Targeted Delivery of Liposomes to the Primate Maternal-Fetal Interface

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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.