Liposomes: a nanoscale drug carrying system to prevent indomethacin passage to the fetus in a pregnant mouse model

Abstract

Objective: Indomethacin (IND) is a prostaglandin production inhibitor that reduces uterine contractions, but crosses the placenta leading to adverse fetal effects. Liposomes (LIP) are nanoscale systems clinically used to preferentially deliver a drug to the tissue of interest and simultaneously prevent distribution to unwanted locations. Our objective was to determine whether LIP could prevent the transfer of IND across the placenta to the fetus while preserving its pharmacological activity.

Study design: Multilamellar LIP were designed with a 150- to 200-nm size, fluorescently labeled, and loaded with IND. Timed pregnant CD1 mice (n = 6/group) on gestational day 18 were administered LIP, LIP-IND (1 mg IND/kg), or saline (SAL) via tail vein injection, or IND (1 mg/kg) via oral gavage. After 4 hours, the uterus, placenta, and fetuses were retrieved. LIP levels were visualized using fluorescent microscopy and quantitatively assessed by National Institutes of Health image processing software. LIP brightness values (mean ± SEM) in arbitrary units (AU) were normalized to the autofluorescence of the same tissue (as measured in SAL group). IND and prostaglandin E2 levels were assessed using liquid chromatography-tandem mass spectrometry and enzyme-linked immunosorbent assay, respectively.

Results: The qualitative analysis of LIP distribution revealed that the system was primarily confined within the uterus, minimally detected within the placenta, and absent in the fetus. LIP fluorescence was greater in the uterus compared to placenta and fetus (uterus 15.3 ± 5.4 AU vs placenta 3.0 ± 3.5 AU vs fetus 4.4 ± 2.5 AU; P = .009). LIP-IND resulted in a 7.6-fold reduction in the IND levels in the fetus compared to IND alone (LIP-IND 10.7 ± 17.1 ng/g vs IND 81.3 ± 24.7 ng/g; P = .041). Prostaglandin E2 levels were significantly reduced in the uterus of animals given LIP-IND and IND compared to LIP and SAL.

Conclusion: LIP localized within the uterus and did not cross the placenta to the fetus. IND within the fetus was reduced 7.6-fold while encapsulated within the LIP and the pharmacologic effects of IND were maintained. Thus, LIP provide a novel therapeutic approach to correct the primary clinical limitation of IND by reducing placental passage to the fetus.

Keywords: indomethacin; liposomes; preterm labor.