Enhancement of scutellarin oral delivery efficacy by vitamin B12-modified amphiphilic chitosan derivatives to treat type II diabetes induced-retinopathy.
Enhancement of scutellarin oral delivery efficacy by vitamin B12-modified amphiphilic chitosan derivatives to treat type II diabetes induced-retinopathy.
复制标题
维生素 B12 修饰的两亲性壳聚糖衍生物增强灯盏乙素口服给药功效治疗 II 型糖尿病引起的视网膜病变
DOI：
10.1186/s12951-017-0251-z
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发表时间：
2017-03-01
影响因子：
10.2
通讯作者：
Deng DY
中科院分区：
文献类型：
--
作者：
Wang J;Tan J;Luo J;Huang P;Zhou W;Chen L;Long L;Zhang LM;Zhu B;Yang L;Deng DY
背景糖尿病视网膜病变是糖尿病患者最常见的并发症，与血管内皮生长因子（VEGF）高表达和微动脉瘤有关。灯盏乙素（Scu）被证明对糖尿病相关的血管内皮细胞功能障碍有效。然而，其生物利用度低限制了其临床应用。在这项研究中，我们配制并表征了一种基于两亲性壳聚糖衍生物的新型肠道靶向纳米颗粒载体结果Chit-DC-VB 12纳米粒在250 μg/ml浓度范围内对人结肠腺癌细胞（Caco-2）和斑马鱼均表现出较低的毒性，且对视网膜病变的治疗效果较好。由于壳聚糖具有良好的生物相容性。然后通过水溶液自组装法制备灯盏乙素Chit-DC-VB 12纳米粒（Chit-DC-VB 12-Scu）。扫描电子显微镜和动态光散射分析表明，Chit-DC-VB 12-Scu纳米颗粒为球形颗粒，粒径在150 ~ 250 nm之间。Chit-DC-VB 12-Scu纳米粒在Caco-2细胞中表现出较高的渗透性，表明其可能有利于人体吸收。我们还发现Chit-DC-VB 12纳米颗粒具有高细胞摄取。在Sprague-Dawley大鼠中进行生物利用度研究，其显示Chit-DC-VB 12-Scu的灯盏乙素曲线下面积比单独的游离灯盏乙素大2至3倍。进一步评估糖尿病视网膜病变的治疗效果，我们发现Chit-DC-VB 12-Scu下调视网膜中央动脉电阻率指数和血管生成蛋白的表达结论载灯盏乙素Chit-DC-VB 12纳米粒的生物利用度和细胞摄取效率均优于Scu，Chit-DC-VB 12-Scu纳米粒可减轻糖尿病视网膜新生血管结构紊乱，并通过下调血管生成蛋白的表达抑制视网膜新生血管的形成。总之，Chit-DC-VB 12纳米粒增强了灯盏乙素口服给药的功效，并显示出作为小肠靶向有希望的纳米载体用于治疗II型糖尿病诱导的视网膜病变的潜力。
BackgroundDiabetic retinopathy is the most common complication in diabetic patients relates to high expression of VEGF and microaneurysms. Scutellarin (Scu) turned out to be effective against diabetes related vascular endothelial cell dysfunction. However, its clinical applications have been limited by its low bioavailability. In this study, we formulated and characterized a novel intestinal target nanoparticle carrier based on amphiphilic chitosan derivatives (Chit-DC-VB12) loaded with scutellarin to enhance its bioavailability and then evaluated its therapeutic effect in experimental diabetic retinopathy model.ResultsChit-DC-VB12 nanoparticles showed low toxicity toward the human colon adenocarcinoma (Caco-2) cells and zebra fish within concentration of 250 μg/ml, owing to good biocompatibility of chitosan. The scutellarin-loaded Chit-DC-VB12 nanoparticles (Chit-DC-VB12-Scu) were then prepared by self-assembly in aqueous solution. Scanning electron microscopy and dynamic light scattering analysis indicated that the Chit-DC-VB12-Scu nanoparticles were spherical particles in the sizes ranging from 150 to 250 nm. The Chit-DC-VB12-Scu nanoparticles exhibited high permeation in Caco-2 cell, indicated it could be beneficial to be absorbed in humans. We also found that Chit-DC-VB12 nanoparticles had a high cellular uptake. Bioavailability studies were performed in Sprague–Dawley rats, which present the area under the curve of scutellarin of Chit-DC-VB12-Scu was two to threefolds greater than that of free scutellarin alone. Further to assess the therapeutic efficacy of diabetic retinopathy, we showed Chit-DC-VB12-Scu down-regulated central retinal artery resistivity index and the expression of angiogenesis proteins (VEGF, VEGFR2, and vWF) of retinas in type II diabetic rats.ConclusionsChit-DC-VB12 nanoparticles loaded with scutellarin have better bioavailability and cellular uptake efficiency than Scu, while Chit-DC-VB12-Scu nanoparticles alleviated the structural disorder of intraretinal neovessels in the retina induced by diabetes, and it also inhibited the retinal neovascularization via down-regulated the expression of angiogenesis proteins. In conclusion, the Chit-DC-VB12 nanoparticles enhanced scutellarin oral delivery efficacy and exhibited potential as small intestinal target promising nano-carriers for treatment of type II diabetes induced-retinopathy.