Selective Targeting of a Novel Vasodilator to the Uterine Vasculature to Treat Impaired Uteroplacental Perfusion in Pregnancy.
Selective Targeting of a Novel Vasodilator to the Uterine Vasculature to Treat Impaired Uteroplacental Perfusion in Pregnancy.
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DOI：
10.7150/thno.19678
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发表时间：
2017
期刊：
影响因子：
12.4
通讯作者：
Harris LK
中科院分区：
文献类型：
--
作者：
Cureton N;Korotkova I;Baker B;Greenwood S;Wareing M;Kotamraju VR;Teesalu T;Cellesi F;Tirelli N;Ruoslahti E;Aplin JD;Harris LK
妊娠期胎儿生长受限（FGR）通常是由子宫胎盘血流受损引起的。血管扩张剂可增强人类和动物模型中的子宫胎盘灌注和胎儿生长；然而，已有对母体和胎儿产生有害副作用的报道。我们假设，血管扩张剂的靶向子宫胎盘递送将增强药物疗效并降低与妊娠期用药相关的风险。噬菌体筛选鉴定出选择性积累在怀孕小鼠子宫胎盘脉管系统中的新型肽。静脉注射后，合成肽CNKGLRNK在体内选择性结合子宫螺旋动脉和胎盘迷路的内皮； CNKGLRNK 修饰的脂质体也选择性地结合到这些区域。一氧化氮供体 2-[[4-[(硝氧基)甲基]苯甲酰基]硫代]-苯甲酸甲酯 (SE175) 在体外诱导小鼠子宫动脉和人胎盘动脉显着松弛；因此，SE175 被封装到这些靶向脂质体中，并给予健康怀孕的 C57BL/6J 小鼠或内皮一氧化氮合酶敲除 (eNOS-/-) 小鼠，这些小鼠表现出子宫胎盘血流和 FGR 受损。在胚胎（E）第11.5、13.5、15.5和17.5天施用含有SE175（0.44mg/kg）或PBS的脂质体；足月时记录胎儿和胎盘的重量，并与注射游离 PBS 或 SE175 的小鼠进行比较。子宫胎盘靶向递送 SE175 对 C57BL/6J 小鼠的胎儿体重没有影响，但在 eNOS-/- 小鼠中显着增加胎儿体重和平均螺旋动脉直径，并降低胎盘重量，表明胎盘效率提高；游离SE175对胎儿体重或螺旋动脉直径没有影响。靶向而非游离的 SE175 还显着降低了 4-羟基壬烯醛、环氧合酶-1 和环氧合酶-2 的胎盘表达，表明胎盘氧化应激减少。这些数据表明，利用血管靶向肽选择性地将 SE175 递送至子宫胎盘脉管系统可能是治疗子宫胎盘灌注受损导致的 FGR 的一种新方法。
Fetal growth restriction (FGR) in pregnancy is commonly caused by impaired uteroplacental blood flow. Vasodilators enhance uteroplacental perfusion and fetal growth in humans and animal models; however, detrimental maternal and fetal side effects have been reported. We hypothesised that targeted uteroplacental delivery of a vasodilator would enhance drug efficacy and reduce the risks associated with drug administration in pregnancy. Phage screening identified novel peptides that selectively accumulated in the uteroplacental vasculature of pregnant mice. Following intravenous injection, the synthetic peptide CNKGLRNK selectively bound to the endothelium of the uterine spiral arteries and placental labyrinth in vivo; CNKGLRNK-decorated liposomes also selectively bound to these regions. The nitric oxide donor 2-[[4-[(nitrooxy)methyl]benzoyl]thio]-benzoic acid methyl ester (SE175) induced significant relaxation of mouse uterine arteries and human placental arteries in vitro; thus, SE175 was encapsulated into these targeted liposomes and administered to healthy pregnant C57BL/6J mice or endothelial nitric oxide synthase knockout (eNOS-/-) mice, which exhibit impaired uteroplacental blood flow and FGR. Liposomes containing SE175 (0.44mg/kg) or PBS were administered on embryonic (E) days 11.5, 13.5, 15.5 and 17.5; fetal and placental weights were recorded at term and compared to mice injected with free PBS or SE175. Targeted uteroplacental delivery of SE175 had no effect on fetal weight in C57BL/6J mice, but significantly increased fetal weight and mean spiral artery diameter, and decreased placental weight, indicative of improved placental efficiency, in eNOS-/- mice; free SE175 had no effect on fetal weight or spiral artery diameter. Targeted, but not free SE175 also significantly reduced placental expression of 4-hydroxynonenal, cyclooxygenase-1 and cyclooxygenase-2, indicating a reduction in placental oxidative stress. These data suggest that exploiting vascular targeting peptides to selectively deliver SE175 to the uteroplacental vasculature may represent a novel treatment for FGR resulting from impaired uteroplacental perfusion.
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