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

Daniel E. Tylawsky, Hiroto Kiguchi, Jake Vaynshteyn, Jeffrey Gerwin, Janki Shah, Taseen Islam, Jacob A. Boyer, Daniel R. Boué, Matija Snuderl, Matthew B. Greenblatt, Yosi Shamay, G. Praveen Raju, Daniel A. Heller

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)391-399
Number of pages9
JournalNature Materials
Volume22
Issue number3
DOIs
StatePublished - Mar 2023
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • Condensed Matter Physics
  • Mechanics of Materials
  • Mechanical Engineering
  • General Materials Science

Fingerprint

Dive into the research topics of 'P-selectin-targeted nanocarriers induce active crossing of the blood–brain barrier via caveolin-1-dependent transcytosis'. Together they form a unique fingerprint.

Cite this