Targeted Delivery of Liposomes to the Primate Maternal-Fetal Interface

将脂质体靶向递送至灵长类母胎界面

基本信息

批准号：
10194571
负责人：
Lynda Katherine Harris
金额：
$ 23.09万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-16 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10194571
关键词：
Address Area Biological Biological Markers Blood flow Caliber Development Endothelium Experimental Models Failure Fetal Growth Retardation Fetal Tissues Fetal Weight Fetal health Fetus Formulation Goals Health Histopathology Homing Human Image Immune response In Vitro Infection Inflammatory Response Insulin-Like Growth Factor II Intervention Investigational Therapies Knowledge Lesion Liposomes Macaca Macaca mulatta Magnetic Resonance Imaging Maternal Physiology Maternal-Fetal Exchange Measurement Methods Modeling Monitor Mothers Mus National Institute of Child Health and Human Development Nitric Oxide Donors Organ Outcome Peptides Perfusion Personal Satisfaction Physiological Placenta Placental Biology Placental Insufficiency Placentation Positioning Attribute Pregnancy Pregnancy Complications Pregnant Women Preparation Primates Publishing Reagent Research Research Personnel Rhesus Risk Rodent Model Safety Spiral Artery of the Endometrium Structure Therapeutic Translating Uterine Monitoring Uterus Weight Work adverse pregnancy outcome clinically relevant experience fetal gene therapy healthy pregnancy human model improved in vivo in vivo Model innovation liposomal delivery mouse model nanoparticle neonatal health nonhuman primate novel particle pregnant prenatal therapy prevent protein aminoacid sequence response safety and feasibility targeted delivery trophoblast

项目摘要

The Human Placenta Project (HPP) has been launched by the NICHD to improve maternal and fetal/neonatal health and well-being, focused on advancing the ability to assess the health of the ongoing pregnancy by developing biomarkers and “omics” of the placenta, and advanced imaging and other measurements to assess troubled pregnancies. The next difficult step will be to intervene in troubled pregnancies by translating knowledge gained into placental therapeutics to improve fetal health. To provide a novel and safe way of administering therapies to the placenta, we have developed targeted liposomes decorated with specific placental homing peptides. Heretofore, these approaches have been limited to mouse models for in vivo targeting, and progress in addressing experimental fetal growth restriction has been made. However, there are limitations to the rodent model, and nonhuman primates (NHP) have enhanced relevance to human placentation, and are a more clinically relevant model for experimental therapeutic approaches. We hypothesize that peptide-decorated liposomes that selectively accumulate in the mouse placenta will also target the primate placenta in vivo. We propose to use the rhesus macaque in this R21 Exploratory/Developmental proposal with two Specific Aims: Aim 1. To determine if trophoblast-targeted liposomes decorated with the iRGD peptide sequence are taken up by the placenta in vivo in an NHP model. We will adapt reagents and methods effective in human placental explants in vitro, and the mouse in vivo, to NHP models and assess safety both in the dam and the fetus, including maternal and fetal tissue histopathology, inflammatory and immune responses at the MFI, and maternal physiological responses to placental therapy. Aim 2. To determine if liposomes decorated with peptides shown to target the murine uterine vasculature are taken up in NHP uterine vessels including spiral arteries. We will assess the distribution of CNKGLRNK-decorated liposomes at the MFI and monitor uterine blood flow following treatment with liposomes. This proposal brings together strengths from both research teams. The Harris lab has published experience with liposome nanoparticles targeting human explants in vitro, and the mouse placenta in vivo. The Golos lab has published experience in NHP pregnancy, imaging the fetus and placenta, and histopathology of the maternal-fetal interface. We will determine if the liposomes can target the NHP placenta and uterine vessels, and if the cargo is transferred to the fetus. These studies will allow NHP investigators to work towards the ultimate goal, to be able to “treat the placenta” to improve the health of both mothers and babies.

NICHD 启动了人类胎盘项目 (HPP)，旨在改善孕产妇和胎儿/新生儿的健康和福祉，重点是通过开发胎盘的生物标志物和“组学”来提高评估持续妊娠健康的能力，下一个困难的步骤是通过将获得的知识转化为胎盘疗法来干预有问题的妊娠，以改善胎儿的健康。迄今为止，这些方法仅限于用于体内靶向的小鼠模型，并且在解决实验性胎儿生长限制方面已取得进展，但是，在啮齿类动物中存在局限性。模型和非人灵长类动物 (NHP) 与人类胎盘形成的相关性增强，并且是实验治疗方法更具临床相关性的模型，我们捕获了在小鼠体内选择性积累的肽修饰脂质体。胎盘还将在体内靶向灵长类胎盘。我们建议在 R21 探索/开发提案中使用恒河猴，有两个具体目标：目标 1. 确定装饰有 iRGD 肽序列的滋养层靶向脂质体是否被摄取。我们将采用在体外人类胎盘外植体和体内小鼠胎盘中有效的试剂和方法来适应 NHP。建立模型并评估母体和胎儿的安全性，包括母体和胎儿组织病理学、MFI 的炎症和免疫反应以及母体对胎盘治疗的生理反应。目标 2. 确定用肽修饰的脂质体是否能靶向小鼠。子宫脉管系统被纳入 NHP 子宫血管中，包括螺旋动脉。我们将评估 CNKGLRNK 修饰的脂质体在 MFI 上的分布并监测子宫。该提案汇集了两个研究团队的优势，Harris 实验室发表了针对体外人类外植体的脂质体纳米粒子的经验，而 Golos 实验室则发表了 NHP 妊娠、成像方面的经验。胎儿和胎盘，以及母胎界面的组织病理学，我们将确定脂质体是否可以靶向 NHP 胎盘和子宫血管，以及货物是否转移到子宫内。这些研究将使 NHP 研究人员能够努力实现最终目标，即能够“治疗胎盘”以改善母亲和婴儿的健康。