P-selectin-targeted nanocarriers induce active crossing of the blood-brain barrier via caveolin-1-dependent transcytosis.
Journal
Nature materials
ISSN: 1476-4660
Titre abrégé: Nat Mater
Pays: England
ID NLM: 101155473
Informations de publication
Date de publication:
03 2023
03 2023
Historique:
received:
25
06
2021
accepted:
18
01
2023
entrez:
2
3
2023
pubmed:
3
3
2023
medline:
7
3
2023
Statut:
ppublish
Résumé
Medulloblastoma is the most common malignant paediatric brain tumour, with ~30% mediated by Sonic hedgehog signalling. Vismodegib-mediated inhibition of the Sonic hedgehog effector Smoothened inhibits tumour growth but causes growth plate fusion at effective doses. Here, we report a nanotherapeutic approach targeting endothelial tumour vasculature to enhance blood-brain barrier crossing. We use fucoidan-based nanocarriers targeting endothelial P-selectin to induce caveolin-1-dependent transcytosis and thus nanocarrier transport into the brain tumour microenvironment in a selective and active manner, the efficiency of which is increased by radiation treatment. In a Sonic hedgehog medulloblastoma animal model, fucoidan-based nanoparticles encapsulating vismodegib exhibit a striking efficacy and marked reduced bone toxicity and drug exposure to healthy brain tissue. Overall, these findings demonstrate a potent strategy for targeted intracranial pharmacodelivery that overcomes the restrictive blood-brain barrier to achieve enhanced tumour-selective penetration and has therapeutic implications for diseases within the central nervous system.
Identifiants
pubmed: 36864161
doi: 10.1038/s41563-023-01481-9
pii: 10.1038/s41563-023-01481-9
pmc: PMC9981459
doi:
Substances chimiques
Hedgehog Proteins
0
HhAntag691
0
Caveolin 1
0
P-Selectin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
391-399Subventions
Organisme : NCI NIH HHS
ID : T32 CA062948
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS116353
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA215719
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS122987
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2023. The Author(s).
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Adapted from ‘Blood Brain Barrier (simple longitudinal)’. BioRender. Accessed 21 January 2023; https://app.biorender.com/biorender-templates