Neutrophil-mediated and low density lipoprotein receptor-mediated dual-targeting nanoformulation enhances brain accumulation of scutellarin and exerts neuroprotective effects against ischemic stroke. Issue 3 (10th January 2019)

• Record Type: Journal Article
• Authors: Dang, Yanxin; An, Chiying; Li, Yutao; Han, Dandan; Liu, Xin; Zhang, Fengming; Xu, Yuan; Zhong, Haijing; Karim Khan, Mewand Khan; Zou, Fengjuan; Sun, Xiaojun
• Is Part Of: RSC advances. Volume 9:Issue 3(2019)
• Page Start: 1299
• Page End: 1318
• Publication Date: 2019-01-10
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c8ra06688d
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : Delivery of poorly permeable drugs across the blood-brain barrier (BBB) is a great challenge in the treatment of ischemic stroke. 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.