Preterm birth affects up to 12% of pregnancies in the United States and is a major contributor to neonatal morbidity and mortality. The treatment of preterm labor includes tocolytic drugs, such as indomethacin, to stop uterine contractions. Although indomethacin is effective in reducing uterine contractions, the primary clinical limitatio with prolonged use of indomethacin is its ability to cross the placenta leading to adverse fetal and neonatal effects such as premature closure of the ductus arteriosus and oligohydramnios. Nanomedicine is an emerging clinical field with one of the main goals of vectoring the drugs preferentially to the disease loci and, thus, increasing the efficacy and reducing associated toxicities and adverse reactions. Nanovectors are nanoscale particles or integrated systems with a variety of physico-chemical and biological properties, such as size, charge and targeting moieties, that can be customized based on the intended use. These properties allow the rational design of the nanovectors to preferentially deliver a drug to the tissue of interest and prevent it distribution to unwanted locations. In this proposal, we will use liposomes, lipid-based nanovectors, currently used in the clinical setting for tumor and infectious disease therapy. Although significant progress has been made with the use of nanomedicine in other clinical areas, the applications of nanovectors in obstetrics are underexplored. Our previous studies in pregnant rodents have shown that transplacental passage can be prevented through modifications of the physico-chemical properties of the nanovectors. Thus, nanovectors represent an uncharted therapeutic opportunity to address the primary limitation of using indomethacin in pregnancy by reducing placental passage of the drug to the fetus. In this exploratory proposal, we aim to determine the ability of a drug-carrying nanovector to direct the delivery of indomethacin to the pregnant uterus and inhibit myometrial uterine contractility. For this purpose, liposomes, loaded with indomethacin will be designed with physicochemical properties to retain in the maternal circulation and enhance the concentration in the uterus. Additionally, we will use oxytocin receptor antagonist peptide on the liposome's surface to allow binding to the oxytocin receptor expressed on the pregnant myometrium. We will use our established ex vivo human model of myometrial contractility to measure the functional ability of the indomethacin carrying liposomes to inhibit uterine contractility. We will also determine the efficacy of the indomethacin carrying liposomes in preventing preterm birth while reducing fetal exposure. Our established in vivo preterm pregnant mouse model will be used to test the ability of the indomethacin carrying liposomes to prevent preterm birth and fetal adverse effects. In this novel, exploratory proposal, carried out by a multi-disciplinary team of investigators, we will extend the benefits of nanomedicine to the field of obstetrics. Beyond the immediate goals of the current project, this study will pave the ground for the new paradigm-shifting direction in the treatment of high risk pregnancies.
Preterm labor resulting in preterm birth affects up to 12% of pregnancies in the United States and is the major contributor to neonatal morbidity and mortality. Indomethacin is a drug used clinically to stop preterm labor, but can lead to serious fetal side effects because it crosses the placenta. This project focuses on the application of nanotechnology to enable targeted administration of indomethacin to the uterus for treatment of preterm labor and prevention of the drug passage to the fetus.
| Ware, Matthew J; Keshishian, Vazrik; Law, Justin J et al. (2016) Generation of an in vitro 3D PDAC stroma rich spheroid model. Biomaterials 108:129-42 |
| Refuerzo, Jerrie S; Alexander, Jenolyn F; Leonard, Fransisca et al. (2015) Liposomes: a nanoscale drug carrying system to prevent indomethacin passage to the fetus in a pregnant mouse model. Am J Obstet Gynecol 212:508.e1-7 |
