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Role of scavenger receptors in peptide-based delivery of plasmid DNA across a blood-brain barrier model
Stockholm University, Faculty of Science, Department of Neurochemistry. Mahidol University, Thailand.
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.
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Number of Authors: 5
2016 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 500, no 1-2, 128-135 p.Article in journal (Refereed) Published
Abstract [en]

Receptor-mediated transcytosis remains a major route for drug delivery across the blood-brain barrier (BBB). PepFect 32 (PF32), a peptide-based vector modified with targeting ligand (Angiopep-2) binding to low-density lipoprotein receptor-related protein-1 (LRP-1), was previously found to be a promising vector for plasmid delivery across an in vitro model of the BBB. Cellular uptake of PF32/plasmid DNA (pDNA) complexes was speculated the internalization via LRP-1 receptor. In this study, we prove that PF32/pDNA nanocomplexes are not only transported into brain endothelial cells via LRP-1 receptor-mediated endocytosis, but also via scavenger receptor class A and B (SCARA3, SCARA5, and SR-BI)-mediated endocytosis. SCARA3, SCARA5, and SR-BI are found to be expressed in the brain endothelial cells. Inhibition of these receptors leads to a reduction of the transfection. In conclusion, this study shows that scavenger receptors also play an essential role in the cellular uptake of the PF32/pDNA nanocomplexes.

Place, publisher, year, edition, pages
2016. Vol. 500, no 1-2, 128-135 p.
Keyword [en]
Blood-brain barrier, bEnd.3, Plasmid transfection, Scavenger receptors, angiopep-2, LRP-1 receptor, Receptor-mediated endocytosis
National Category
Physical Chemistry Biochemistry and Molecular Biology Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:su:diva-128163DOI: 10.1016/j.ijpharm.2016.01.014ISI: 000370049900013PubMedID: 26773601OAI: oai:DiVA.org:su-128163DiVA: diva2:915151
Available from: 2016-03-29 Created: 2016-03-21 Last updated: 2016-04-25Bibliographically approved
In thesis
1. Peptide-based delivery to glioblastoma cells studied by the blood-brain barrier model
Open this publication in new window or tab >>Peptide-based delivery to glioblastoma cells studied by the blood-brain barrier model
2016 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Crossing the blood-brain barrier (BBB) is a great challenge for delivery of highly charged macromolecules such as nucleic acids and proteins to the brain. Cell-penetrating peptides (CPPs) are promising vectors to deliver various cargoes ranging from small molecules to large molecules such as antibodies, proteins, and nucleic acids. The BBB limits the passage of all large molecules to central nervous system (CNS), thus, CPP is a potential vector to use for oligonucleotide delivery across the BBB. In paper I, various CPPs were covalently conjugated with two different glioma-targeting peptides, glioma-homing peptide (gHo) and angiopep-2 (ANG). PepFect 32 (PF32), a conjugation between truncated PepFect 14 and ANG, was the most efficient vector to deliver plasmid DNA (pDNA) across a setup in vitro model of the BBB and showed the highest transfection in glioma cells. LRP-1 receptors, which are over-expressed in brain endothelial cells and glioma cells, were speculated to mediate the transcytosis of PF32:pDNA complexes across the BBB model since the ANG could target to LRP-1. In paper II, scavenger receptors class A and B (SCARA3, SCARA5, and SR-BI) were found to be expressed in the brain endothelial cells. Inhibition of these scavenger receptors led to a reduction of the transfection of PF32:pDNA complexes in the brain endothelial cells. Therefore, in the BBB model scavenger receptors also played a vital role as well as LRP-1 in the transport of oligonucleotides in the complex with peptide-based vector PF32.

In conclusion, PF32 is a potential vector to deliver pDNA across the BBB model and target to the glioma cells. The complexes of PF32:pDNA transport across the brain endothelial cells via receptor-mediated endocytosis pathway recognized by scavenger receptors and LRP-1. To improve the specificity and enhance the transport into the brain, the brain-homing devices are considered as a promising strategy for CNS drug delivery.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, 2016. 33 p.
Keyword
peptide-based delivery, blood-brain barrier, glioblastoma
National Category
Other Chemistry Topics
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-129528 (URN)978-91-7649-432-5 (ISBN)
Presentation
2016-05-13, Heilbronnsalen, C458, Svante Arrhenius väg 16B, Stockholm, 13:00 (English)
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Available from: 2016-04-25 Created: 2016-04-25 Last updated: 2016-04-25Bibliographically approved

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Srimanee, ArtitaRegberg, JakobHällbrink, MattiasLangel, Ülo
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