kasandra Bélanger
Danica B. Stanimirovic
AuthorAffiliation Human Health Therapeutics Research Center , National Research Council Canada , Ottawa , ON , Canada
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  givenname: Danica B.
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Edited by: Sumio Ohtsuki, Kumamoto University, Japan
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Snippet The delivery of therapeutics into the brain is highly limited by the blood-brain barrier (BBB). Although this is essential to protect the brain from...
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pubmedcentral
crossref
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Enrichment Source
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SubjectTerms blood-brain barrier
Drug Delivery
receptor-mediated transcytosis
RM1-950
RMT receptors
Therapeutics. Pharmacology
trafficking
Title Receptor-mediated transcytosis for brain delivery of therapeutics: receptor classes and criteria
URI https://cir.nii.ac.jp/crid/1873118016387592448
https://pubmed.ncbi.nlm.nih.gov/PMC12363266
https://doaj.org/article/baaff64b5c94438e9cc981649283ff6d
Volume 4
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