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Uterus-targeted liposomes for preterm labor management: studies in pregnant mice.

ABSTRACT: Preterm labor caused by uterine contractions is a major contributor to neonatal morbidity and mortality. Treatment intended to reduce uterine contractions include tocolytic agents, such as indomethacin. Unfortunately, clinically used tocolytics are frequently inefficient and cross the placenta causing fetal side effects. Here we show for the first time in obstetrics the use of a targeted nanoparticle directed to the pregnant uterus and loaded with a tocolytic for reducing its placental passage and sustaining its efficacy. Nanoliposomes encapsulating indomethacin and decorated with clinically used oxytocin receptor antagonist were designed and evaluated in-vitro, ex-vivo and in-vivo. The proposed approach resulted in targeting uterine cells in-vitro, inhibiting uterine contractions ex-vivo, while doubling uterine drug concentration, decreasing fetal levels, and maintaining the preterm birth rate in vivo in a pregnant mouse model. This promising approach opens new horizons for drug development in obstetrics that could greatly impact preterm birth, which currently has no successful treatments.

SUBMITTER: Refuerzo JS

PROVIDER: S-EPMC5057095 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Uterus-targeted liposomes for preterm labor management: studies in pregnant mice.

Refuerzo Jerrie S JS Leonard Fransisca F Bulayeva Nataliya N Gorenstein David D Chiossi Giuseppe G Ontiveros Alejandra A Longo Monica M Godin Biana B

Scientific reports 20161011

Preterm labor caused by uterine contractions is a major contributor to neonatal morbidity and mortality. Treatment intended to reduce uterine contractions include tocolytic agents, such as indomethacin. Unfortunately, clinically used tocolytics are frequently inefficient and cross the placenta causing fetal side effects. Here we show for the first time in obstetrics the use of a targeted nanoparticle directed to the pregnant uterus and loaded with a tocolytic for reducing its placental passage a ...[more]

PMID: 27725717

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Project description:ObjectiveUterine overdistention is thought to induce preterm labor in women with twin and multiple pregnancies, but the pathophysiology remains unclear. We investigated for the first time the pathogenesis of preterm birth associated with rapid uterine distention in a pregnant nonhuman primate model.Study designA nonhuman primate model of uterine overdistention was created using preterm chronically catheterized pregnant pigtail macaques (Macaca nemestrina) by inflation of intraamniotic balloons (N = 6), which were compared to saline controls (N = 5). Cesarean delivery was performed due to preterm labor or at experimental end. Microarray, quantitative reverse transcriptase polymerase chain reaction, Luminex (Austin, TX), and enzyme-linked immunosorbent assay were used to measure messenger RNA (mRNA) and/or protein levels from monkey (amniotic fluid, myometrium, maternal plasma) and human (amniocytes, amnion, myometrium) tissues. Statistical analysis employed analysis of covariance and Wilcoxon rank sum. Biomechanical forces were calculated using the law of Laplace.ResultsPreterm labor occurred in 3 of 6 animals after balloon inflation and correlated with greater balloon volume and uterine wall stress. Significant elevations of inflammatory cytokines and prostaglandins occurred following uterine overdistention in an "inflammatory pulse" that correlated with preterm labor (interleukin [IL]-1β, tumor necrosis factor [TNF]-α, IL-6, IL-8, CCL2, prostaglandin E2, prostaglandin F2α, all P < .05). A similar inflammatory response was observed in amniocytes in vitro following mechanical stretch (IL1β, IL6, and IL8 mRNA multiple time points, P < .05), in amnion of women with polyhydramnios (IL6 and TNF mRNA, P < .05) and in amnion (TNF-α) and myometrium of women with twins in early labor (IL6, IL8, CCL2, all P < .05). Genes differentially expressed in the nonhuman primate after balloon inflation and in women with polyhydramnios and twins are involved in tissue remodeling and muscle growth.ConclusionUterine overdistention by inflation of an intraamniotic balloon is associated with an inflammatory pulse that precedes and correlates with preterm labor. Our results indicate that inflammation is an early event after a mechanical stress on the uterus and leads to preterm labor when the stress is sufficiently great. Further, we find evidence of uterine tissue remodeling and muscle growth as a common, perhaps compensatory, response to uterine distension.

Project description:BackgroundLabor pain is the nastiest conceivable pain women are involved in during labor and delivery. In this way, the end of labor pain is frequently outlined by myths and equivocalness. Hence, giving a compelling absence of pain in labor remained a challenge specifically in developing countries including Ethiopia.ObjectivesThis systematic review and meta-analysis aimed to explore the pooled prevalence of labor analgesia and associated factors to pregnant women in Ethiopia.DesignA systematic review and meta-analysis were utilized in agreement with the Preferred Reporting Items for Systematic Reviews.Data sourcesPubMed/Medline, SCOPUS, EMBASE, Web of Science, Google Scholars, and the Cochrane Library and supplemented it with manual were deliberately looked at until January 1-30, 2024.MethodsTwo authors independently extricated all principal information utilizing standardized data extraction designs, and the analysis was done utilizing STATA version 17. Heterogeneity over the studies was evaluated utilizing I2 measurement. The funnel plot and Egger's weighted regression tests were utilized to assess subjective and objective publication biases respectively. Also, the pooled effect of labor pain management and the associations were evaluated utilizing a random-effects model.ResultsThe general pooled prevalence of labor analgesia in the present study was 23.3% with a (95% confidence interval (CI): 13.5, 33.1). Maternal age (odds ratio (OR): 1.91; 95% CI: 1.11, 2.77), parity of the mother (OR: 0.28; 95% CI: 0.06, 0.63), history of pregnancy misfortune (OR: 0.12; 95% CI: 0.11, 0.36), length of labor (OR: 2.09; 95% CI: 1.06, 3.13), and awareness about labor analgesia (OR: 1.91; 95% CI: 0.34, 3.49) were significantly related with labor analgesia among pregnant women in Ethiopia.ConclusionsThe generally pooled prevalence of labor analgesia among pregnant women in Ethiopia was low. Maternal age, parity of the mother, history of pregnancy loss, length of labor, and awareness of labor analgesia were factors influencing labor analgesia among pregnant women in Ethiopia. This finding proposes exceptional consideration to make laboring mothers free of pain by scaling up the strategies and utilizing labor pain administration in a way that universally recognized standards are met.Registration numberPROSPERO CRD: 42024525636.

Dataset Information

Uterus-targeted liposomes for preterm labor management: studies in pregnant mice.

Publications

Uterus-targeted liposomes for preterm labor management: studies in pregnant mice.

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