Modulating circulating sFlt1 in an animal model of preeclampsia using PAMAM nanoparticles for siRNA delivery
Modulating circulating sFlt1 in an animal model of preeclampsia using PAMAM nanoparticles for siRNA delivery
复制标题
使用 PAMAM 纳米颗粒进行 siRNA 递送来调节先兆子痫动物模型中的循环 sFlt1
DOI：
10.1016/j.placenta.2017.07.360
复制
发表时间：
2017-10-01
期刊：
影响因子：
3.8
通讯作者：
Feng, Ling
中科院分区：
文献类型：
--
作者：
Yu, Jun;Jia, Jing;Feng, Ling
前言：过量的循环sFlt 1在先兆子痫（PE）的发病机制中起着重要作用。利用RNAi沉默sFlt 1可能成为治疗PE的一种方法。由于siRNA的快速降解，体内基因治疗仍然受到限制。PAMAM（Poly-amidoamine）是一种优良的siRNA纳米载体，无明显毒性。方法：本研究的目的是研究siRNA-sFlt 1-PAMAM对PE的治疗作用。分析了siRNA-sFlt 1-PAMAM复合物的生物物理性质。接下来，将HTR-8/SVneo细胞与复合物一起孵育。检测转染效率、沉默效果和细胞增殖。将定时妊娠大鼠分组以测试siRNA-sFlt 1 PAMAM对PE的体内作用。通过注射肿瘤坏死因子-α（TNF-α）建立PE模型，治疗组同时注射TNF-α和siRNA-sFlt 1-PAMAM。测定平均动脉压、血清sFlt 1水平和24 h尿蛋白定量。结果：siRNA-sFlt 1-PAMAM复合物具有较高的细胞摄取率和良好的siRNA包封能力。siRNA-sFlt 1-PAMAM显著降低HTR-8/SVneo细胞的sFlt 1分泌（p = 0.001），而对HTR-8/SVneo细胞增殖几乎没有影响。TNF-α组sFlt 1水平、平均动脉压、尿蛋白水平均较对照组显著升高，而胎儿和胎盘重量较对照组显著降低（p < 0.05）。结论：siRNA-sFlt 1-PAMAM能有效抑制子痫前期大鼠sFlt 1的分泌，改善妊娠结局，为子痫前期的治疗提供了新的思路。(C)2017爱思唯尔有限公司版权所有
Introduction: Excessive circulating sFlt1 plays a major role in the pathogenesis of preeclampsia (PE). Using RNAi to silence sFlt1 may be a therapy for treating PE. Because of the rapid degradation of siRNA, gene therapy in vivo remains limited. Poly-amidoamine (PAMAM) has been demonstrated to be an excellent nanocarrier for siRNA delivery with no discernible toxicity.Methods: The aim of the present study was to investigate the therapeutic effect of siRNA-sFlt1-PAMAM on PE. The biophysical properties of siRNA-sFlt1-PAMAM complexes were analysed. Next, HTR-8/SVneo cells were incubated with the complexes. The transfection efficiency, silencing effect, and cell proliferation were examined. The timed pregnant rats were grouped to test the in vivo effect of siRNA-sFlt1PAMAM on PE. The PE model was established by injection of tumour necrosis factor-alpha (TNF-alpha), while treatment group rats were injected with both TNF-a and siRNA-sFlt1-PAMAM. The mean arterial pressure, serum levels of sFlt1, and 24-h urinary protein were measured. The number of viable pups, and weights of individual pups and placentae were determined.Results: siRNA-sFlt1-PAMAM complexes showed high cellular uptake and excellent siRNA encapsulation ability. siRNA-sFlt1-PAMAM significantly decreased sFlt1 secretion from HTR-8/SVneo cells (p = 0.001) with little effect on HTR-8/SVneo cell proliferation. The circulating level of sFlt1, mean arterial pressure, and urine protein level in the TNF-a group were significantly increased compared to that in the control group, while the weights of foetuses and placentae were significantly decreased compared to that in the control group (p < 0.05). All preeclamptic symptoms were greatly attenuated by siRNA-sFlt1-PAMAM (p < 0.05).Conclusions: These data suggest that siRNA-sFlt1-PAMAM effectively decreased sFlt1 secretion and improved pregnancy outcomes in a preeclamptic rat model, which may provide a new therapeutic strategy for PE. (C) 2017 Elsevier Ltd. All rights reserved.