P-selectin-targeted nanocarriers induce active crossing of the blood–brain barrier via caveolin-1-dependent transcytosis Journal Article

   

Authors:	Tylawsky, D. E.; Kiguchi, H.; Vaynshteyn, J.; Gerwin, J.; Shah, J.; Islam, T.; Boyer, J. A.; Boué, D. R.; Snuderl, M.; Greenblatt, M. B.; Shamay, Y.; Raju, G. P.; Heller, D. A.
Article Title:	P-selectin-targeted nanocarriers induce active crossing of the blood–brain barrier via caveolin-1-dependent transcytosis
Abstract:	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. © 2023, The Author(s).
Keywords:	animal; animals; sonic hedgehog protein; hedgehog proteins; blood; brain; tumors; medulloblastoma; blood brain barrier; blood-brain barrier; bone; cerebellar neoplasms; pediatrics; p-selectin; padgem protein; tumor microenvironment; cerebellum tumor; nanocarriers; vismodegib; transcytosis; caveolin 1; caveolin-1; sonic hedgehogs; hedgehog signalling; fucoidans; paediatric brain tumours
Journal Title:	Nature Materials
Volume:	22
Issue:	3
ISSN:	1476-1122
Publisher:	Nature Publishing Group
Date Published:	2023-03-01
Start Page:	391
End Page:	399
Language:	English
DOI:	10.1038/s41563-023-01481-9
PUBMED:	36864161
PROVIDER:	scopus
PMCID:	PMC9981459
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85149309774&doi=10.1038%2fs41563-023-01481-9&partnerID=40&md5=4e91c1978ec38f60f6a88fadf24367ce
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Daniel Heller -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/204415