Enhanced anti-ischemic stroke of ZL006 by T7-conjugated PEGylated liposomes drug delivery system

Abstract

The treatment for ischemic stroke is one of the most challenging problems and the therapeutic effect remains unsatisfied due to the poor permeation of drugs across the blood brain barrier (BBB). In this study, HAIYPRH (T7), a peptide that targeted to transferrin receptor (TfR) can mediate the transport of nanocarriers across the BBB, was conjugated to liposomes for ischemic stroke targeting treatment of a novel neuroprotectant (ZL006). T7-conjugated PEGylated liposomes (T7-P-LPs) loaded with ZL006 (T7-P-LPs/ZL006) were showed satisfactory vesicle size and size distribution. Furthermore, the cellular uptake results showed that T7 modification increased liposomes uptake by the brain capillary endothelial cells (BCECs) and little cytotoxicity of liposomes with or without ZL006 was observed. The in vivo biodistribution and near-infrared fluorescence imaging evidenced that T7 modification rendered liposomes significantly enhanced the transport of liposomes across the BBB. The pharmacodynamic study suggested that, T7-P-LPs/ZL006 exhibited reduced infarct volume and ameliorated neurological deficit compared with unmodified liposomes or free ZL006. T7-P-LPs/ZL006 could be targeted to brain and displayed remarkable neuroprotective effects. They could be used as a potential targeted drug delivery system of ischemic stroke treatment.

Small molecule inhibitors of PSD95–nNOS protein–protein interactions suppress formalin-evoked Fos protein expression and nociceptive behavior in rats

“…Our study is the first to demonstrate that the small molecule protein-protein interaction inhibitor ZL006 produces antinociception in rats. ZL006, has been reported to exhibit limited blood brain barrier penetration (Wang et al, 2015) but efficacy exhibited by this compound in models of post-traumatic stress disorder (Shekar, 2012) and depression (Doucet et al, 2013) argue for central sites of action of ZL006. By contrast, ZL007 was ineffective in suppressing either formalin-evoked pain behavior or formalin-evoked Fos protein expression in rats.…”

PDZ Domains as Drug Targets

“…Screening of a 150 000 compound library identified IC87201 (2-((1H-benzo[d] [1,2,3]triazol-5-ylamino)methyl)-4,6-dichlorophenol) as an inhibitor of the PSD-95/nNOS interaction with an IC 50 of 31 µm. [126] The T7-P-ZL006 formulation increased the cellular uptake compared to ZL006 and T7-P-ZL006 showed a decrease in infarct volume following MCAO after i.v. administration and showed a significant pain reducing effect at 100 pmol in the presence of NMDA, with no effect in the absence of NMDA.…”

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

“…Conjugating these liposomes results in better target penetration, e.g. in myocardial cells (Dasa et al, 2017) and CNS (Wang et al, 2015c). HAIYPRH (T7), a peptide targeted to the transferrin receptor that is highly expressed on brain capillary endothelial cells, can mediate transport of nanocarriers across the BBB.…”

“…HAIYPRH (T7), a peptide targeted to the transferrin receptor that is highly expressed on brain capillary endothelial cells, can mediate transport of nanocarriers across the BBB. Recently, T7-conjugated PEGylated liposomes loaded with the neuroprotectant agent ZL006, which blocks neuronal NOS and PSD-95 interaction, reduced infarct volume and neurological deficits in the rat MCAO model when delivered IV at the time of reperfusion (Wang et al, 2015c). In addition, dexamethasone conjugated DNA nanotubes demonstrated a promising anti-inflammatory response in post-ischemic mice muscle tissue (Sellner et al, 2017).…”