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Issue 3, 2019, Issue in Progress
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Neutrophil-mediated and low density lipoprotein receptor-mediated dual-targeting nanoformulation enhances brain accumulation of scutellarin and exerts neuroprotective effects against ischemic stroke

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Abstract

Delivery of poorly permeable drugs across the blood-brain barrier (BBB) is a great challenge in the treatment of ischemic stroke. In order to construct a suitable delivery system for this purpose, we developed a dual-targeting nanoformulation to transfer therapeutic agents targeting the inflammatory sites of the ischemic brain. The matrix of this system is a hydroxyl-terminated polyamidoamine dendrimer with excellent biodegradability. The surface of the matrix is functionalized with two targeting peptides: Angiopep-2 is a low density lipoprotein receptor-mediated peptide with high BBB transcytosis capacity with ligands expressed on brain endothelial cells; N-acetylated proline-glycine-proline (PGP) has high affinity to CXCR2 expressed on infiltrating neutrophils. This system proved to be a high-loading formulation for the neuroprotective compound, scutellarin (STA), and significantly improved its therapeutic efficacy in a rodent model of ischemic stroke. The molecular mechanism underlying the therapeutic efficacy of this formulation is associated with significant down-regulation of the inflammatory cytokines, neutrophils infiltration and intracellular calcium overload and blockade of the inflammatory signaling pathway HMGB1/TLRs/MyD88/TRIF/NF-κB. Our results suggest that this dual-targeting delivery system is a promising drug delivery vehicle for ischemic stroke, and possibly other CNS diseases where neuroinflammation is involved.

Graphical abstract: Neutrophil-mediated and low density lipoprotein receptor-mediated dual-targeting nanoformulation enhances brain accumulation of scutellarin and exerts neuroprotective effects against ischemic stroke

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Supplementary files

Article information


Submitted
09 Aug 2018
Accepted
05 Dec 2018
First published
10 Jan 2019

This article is Open Access

RSC Adv., 2019,9, 1299-1318
Article type
Paper

Neutrophil-mediated and low density lipoprotein receptor-mediated dual-targeting nanoformulation enhances brain accumulation of scutellarin and exerts neuroprotective effects against ischemic stroke

Y. Dang, C. An, Y. Li, D. Han, X. Liu, F. Zhang, Y. Xu, H. Zhong, M. K. Karim Khan, F. Zou and X. Sun, RSC Adv., 2019, 9, 1299
DOI: 10.1039/C8RA06688D

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