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.
Highlights
The impact of stroke, ischemic stroke, can be devastating, and unlike other disabling neurological diseases, stroke has a high incidence, prevalence and rate of subsequent disability
The in vivo anti-ischemic stroke efficacy of T7-P-LPs/ZL006 was evaluated through rats middle cerebral artery occlusion (MCAO) model
The time-related experiment exhibited that the fluorescence intensity of coumarin-6-labeled T7-P-LPs on brain capillary endothelial cells (BCECs) was significantly enhanced when compared with that of P-LPs at all experiment time points (Fig. 4B). These results indicated that T7 played an active targeting role in T7-P-LPs uptake by BCECs via transferrin receptor mediated endocytosis
Summary
The impact of stroke, ischemic stroke, can be devastating, and unlike other disabling neurological diseases, stroke has a high incidence, prevalence and rate of subsequent disability. We developed T7 peptide modified ZL006 loading liposome (T7-P-LPs/ ZL006) to improve the drug delivery to brain and enhance the therapeutic effect against ischemic stroke for ZL006 in this study. The results shows that BCECs treated with either coumarin-6-labeled P-LPs or T7-P-LPs exhibited fluorescent intensity corresponding to incubation concentration (Fig. 3).
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