Targeted Delivery of Liposomes to the Primate Maternal-Fetal Interface

人类胎盘项目（HPP）由NICHD发起，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”，以及先进的成像和其他测量方法来评估问题妊娠，从而提高评估正在进行的妊娠健康的能力。下一个困难的步骤将是通过将获得的知识转化为胎盘治疗来干预问题妊娠，以改善胎儿健康。为了提供一种新的、安全的方法来治疗胎盘，我们开发了靶向脂质体，用特定的胎盘归巢肽修饰。到目前为止，这些方法仅限于小鼠体内靶向模型，并且在解决实验性胎儿生长限制方面取得了进展。然而，啮齿动物模型存在局限性，非人灵长类动物（NHP）与人类胎盘的相关性增强，并且是实验治疗方法中更具有临床相关性的模型。我们假设在小鼠胎盘中选择性积累的肽修饰脂质体也会在体内靶向灵长类动物胎盘。我们建议在这个R21探索性/发展性提案中使用恒河猴，有两个具体目标：目标1。在NHP模型中，确定iRGD肽序列修饰的滋养细胞靶向脂质体是否被胎盘吸收。我们将采用在体外人类胎盘移植体和小鼠体内有效的试剂和方法，用于NHP模型，并评估其在母体和胎儿中的安全性，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。目的：确定以肽修饰的脂质体是否被NHP子宫血管（包括螺旋动脉）所占据。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量。该提案汇集了两个研究团队的优势。哈里斯实验室已经发表了脂质体纳米颗粒在体外靶向人类外植体和小鼠胎盘的经验。Golos实验室已经发表了在NHP妊娠、胎儿和胎盘成像以及母胎界面组织病理学方面的经验。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体内。这些研究将使NHP研究人员朝着最终目标努力，即能够“治疗胎盘”以改善母亲和婴儿的健康。

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.