Neutrophil-mediated and low density lipoprotein receptor-mediated dual-targeting nanoformulation enhances brain accumulation of scutellarin and exerts neuroprotective effects against ischemic stroke
2019
Dang, Yanxin | An, Chiying | Li, Yutao | Han, Dandan | Liu, Xin | Zhang, Fengming | Xu, Yuan | Zhong, Haijing | Karim Khan, Mewand Khan | Zou, Fengjuan | Sun, Xiaojun
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.
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