The influx/efflux mechanisms of d-peptide ligand of nAChRs across the blood-brain barrier and its therapeutic value in treating glioma
Copyright © 2020 Elsevier B.V. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:327 |
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| Enthalten in: |
Journal of controlled release : official journal of the Controlled Release Society - 327(2020) vom: 10. Nov., Seite 384-396 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Han, Bing [VerfasserIn] |
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| Links: |
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| Themen: |
Blood-brain barrier |
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| Anmerkungen: |
Date Completed 17.06.2021 Date Revised 17.06.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jconrel.2020.08.010 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM313657645 |
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| 100 | 1 | |a Han, Bing |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The influx/efflux mechanisms of d-peptide ligand of nAChRs across the blood-brain barrier and its therapeutic value in treating glioma |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Completed 17.06.2021 | ||
| 500 | |a Date Revised 17.06.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 Elsevier B.V. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Blood-brain barrier | |
| 650 | 4 | |a D-type polypeptide | |
| 650 | 4 | |a Efflux | |
| 650 | 4 | |a Glioma | |
| 650 | 4 | |a Transport mechanism | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Liposomes |2 NLM | |
| 650 | 7 | |a Peptides |2 NLM | |
| 650 | 7 | |a Receptors, Nicotinic |2 NLM | |
| 700 | 1 | |a Xie, Weiyi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yanxia |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Shilin |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Jiahong |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Ruifeng |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Yuqing |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiaoyi |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Dawei |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yinhang |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Jiasheng |e verfasserin |4 aut | |
| 700 | 1 | |a Ning, Fengling |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Fuming |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Cai, Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Xin, Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Weiyue |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xuemei |e verfasserin |4 aut | |
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| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.jconrel.2020.08.010 |3 Volltext |
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