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

• 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
• 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

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.

人类胎盘项目(HPP)由NICHD发起，旨在改善产妇和胎儿/新生儿的健康和福祉，重点是通过开发胎盘的生物标记物和“组学”以及先进的成像和其他测量来评估问题妊娠，从而提高评估持续妊娠健康的能力。下一个困难的步骤将是通过将所获得的知识转化为胎盘疗法来干预问题妊娠，以改善胎儿健康。为了给胎盘提供一种新的安全的治疗方法，我们开发了用特定的胎盘归巢多肽装饰的靶向脂质体。到目前为止，这些方法仅限于体内靶向的小鼠模型，在解决实验性胎儿生长受限方面取得了进展。然而，啮齿动物模型也有局限性，非人类灵长类动物(NHP)与人类胎盘形成的相关性增强，是一种更具临床相关性的实验性治疗方法。我们假设，在小鼠胎盘中选择性积累的多肽修饰脂质体也将在体内靶向灵长类胎盘。我们建议在这项R21探索/发展计划中使用猕猴，有两个特定的目的：目的1.在NHP模型中确定修饰了IRGD肽序列的滋养细胞靶向脂质体是否被体内的胎盘摄取。我们将使在体外人类胎盘移植和在体小鼠身上有效的试剂和方法适应NHP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。目的2.确定以小鼠子宫血管为靶点的多肽修饰的脂质体是否被NHP子宫血管包括螺旋动脉所摄取。我们将评估CNKGLRNK修饰的脂质体在MFI的分布，并监测脂质体治疗后的子宫血流。这项提议汇集了两个研究团队的优势。哈里斯实验室已经发表了在体外针对人类外植体和在体内针对小鼠胎盘的脂质体纳米粒的经验。Golos实验室已经发表了NHP怀孕、胎儿和胎盘成像以及母胎界面组织病理学的经验。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胎儿。这些研究将使NHP的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。