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P-selectin-targeted nanocarriers induce active crossing of the blood–brain barrier via caveolin-1-dependent transcytosis
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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9981459/ https://www.ncbi.nlm.nih.gov/pubmed/36864161 http://dx.doi.org/10.1038/s41563-023-01481-9 |
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author | Tylawsky, Daniel E. Kiguchi, Hiroto Vaynshteyn, Jake Gerwin, Jeffrey Shah, Janki Islam, Taseen Boyer, Jacob A. Boué, Daniel R. Snuderl, Matija Greenblatt, Matthew B. Shamay, Yosi Raju, G. Praveen Heller, Daniel A. |
author_facet | Tylawsky, Daniel E. Kiguchi, Hiroto Vaynshteyn, Jake Gerwin, Jeffrey Shah, Janki Islam, Taseen Boyer, Jacob A. Boué, Daniel R. Snuderl, Matija Greenblatt, Matthew B. Shamay, Yosi Raju, G. Praveen Heller, Daniel A. |
author_sort | Tylawsky, Daniel E. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9981459 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-99814592023-03-04 P-selectin-targeted nanocarriers induce active crossing of the blood–brain barrier via caveolin-1-dependent transcytosis Tylawsky, Daniel E. Kiguchi, Hiroto Vaynshteyn, Jake Gerwin, Jeffrey Shah, Janki Islam, Taseen Boyer, Jacob A. Boué, Daniel R. Snuderl, Matija Greenblatt, Matthew B. Shamay, Yosi Raju, G. Praveen Heller, Daniel A. Nat Mater Article 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. Nature Publishing Group UK 2023-03-02 2023 /pmc/articles/PMC9981459/ /pubmed/36864161 http://dx.doi.org/10.1038/s41563-023-01481-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Tylawsky, Daniel E. Kiguchi, Hiroto Vaynshteyn, Jake Gerwin, Jeffrey Shah, Janki Islam, Taseen Boyer, Jacob A. Boué, Daniel R. Snuderl, Matija Greenblatt, Matthew B. Shamay, Yosi Raju, G. Praveen Heller, Daniel A. P-selectin-targeted nanocarriers induce active crossing of the blood–brain barrier via caveolin-1-dependent transcytosis |
title | P-selectin-targeted nanocarriers induce active crossing of the blood–brain barrier via caveolin-1-dependent transcytosis |
title_full | P-selectin-targeted nanocarriers induce active crossing of the blood–brain barrier via caveolin-1-dependent transcytosis |
title_fullStr | P-selectin-targeted nanocarriers induce active crossing of the blood–brain barrier via caveolin-1-dependent transcytosis |
title_full_unstemmed | P-selectin-targeted nanocarriers induce active crossing of the blood–brain barrier via caveolin-1-dependent transcytosis |
title_short | P-selectin-targeted nanocarriers induce active crossing of the blood–brain barrier via caveolin-1-dependent transcytosis |
title_sort | p-selectin-targeted nanocarriers induce active crossing of the blood–brain barrier via caveolin-1-dependent transcytosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9981459/ https://www.ncbi.nlm.nih.gov/pubmed/36864161 http://dx.doi.org/10.1038/s41563-023-01481-9 |
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