Neutrophil affinity for PGP and HAIYPRH (T7) peptide dual-ligand functionalized nanoformulation enhances the brain delivery of tanshinone IIA and exerts neuroprotective effects against ischemic stroke by inhibiting proinflammatory signaling pathways

作者：Li, Yutao; An, Chiying; Han, Danan; Dang, Yanxin; Liu, Xin^*; Zhang, Fengming; Xu, Yuan; Zhong, Haijing; Sun, Xiaojun^*

来源：New Journal of Chemistry, 2018, 42(23): 19043-19061.

DOI：10.1039/c8nj04819c

• FOCAL CEREBRAL-ISCHEMIA
• NF-KAPPA-B
• DRUG-DELIVERY
• TARGETING THERAPY
• DISSOLUTION RATE
• NANOPARTICLES
• PACLITAXEL
• GLIOMA
• INJURY
• DOXORUBICIN

A great challenge to the therapy of ischemic stroke is the poor physicochemical properties and inability of the drug to cross the blood-brain barrier (BBB). In order to overcome these hurdles, we have developed a novel ischemic inflammatory site-recognizing and BBB-penetrating dual-targeting nano-drug system. The nanoformulation is functionalized with two targeting peptides: T7 is a transferrin receptor-mediated peptide with high BBB transcytosis capacity with ligands expressed on brain endothelial cells; N-acetylated proline-glycine-proline (PGP) has a high affinity for CXCR2 expressed on infiltrating neutrophils. This system has been proved to be a high-loading formulation for the neuroprotective compound, tanshinone IIA (TSIIA), and significantly improved its brain accumulation and therapeutic efficacy in a rodent model of ischemic stroke. The anti-ischemic stroke efficacy of TSIIA-loaded T7-PGP dual-modified PEGylated generation-5 (G5.0) hydroxyl-terminated polyamidoamine dendrimers NPs is verified by its ameliorated neuronal apoptosis and overload of intracellular Ca2+ and proinflammatory cytokines (IL-12p40, IL-13, IL-17 and IL-23). The molecular mechanism underlying the therapeutic efficacy of this formulation is associated with significant down-regulation of HMGB1/TLRs/MyD88/TRIF/IRAK inflammatory signaling pathways in ischemic stroke. The evidence highlights the potential of this dual-targeting delivery system in overcoming the main problem in drug delivery for CNS diseases where neuroinflammation is involved.

• 出版日期2018-12-7
• 单位黑龙江省康复医院; 哈尔滨医科大学; 哈尔滨学院