Document type
ArticleVersion
Accepted versionPublication date
Publication license
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/200976
Altered blood-brain barrier transport of nanotherapeutics in lysosomal storage diseases
Journal Title
Director/Tutor
Journal ISSN
Volume Title
Related resource
Abstract
Treatment of neurological lysosomal storage disorders (LSDs) are limited because of impermeability of the blood-brain barrier (BBB) to macromolecules. Nanoformulations targeting BBB transcytosis are being explored, but the status of these routes in LSDs is unknown. We studied nanocarriers (NCs) targeted to the transferrin receptor (TfR), ganglioside GM1 or ICAM1, associated to the clathrin, caveolar or cell adhesion molecule (CAM) routes, respectively. We used brain endothelial cells and mouse models of acid sphingomyelinase-deficient Niemann Pick disease (NPD), and postmortem LSD patients' brains, all compared to respective controls. NC transcytosis across brain endothelial cells and brain distribution in mice were affected, yet through different mechanisms. Reduced TfR and clathrin expression were found, along with decreased transcytosis in cells and mouse brain distribution. Caveolin-1 expression and GM1 transcytosis were also reduced, yet increased GM1 levels seemed to compensate, providing similar NC brain distribution in NPD vs. control mice. A tendency to lower NHE-1 levels was seen, but highly increased ICAM1 expression in cells and human brains correlated with increased transcytosis and brain distribution in mice. Thus, transcytosis-related alterations in NPD and likely other LSDs may impact therapeutic access to the brain, illustrating the need for these mechanistic studies.Copyright © 2022 Elsevier B.V. All rights reserved.
Subject
Subject (English)
Citation
Citation
SOLOMON, Melani, et al. Altered blood-brain barrier transport of nanotherapeutics in lysosomal storage diseases. Journal Of Controlled Release. 2022. Vol. 349, num. 1031-1044. ISSN 1873-4995. [consulted: 15 of June of 2026]. Available at: https://hdl.handle.net/2445/200976