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：
9979328
负责人：
THADDEUS G GOLOS
金额：
$ 19.56万
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 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979328
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 Neonatal 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 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已发起了人类pliceta项目（HPP），以改善产妇/新生儿健康和福祉，重点是推进通过开发斑点的生物标志物和“ OMICS”来评估正在进行的怀孕的能力，以及高级影像和其他测量以评估疾病的怀孕。下一个困难的步骤是通过将知识转化为安置疗法以改善胎儿健康，干预陷入困境的怀孕。为了提供一种新颖且安全的方法来对plapeta进行疗法，我们开发了针对特定胎盘居住宠物的靶向脂质体。迄今为止，这些方法仅限于用于体内靶向的小鼠模型，并且已经在解决实验性胎儿生长限制方面进行了进展。但是，啮齿动物模型存在局限性，非人类隐私（NHP）与人类放置的相关性增强了，并且是实验疗法方法的临床相关模型。我们假设有选择地积聚在小鼠胎盘中的肽装饰的脂质体也将靶向体内的主要胎盘。我们建议在此R21探索性/发育建议中使用两个具体目的：目标1。确定是否在NHP模型中，体内将胎盘序列在体内占用IRGD剥离序列，以确定用IRGD剥离序列装饰的滋养细胞靶向脂质体。我们将在体外对人的占位植体和小鼠体内有效的试剂和方法进行调整，并在大坝和胎儿中的NHP模型和评估安全性，包括MFI的母体和胎儿组织组织病理学，炎症和免疫反应，以及对占余疗法的母体物理反应。目的2。确定是否用显示针对鼠子宫脉管系统的辣椒装饰的脂质体在包括螺旋动脉在内的NHP子宫血管中占用。我们将评估CNKGLRNK装饰的脂质体在MFI上的分布，并在用脂质体治疗后监测子宫血流。该建议汇集了两个研究团队的优势。哈里斯实验室（Harris Lab）发表了针对人体外植体的脂质体纳米颗粒和体内小鼠胎盘的经验。 Golos实验室已经发表了NHP妊娠的经验，想象胎儿和胎盘以及母体狂热界面的组织病理学。我们将确定脂质体是否可以瞄准NHP胎盘和子宫vissels，以及将货物转移到胎儿中。这些研究将使NHP研究人员能够朝着最终目标努力，能够“治疗胎盘”以改善母亲和婴儿的健康。