Department of Obstetrics and Gynaecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
Department of Obstetrics and Gynaecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China.
ACS Biomater Sci Eng. 2020 Oct 12;6(10):5866-5873. doi: 10.1021/acsbiomaterials.0c00826. Epub 2020 Sep 30.
Preeclampsia has impacted 3-5% pregnancies among the world and its complications lead to both maternal and fetal morbidity and mortality. However, management of preeclampsia is limited. Nanoparticles targeting chondroitin sulfate A (CSA) can deliver drugs to placenta. Inactivation of soluble fms-like tyrosine kinase (sFlt-1) and nuclear factor-erythroid 2-like 2 (Nrf2) has been proved to alleviate preeclampsia and improve maternal and fetal outcomes. Carboxyl-polyethylene glycol-poly (d,l-lactide) (COOH-PEG5K-PLA8K), cationic lipid DOTAP, and siNrf2 and sisFlt-1 were used to construct the nanoparticles and conjugating peptides targeting CSA was fabricated to it. The expression levels of proteins and RNAs were estimated by qRT-PCR and Western blot assays. ELISA assays were performed to evaluate levels of circulating sFlt-1. The nanoparticles containing siNrf2 and sisFlt-1 are targeted to the placenta trophoblasts and downregulated the expression levels of Nrf2 and sFlt-1 as well as their downstream genes in the placental cells of model mice. Treatment of nanoparticles induced the expression of angiogenic factors in placenta. Knocking down Nrf2 and sFlt-1 synchronously alleviated the preeclampsia and increased the maternal and fetal outcomes in preeclampsia model mice. Nanoparticle-mediated simultaneous downregulation of placental Nrf2 and sFlt1 improved maternal and fetal outcomes in a preeclampsia mouse model.
子痫前期影响了全球 3-5%的妊娠，其并发症导致母婴发病率和死亡率上升。然而，子痫前期的治疗方法有限。靶向硫酸软骨素 A（CSA）的纳米颗粒可以将药物递送到胎盘。已证明抑制可溶性 fms 样酪氨酸激酶（sFlt-1）和核因子-红细胞 2 样 2（Nrf2）的活性可以缓解子痫前期并改善母婴结局。羧基-聚乙二醇-聚（d，l-乳酸）（COOH-PEG5K-PLA8K）、阳离子脂质 DOTAP 和 siNrf2 和 sisFlt-1 被用于构建纳米颗粒，并将靶向 CSA 的缀合肽与之连接。通过 qRT-PCR 和 Western blot 测定来评估蛋白质和 RNA 的表达水平。通过 ELISA 测定来评估循环 sFlt-1 的水平。载有 siNrf2 和 sisFlt-1 的纳米颗粒靶向胎盘滋养层，并下调模型小鼠胎盘细胞中 Nrf2 和 sFlt-1 及其下游基因的表达水平。纳米颗粒处理诱导胎盘血管生成因子的表达。同时敲低 Nrf2 和 sFlt-1 可同步缓解子痫前期并增加子痫前期模型中小鼠的母婴结局。纳米颗粒介导的胎盘 Nrf2 和 sFlt1 的同时下调改善了子痫前期小鼠模型的母婴结局。
