Wei Hanmei, Liu Tuo, Jiang Ning, Zhou Kang, Yang Kangqiang, Ning Weimin, Yu Yang
J Biomed Nanotechnol. 2018 Jul 1;14(7):1252-1262. doi: 10.1166/jbn.2018.2581.
The blood-brain barrier (BBB) poses a challenge for the treatment of cerebrovascular diseases including cerebral ischemia-reperfusion injury, Parkinson's syndrome, and cerebral tumors. Nanotechnology has developed as a promising strategy for drug delivery applications to the brain, especially liposomes (Lps) that have shown an intrinsic ability to cross the BBB. Angiopep-2 (ANG), a ligand for low-density lipoprotein receptor-related protein-1 (LRP1), is a good prospect for use as a targeting ligand for brain delivery using Lps. It was also reported that Polysorbate 80 (Tween 80, T80) plays a special role in brain targeting. Moreover, the nasal drug delivery method has attracted increased attention with its brain targeting capability in the clinical treatment of cerebrovascular diseases. The aim of this work was to evaluate the capability of Angiopep-conjugated Polysorbate 80-Coated Liposomes in the delivery of cyclovirobuxine D across the BBB in vitro and in vivo. For this purpose, we first synthesized DSPE-PEG2000-Angiopep-2 then cyclovirobuxine D was encapsulated in Angiopep-conjugated Polysorbate 80-Coated Liposomes (T80-An2-CVB-D-Lps) prepared by thin film evaporation and an ultrasonic technique. Formulations were characterized in terms of encapsulation efficiency, transmission electron microscope (TEM) morphology, size distribution, and zeta potential. Angiopep-conjugated Polysorbate 80-Coated Liposomes enhanced in vitro BBB transport of CVB-D compared to the nontargeted liposomes and the CVB-D solution in the BBB model consisting of brain microvascular endothelial (bEnd.3) cells. To evaluate the brain targeting of T80-An2-CVB-D-Lps in vivo, microdialysis samples were collected from the striatum and blood simultaneously. Rats were dosed with brain-targeting liposomes, CVB-D liposomes and CVB-D solution by intranasal administration and with brain-targeting liposomes by intravenous injection. The results showed that T80-An2-CVB-D-Lps were spherical, small (approximately 80 nm), homogeneously dispersed, negatively charged and possessed a high encapsulation efficiency. T80-An2-CVB-D-Lps crossed the BBB model better than the other treatments did. In addition, in a pharmacodynamic study, there was a higher AUC in the brain after T80-An2-CVB-D-Lps by intranasal administration. In conclusion, T80-An2-Lps can enhance the BBB permeability and improve the transport of CVB-D to the brain. This coadministration strategy can be utilized to enhance the brain accumulation in other cerebrovascular diseases.
血脑屏障（BBB）对包括脑缺血-再灌注损伤、帕金森综合征和脑肿瘤在内的脑血管疾病的治疗构成了挑战。纳米技术已发展成为一种有前景的脑部药物递送策略，尤其是脂质体（Lps），其已显示出穿越血脑屏障的内在能力。血管活性肠肽-2（ANG）是低密度脂蛋白受体相关蛋白-1（LRP1）的配体，是用作脂质体脑部递送靶向配体的良好候选物。另据报道，聚山梨酯80（吐温80，T80）在脑部靶向中发挥特殊作用。此外，鼻腔给药方法因其在脑血管疾病临床治疗中的脑部靶向能力而受到越来越多的关注。本研究的目的是评估血管活性肠肽偶联聚山梨酯80包被脂质体在体外和体内递送环维黄杨星D穿越血脑屏障的能力。为此，我们首先合成了DSPE-PEG2000-血管活性肠肽-2，然后将环维黄杨星D包封于通过薄膜蒸发和超声技术制备的血管活性肠肽偶联聚山梨酯80包被脂质体（T80-An2-CVB-D-Lps）中。通过包封率、透射电子显微镜（TEM）形态、粒径分布和zeta电位对制剂进行表征。与非靶向脂质体和由脑微血管内皮（bEnd.3）细胞组成的血脑屏障模型中的环维黄杨星D溶液相比，血管活性肠肽偶联聚山梨酯80包被脂质体增强了环维黄杨星D的体外血脑屏障转运。为了评估T80-An2-CVB-D-Lps在体内的脑部靶向性，同时从纹状体和血液中收集微透析样品。通过鼻腔给药给大鼠施用脑部靶向脂质体、环维黄杨星D脂质体和环维黄杨星D溶液，并通过静脉注射施用脑部靶向脂质体。结果表明，T80-An2-CVB-D-Lps呈球形，粒径小（约80 nm），均匀分散，带负电荷，且具有高包封率。T80-An2-CVB-D-Lps穿越血脑屏障模型的能力优于其他处理。此外，在药效学研究中，鼻腔给药T80-An2-CVB-D-Lps后脑部的AUC更高。总之，T80-An2-Lps可增强血脑屏障通透性并改善环维黄杨星D向脑部的转运。这种联合给药策略可用于增强其他脑血管疾病中的脑部蓄积。
