@article{6deca940b6dd4d1e819b860678a2ef39,
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.",
author = "Tylawsky, {Daniel E.} and Hiroto Kiguchi and Jake Vaynshteyn and Jeffrey Gerwin and Janki Shah and Taseen Islam and Boyer, {Jacob A.} and Bou{\'e}, {Daniel R.} and Matija Snuderl and Greenblatt, {Matthew B.} and Yosi Shamay and Raju, {G. Praveen} and Heller, {Daniel A.}",
note = "Funding Information: We thank the following core facilities: Molecular Cytology, Flow Cytometry and Small Animal Imaging at MSKCC, and the Center for Translational Pathology at Weill Cornell Medicine. We also thank R. Sridharan (MSKCC) for her collaboration in the development of CAV1 KO bEnd.3 cells, M. Manzari (MSKCC) for assistance with electron microscopy studies and O. Majekodunmi (MSKCC) for her assistance with formulation and characterization of gold nanoparticles. Figure was created with BioRender.com (ref. ). This work was supported in part by the NCI (nos. R01-CA215719, T32-CA062948 and the Cancer Center Support Grant, P30-CA008748), NINDS (nos. R01-NS116353 and R56-NS122987), the American Cancer Society Research Scholar Grant (no. GC230452), Unravel Pediatric Cancer, Emerson Collective, the Pershing Square Sohn Cancer Research Alliance, The Hartwell Foundation, the Expect Miracles Foundation – Financial Services Against Cancer, MSK{\textquoteright}s Cycle for Survival{\textquoteright}s Equinox Innovation Award in Rare Cancers, the Louis and Rachel Rudin Foundation, the Alan and Sandra Gerry Metastasis Research Initiative, Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center, the Imaging & Radiation Sciences Program and the Center for Molecular Imaging and Nanotechnology of MSKCC. Funding Information: We thank the following core facilities: Molecular Cytology, Flow Cytometry and Small Animal Imaging at MSKCC, and the Center for Translational Pathology at Weill Cornell Medicine. We also thank R. Sridharan (MSKCC) for her collaboration in the development of CAV1 KO bEnd.3 cells, M. Manzari (MSKCC) for assistance with electron microscopy studies and O. Majekodunmi (MSKCC) for her assistance with formulation and characterization of gold nanoparticles. Figure 3j was created with BioRender.com (ref.38). This work was supported in part by the NCI (nos. R01-CA215719, T32-CA062948 and the Cancer Center Support Grant, P30-CA008748), NINDS (nos. R01-NS116353 and R56-NS122987), the American Cancer Society Research Scholar Grant (no. GC230452), Unravel Pediatric Cancer, Emerson Collective, the Pershing Square Sohn Cancer Research Alliance, The Hartwell Foundation, the Expect Miracles Foundation – Financial Services Against Cancer, MSK{\textquoteright}s Cycle for Survival{\textquoteright}s Equinox Innovation Award in Rare Cancers, the Louis and Rachel Rudin Foundation, the Alan and Sandra Gerry Metastasis Research Initiative, Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center, the Imaging & Radiation Sciences Program and the Center for Molecular Imaging and Nanotechnology of MSKCC. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = mar,
doi = "10.1038/s41563-023-01481-9",
language = "English (US)",
volume = "22",
pages = "391--399",
journal = "Nature Materials",
issn = "1476-1122",
publisher = "Nature Publishing Group",
number = "3",
}