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