A Novel Protein Delivery System for Therapy of Preeclampsia

用于治疗先兆子痫的新型蛋白质递送系统

• 批准号: 8613787
• 负责人: Gene Leflore Bidwell
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-15 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8613787
• 关键词: Affect; Amino Acid Motifs; Amino Acids; Angiogenic Proteins; Anti-Inflammatory Agents; Anti-inflammatory; Blood Circulation; Brain Hypoxia-Ischemia; Cardiovascular Physiology; Cardiovascular system; Cessation of life; Characteristics; Chimera organism; Chronic; Data; Development; Disease; Drug Carriers; Drug Delivery Systems; Drug Kinetics; Elastin; Endothelial Cells; Environment; Escherichia coli; Exclusion; Failure; Fetal Tissues; Fetus; Functional disorder; Goals; Hypertension; In Vitro; Infant; Inflammatory; Inflammatory Response; Ischemia; Lead; Left; Mediating; Modeling; Molecular; Molecular Weight; Morbidity - disease rate; Mothers; NF-kappa B; Nuclear Import; Nuclear Translocation; Pathway interactions; Peptides; Perinatal; Phase; Physiological; Placenta; Plasma; Polymers; Pre-Eclampsia; Pregnancy; Premature Birth; Proline; Proteins; Proteinuria; Rattus; Seizures; Signal Transduction; System; Testing; Therapeutic; Therapeutic Agents; Tissues; Treatment Efficacy; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factors; base; cytokine; effective intervention; fetal; immunogenicity; in vivo; inhibitor/antagonist; macromolecule; meetings; mortality; novel; novel therapeutics; offspring; polypeptide; pregnancy disorder; prevent; public health relevance; response; small molecule; therapeutic protein; therapeutic target; vector

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. !

抽象的。 先兆子痫是一种常见的妊娠期高血压疾病， 孕产妇、胎儿和围产期发病率和死亡率。在美国，先兆子痫影响了约8%的妊娠， 表现为特征性高血压、蛋白尿和心血管功能改变，如果不加检查， 导致产妇癫痫发作和死亡。目前没有有效的干预先兆子痫短 这就是为什么它也是早产的主要原因。改善 先兆子痫的治疗由于各种建议的小- 分子疗法对发育中的胎儿的影响。拟议研究的目的是开发一种药物， 能够在母体循环中稳定新治疗剂同时保护它们的递送系统 进入胎儿的血液循环先兆子痫的发作和进展是由两个主要因素驱动的。 血管内皮生长因子通路、VEGF拮抗剂sFlt-1的分泌和在血管内皮细胞中高度炎症环境的诱导 母亲我们已经开发了两种针对这些途径的新药物，一种补充VEGF 治疗以抵消增加的sFlt-1水平和NF-B抑制肽治疗以阻断sFlt-1水平。 炎症反应。这些治疗剂附着在一种名为弹性蛋白样的药物递送载体上 多肽（ELP），稳定他们在母体循环，同时防止他们穿越 胎盘进入胎儿循环。本提案的目的是：1）评估药代动力学， 生物分布、胎盘靶向和胎儿排斥，2）评价该药物载体的几次迭代， ELP-VEGF治疗剂在大鼠先兆子痫模型中的体外机制和体内功效，3）评估 ELP融合的NF-B抑制性治疗剂在大鼠中的体外机制和体内功效 先兆子痫模型，以及4）评估先兆子痫母亲的后代中高血压的发展 用这些测试剂治疗。 !