Hacker, T. | Search bioRxiv

bioRxiv2024

Nanoparticle-mediated delivery of placental gene therapy via uterine artery catheterization in a pregnant rhesus macaque

Nanoparticles offer promise as a mechanism to non-invasively deliver targeted placental therapeutics. Our previous studies utilizing intraplacental administration demonstrate efficient nanoparticle uptake into placental trophoblast cells and overexpression of human IGF1 (hIGF1). Nanoparticle-mediated placental overexpression of hIGF1 in small animal models of placental insufficiency and fetal growth restriction improved nutrient transport and restored fetal growth. The objective of this pilot study was to extend these studies to the pregnant nonhuman primate and develop a method for local delivery of nanoparticles to the placenta via maternal blood flow from the uterine artery. Nanoparticles containing hIGF1 plasmid driven by the placenta-specific PLAC1 promoter were delivered to a mid-gestation pregnant rhesus macaque via a catheterization approach that is clinically used for uterine artery embolization. Maternal-fetal interface, fetal and maternal tissues were collected four days post-treatment to evaluate the efficacy of hIGF1 treatment in the placenta. The uterine artery catheterization procedure and nanoparticle treatment was well tolerated by the dam and fetus through the four-day study period following catheterization. Nanoparticles were taken up by the placenta from maternal blood as plasmid-specific hIGF1 expression was detected in multiple regions of the placenta via in situ hybridization and qPCR. The uterine artery catheterization approach enabled successful delivery of nanoparticles to maternal circulation in close proximity to the placenta with no concerns to maternal or fetal health in this short-term feasibility study. In the future, this delivery approach can be used for preclinical evaluation of the long-term safety and efficacy of nanoparticle-mediated placental therapies in a rhesus macaque model. HighlightsNovel method to deliver therapeutics to maternal-fetal interface Delivery of nanoparticles to the placenta via maternal catheterization

physiology↗

bioRxiv2023

Biventricular interaction during acute left ventricular ischemia in mice: a combined in-vivo and in-silico approach

Computational models provide an efficient paradigm for integrating and linking multiple spatial and temporal scales. However, these models are difficult to parameterize and match to experimental data. Recent advances in both data collection and model analyses have helped overcome this limitation. Here, we combine a multiscale, biventricular interaction model with mouse data before and after left ventricular (LV) ischemia. Sensitivity analyses are used to identify the most influential parameters on pressure and volume predictions. The subset of influential model parameters are calibrated to biventricular pressure-volume loop data (n=3) at baseline. Each mouse underwent left anterior descending coronary artery ligation, during which changes in fractional shortening and RV pressure-volume dynamics were recorded. Using the calibrated model, we simulate acute LV ischemia and contrast outputs at baseline and in simulated ischemia. Our baseline simulations align with the LV and RV data, and our predictions during ischemia complement recorded RV data and prior studies on LV function during myocardial infarction. We show that a model with both biventricular mechanical interaction and systems level cardiovascular dynamics can quantitatively reproduce in-vivo data and qualitatively match prior findings from animal studies on LV ischemia.

bioengineering↗