Folate Receptor-Targeted Transplacental Delivery of Digoxin for the Treatment of Fetal Arrhythmia

Abstract

Fetal tachyarrhythmias is one of the leading causes of fetal hydrops and, ultimately, fetal demise. This condition is typically treated with transplacental digoxin by maternal administration. However, maternal digoxin administration is associated with nausea, vomiting, heart block and sinus bradycardia. Additionally, placental efflux mechanisms limit the transfer of digoxin to the fetus. When transplacental digoxin therapy fails, direct fetal injection of digoxin is performed. This can result in fetal injury, infection, and in severe cases, fetal demise. The purpose of this project is to develop a novel therapeutic strategy using nanoparticles targeting the placenta to increase digoxin delivery to the fetus. Biocompatible digoxin-loaded polymeric nanoparticles were prepared and their physicochemical and drug release characteristics were determined. Using BeWo (choriocarcinoma) cells as an in vitro transplacental transport model, we were able to show that these nanoparticles increase permeability of digoxin across the placenta by evading placental efflux. Conjugation of folic acid to the surface of these nanoparticles increased the transplacental transfer of digoxin due to folate receptor-mediated endocytosis. Folate receptors are highly expressed in the placental trophoblast throughout pregnancy due to the importance of folic acid in fetal and placental development. We believe that this novel treatment strategy may increase the transfer of digoxin to the fetus and ultimately reduce maternal side effects and the need for direct fetal digoxin administration. This should result in better maternal and fetal outcomes in cases of fetal tachyarrhythmia.