A Novel Protein Delivery System for Therapy of Preeclampsia

抽象的。 子痫前期是一种常见的妊娠期高血压疾病，是导致 孕产妇、胎儿和围产儿发病率和死亡率。在美国，先兆子痫影响到约8%的妊娠 表现出特征性的高血压、蛋白尿和心血管功能改变，如果不加控制，可能 导致产妇癫痫发作和死亡。目前还没有有效的干预措施来治疗先兆子痫 引产，这就是为什么它也是早产的主要原因。改进了 先兆子痫的治疗在很大程度上被扼杀了，因为各种拟议的小- 发育中胎儿的分子疗法。拟议研究的目标是开发一种药物 能够稳定母体循环中的新型治疗药物同时保护它们的递送系统 进入胎儿循环。先兆子痫的发生和发展由两个主要因素推动 血管内皮生长因子拮抗剂sFlt-1的途径、分泌及高炎症环境的诱导 母亲。我们已经开发了两种针对每种途径的新型药物，一种补充的血管内皮生长因子 抗sFlt-1水平升高的治疗和核因子-B抑制肽治疗以阻断 炎症反应。这些治疗药物附着在一种名为类弹性蛋白的药物输送载体上 多肽(ELP)，在母体循环中稳定它们，同时防止它们越过 胎盘进入胎儿循环。这项建议的目的是1)评估药物动力学， 这种药物载体几次重复的生物分布、胎盘靶向性和胎儿排斥性，2)评估 ELP-VEGF治疗大鼠先兆子痫的体外机制及体内疗效评价 ELP融合核因子-βB抑制治疗大鼠的体外机制及体内疗效 子痫前期模型，以及4)评估子痫前期母亲的后代中高血压的发展。 用这些试剂剂治疗。 好了！

Abstract. Preeclampsia is a common hypertensive disorder of pregnancy and is one of the leading causes of maternal, fetal, and perinatal morbidity and mortality. Affecting ~8% of all pregnancies in the US, preeclampsia displays characteristic hypertension, proteinuria, and altered cardiovascular function and, if left unchecked, can lead to maternal seizures and death. There is currently no effective intervention for preeclampsia short of induced delivery of the fetus, which is why it is also a leading cause of premature birth. Improvements in preeclampsia management have been largely stifled due to deleterious effects of various proposed small- molecule therapeutics on the developing fetus. The objective of the proposed studies is to develop a drug delivery system capable of stabilizing novel therapeutic agents in the maternal circulation while protecting them from entering the fetal circulation. The onset and progression of preeclampsia is driven by two major pathways, secretion of the VEGF antagonist sFlt-1 and induction of a highly inflammatory environment in the mother. We have developed two novel agents targeting each of these pathways, a supplementary VEGF therapy to counteract the increased sFlt-1 levels and an NF-¿B inhibitory peptide therapy to block the inflammatory response. These therapeutics are attached to a drug delivery vector called elastin-like polypeptide (ELP) that stabilizes them in the maternal circulation while preventing them from crossing the placenta into the fetal circulation. The aims of this proposal are to 1) assess the pharmacokinetics, biodistribution, placental targeting, and fetal exclusion of several iterations of this drug carrier, 2) evaluate the in vitro mechanisms and in vivo efficacy of the ELP-VEGF therapeutic in a rat preeclampsia model, 3) evaluate the in vitro mechanisms and in vivo efficacy of the ELP-fused NF-¿B inhibitory therapeutic in a rat preeclampsia model, and 4) assess the development of hypertension in the offspring of preeclamptic mothers treated with these test agents. !