The proton permeability of self-assembled polymersomes and their neuroprotection by enhancing a neuroprotective peptide across the blood-brain barrier after modification with lactoferrin.
The proton permeability of self-assembled polymersomes and their neuroprotection by enhancing a neuroprotective peptide across the blood-brain barrier after modification with lactoferrin.
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DOI：
10.1039/c3nr05196j
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发表时间：
2014-02
期刊：
影响因子：
6.7
通讯作者：
Yuan Yu;Xin-guo Jiang;Shuyu Gong;Liang Feng;Yan-qiang Zhong;Z. Pang
中科院分区：
文献类型：
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作者：
Yuan Yu;Xin-guo Jiang;Shuyu Gong;Liang Feng;Yan-qiang Zhong;Z. Pang
生物治疗药物如肽类药物具有治疗难治性神经系统疾病的强大潜力。然而，由于其低稳定性和血脑屏障（BBB）的不渗透性，生物治疗药物难以通过静脉注射转运到脑实质中。在此，我们提出了一种新的聚（乙二醇）-聚（d，l-乳酸-共-乙醇酸）聚合物纳米药物与自组装双层，这是功能化的乳铁蛋白（Lf-POS），以促进运输的神经保护肽进入大脑。H（+）通过聚合物囊泡膜的表观扩散系数（D*）为5.659 × 10（-26）cm（2）s（-1），而脂质体的表观扩散系数（D *）为1.017 × 10（-24）cm（2）s（-1）。聚合物囊泡膜的稳定性远高于脂质体。小鼠脑毛细血管内皮细胞对聚合物囊泡的摄取证明，乳铁蛋白的最佳密度为每个聚合物囊泡101个分子。荧光成像表明Lf 101-POS被有效地转移到脑中。在药代动力学方面，与转铁蛋白修饰的聚合物囊泡和阳离子牛血清白蛋白修饰的聚合物囊泡相比，Lf-POS获得了最大的BBB渗透表面积和每克注射剂量的百分比（%ID/g）。此外，Lf-POS持有S14 G-humanin保护大鼠对淀粉样蛋白β25-35诱导的学习和记忆障碍。蛋白质印迹法显示，纳米药物提供了神经保护，防止过度表达的凋亡蛋白，表现出神经元缠结病理。这些结果表明，聚合物囊泡可以被开发为一种有前途的非侵入性纳米药物，能够介导肽治疗递送和控制药物向中枢神经系统的释放。
Biotherapeutics such as peptides possess strong potential for the treatment of intractable neurological disorders. However, because of their low stability and the impermeability of the blood-brain barrier (BBB), biotherapeutics are difficult to transport into brain parenchyma via intravenous injection. Herein, we present a novel poly(ethylene glycol)-poly(d,l-lactic-co-glycolic acid) polymersome-based nanomedicine with self-assembled bilayers, which was functionalized with lactoferrin (Lf-POS) to facilitate the transport of a neuroprotective peptide into the brain. The apparent diffusion coefficient (D*) of H(+) through the polymersome membrane was 5.659 × 10(-26) cm(2) s(-1), while that of liposomes was 1.017 × 10(-24) cm(2) s(-1). The stability of the polymersome membrane was much higher than that of liposomes. The uptake of polymersomes by mouse brain capillary endothelial cells proved that the optimal density of lactoferrin was 101 molecules per polymersome. Fluorescence imaging indicated that Lf101-POS was effectively transferred into the brain. In pharmacokinetics, compared with transferrin-modified polymersomes and cationic bovine serum albumin-modified polymersomes, Lf-POS obtained the greatest BBB permeability surface area and percentage of injected dose per gram (%ID per g). Furthermore, Lf-POS holding S14G-humanin protected against learning and memory impairment induced by amyloid-β25-35 in rats. Western blotting revealed that the nanomedicine provided neuroprotection against over-expression of apoptotic proteins exhibiting neurofibrillary tangle pathology in neurons. The results indicated that polymersomes can be exploited as a promising non-invasive nanomedicine capable of mediating peptide therapeutic delivery and controlling the release of drugs to the central nervous system.