Wang Zhongyuan, Zhao Yue, Jiang Yan, Lv Wei, Wu Lin, Wang Baoyan, Lv Lingyan, Xu Qunwei, Xin Hongliang
Department of Pharmaceutics, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
Sci Rep. 2015 Jul 29;5:12651. doi: 10.1038/srep12651.
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.
缺血性中风的治疗是最具挑战性的问题之一，由于药物难以透过血脑屏障（BBB），其治疗效果仍不尽人意。在本研究中，将一种靶向转铁蛋白受体（TfR）的肽HAIYPRH（T7）与脂质体偶联，用于对新型神经保护剂（ZL006）进行缺血性中风的靶向治疗，该肽可介导纳米载体透过血脑屏障。载有ZL006的T7偶联聚乙二醇化脂质体（T7-P-LPs/ZL006）显示出令人满意的囊泡大小和大小分布。此外，细胞摄取结果表明，T7修饰增加了脑毛细血管内皮细胞（BCECs）对脂质体的摄取，并且未观察到载有或未载有ZL006的脂质体有明显的细胞毒性。体内生物分布和近红外荧光成像证明，T7修饰使脂质体透过血脑屏障的转运显著增强。药效学研究表明，与未修饰的脂质体或游离ZL006相比，T7-P-LPs/ZL006的梗死体积减小，神经功能缺损得到改善。T7-P-LPs/ZL006可以靶向脑部并显示出显著的神经保护作用。它们可作为缺血性中风治疗的潜在靶向给药系统。
