Nanoparticle-mediated placental imaging and magnetic hyperthermia for management of ectopic pregnancy - Summary/Abstract Ectopic pregnancy is the leading cause of maternity-related death during the first trimester of pregnancy. Approximately 98 % of ectopic implantations occur in the fallopian tube and, in the event of tubal rupture, prompt treatment is critical to avoid hemorrhage and maternal death. Ectopic pregnancies account for about one in every 50 pregnancies (120,000 per year) in the United States. Current ultrasonography procedures misdiagnose ectopic pregnancy in up to 40% of cases, while methotrexate treatment for confirmed EP has a failure rate of more than 10%. During the time prior to ultrasonographic visualization, the pregnancy biomarker human chorionic gonadotropin (hCG) is used to evaluate growth but is a poor measure of the implantation site. This project aims to establish an imaging modality for localization of the early placenta utilizing nanoparticles targeting the trophoblast layer of the placenta. Contrast-enhanced imaging modalities (e.g., MRI) can substantially improve ectopic pregnancy detection. However, the use of conventional contrast agents, including gadolinium- based MRI contrast agents, is discouraged as low molecular weight compounds cross the placenta and can incur fetal toxicity in viable pregnancies. To address this challenge, a biocompatible polymeric nanoplatform will be utilized that accumulates specifically in placental tissue, but not the fetus, after intravenous injection. This nanoplatform will be loaded with newly developed magnetic nanoparticles that are highly efficient MRI contrast agents, and placenta accumulation/detection/visualization will be assessed in placenta cells and small animal models. Furthermore, the ability to impair the developing placenta, and thus terminate ectopic pregnancy, will be demonstrated by magnetic hyperthermia mediated by trophoblast-targeted nanoparticles. The premise of this proposal is that specifically designed nanoparticles can detect early placentation, and subsequent magnetic hyperthermia can provide a non-invasive option to treat ectopic pregnancy. To advance the proposed approach for ectopic pregnancy management, our multidisciplinary team of investigators with complementary expertise in nanomedicine, magnetic hyperthermia, and clinical placenta research proposes, in Aim 1, to evaluate the biodistribution profile and placenta uptake of the developed nanoparticles (non-targeted and trophoblast- targeted) in human/macaque placental cells and in mice. In Aim 2, the MRI imaging efficiency and short- and long-term toxicity of the placenta-targeted nanoparticles will be evaluated in pregnant mice. In Aim 3, the safety and therapeutic efficacy of magnetic hyperthermia mediated by our magnetic nanoparticles will be accessed for simulated treatment of human ectopic pregnancy in mice and non-human primates, aiming to demonstrate a novel, effective and non-invasive approach for ectopic pregnancy management.
