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The influx/efflux mechanisms of d-peptide ligand of nAChRs across the blood–brain barrier and its therapeutic value in treating glioma.
- Source :
-
Journal of Controlled Release . Nov2020, Vol. 327, p384-396. 13p. - Publication Year :
- 2020
-
Abstract
- A d -peptide ligand of the nicotine acetylcholine receptors (nAChRs), termed DCDX, enables drug delivery to the brain when incorporated into liposomes and has shown promise as a nanocarrier for treating brain diseases. However, few reports have described the mechanisms whereby DCDX-modified liposomes traverse the blood–brain barrier (BBB). Here, we studied the molecular mechanisms enabling DCDX (and its associated liposomes) to cross an in vitro BBB using a simulated cerebral endothelium monolayer formed by brain capillary endothelial cells (bEnd.3 cells). We also examined the mechanisms whereby DCDX-modified liposomes cross the BBB in vivo using the brain efflux-index method. Transport of DCDX and its modified liposomes was dominantly mediated via the lipid raft/caveolae endocytic pathway. Both the endoplasmic reticulum (ER) and Golgi complex participated in delivering DCDX-modified liposomes to the plasma membrane (PM). DCDX-modified liposomes also participated in the endosome/lysosome pathway (with high-efficiency BBB crossing observed in vitro), while competing for the ER/Golgi/PM pathway. In addition, nAChR α7 did not promote the transportation of DCDX-modified liposomes in vivo or in vitro , as assessed with α7-knockout mice and by performing α-bungarotoxin (α-Bgt) binding-competition experiments. P-glycoprotein (P-gp) was identified as the main efflux transporter across the BBB, in vivo and in vitro. Using a xenograft nude mouse model of human glioblastoma multiforme, blocking the efflux function of P-gp with verapamil enhanced the therapeutic efficiency of DCDX-modified liposomes that were formulated with doxorubicin against glioblastoma. The findings of this study reveal novel mechanisms underlying crossing of the BBB by DCDX-modified liposomes, suggesting that DCDX-modified liposomes can potentially serve as a powerful therapeutic tool for treating glioma. Unlabelled Image • We studied DCDX (and its associated liposomes) BBB crossing in vitro and in vivo. • Lipid rafts/caveolae mediated the transport of DCDX and its modified liposomes. • The ER and Golgi complex helped deliver DCDX-modified liposomes to the PM. • P-gp acted as the main efflux transporter across the BBB, in vivo and in vitro. • Blocking P-gp with verapamil enhanced the efficiency of DCDX-LP/DOX against GBM. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 01683659
- Volume :
- 327
- Database :
- Academic Search Index
- Journal :
- Journal of Controlled Release
- Publication Type :
- Academic Journal
- Accession number :
- 146751629
- Full Text :
- https://doi.org/10.1016/j.jconrel.2020.08.010