Making healthy babies: Holistic evaluation and optimization of targeted nanomedicines to treat placental dysfunction in common pregnancy complications - PROJECT SUMMARY Placental dysfunction is the major underlying cause of the serious pregnancy complications preeclampsia (PE), intrauterine growth restriction (IUGR) and stillbirth, which affect up to 15% of pregnancies in the US. No treatments are available, leaving clinicians reliant on prenatal monitoring and early delivery, which can further exacerbate adverse maternal and infant outcomes. Developing new therapeutics for use in pregnancy is hampered by the potential risk of harmful side effects and teratogenesis, severely limiting investment and progress in this area. To address this roadblock, we have created targeted nanoparticles decorated with placental homing peptides, which can selectively deliver a wide range of drugs directly to the placenta, but do not cross to the baby. The overarching aim of this project is to conduct robust pharmacokinetic/ pharmacodynamic (PK/PD), safety and efficacy studies to quantify, optimize and model the true benefits of this placental-specific drug delivery approach. Using well-characterized mouse models of healthy pregnancy and diet-induced placental dysfunction, human placental explant cultures and computational modeling, we will comprehensively assess the biodistribution and actions of three drugs with proven efficacy to treat placental dysfunction: aspirin, melatonin and SE175. We will test the hypothesis that administration of these drugs in targeted liposomes decorated with the well-characterized placental homing peptide iRGD will increase their safety, efficacy and uteroplacental-specific delivery, compared to administration of the free drug. We will perform biodistribution studies in mice to quantify and model changes in the drug concentrations in maternal, placental and pup tissues over time. We will also perform a treatment study to compare the effects of systemic versus targeted delivery of drugs on (i) placental structure, gene and protein expression, and levels of placental inflammation and oxidative stress, (ii) pup outcomes and anthropometric measurements, and (iii) inflammatory biomarkers in maternal and pup plasma, to assess the extent of rescue of placental dysfunction. Using data from our in vivo studies, we will build computational models of drug/liposome tissue distribution and clearance over time, then incorporate uptake data from human placental explant cultures to create physiological-based pharmacokinetic (PBPK) models, which will predict the liposome concentrations and dosing strategies required to achieve optimal therapeutic responses in rodents, non-human primates and humans. This research supports the mission of NICHD to develop safe and effective placental-specific therapeutics for the treatment of placental dysfunction. Accurate quantitation of maternal, placental and pup drug distribution and clearance, as well as the global and placental-specific drug effects observed, is imperative to facilitate data-driven approaches to better inform the design and success of future pre-clinical and clinical pregnancy studies, a key hurdle that currently impedes clinical translation of obstetric therapeutics.
