Placental Homing Peptide-microRNA Inhibitor Conjugates for Targeted Enhancement of Intrinsic Placental Growth Signaling,Theranostics

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Placental Homing Peptide-microRNA Inhibitor Conjugates for Targeted Enhancement of Intrinsic Placental Growth Signaling
Theranostics ( IF 12.4 ) Pub Date : 2017-07-14 , DOI: 10.7150/thno.18845
Frances Beards _{1,

2} , Lisa E Jones _{1,

2,

3} , Jayne Charnock _{1,

2,

4} , Karen Forbes _{1,

2,

5} , Lynda K Harris _{1,

2,

6}

Affiliation

Suboptimal placental growth and development are the underlying cause of many pregnancy complications. No treatments are available, primarily due to the risk of causing fetal teratogenicity. microRNAs (miRNAs) are short, non-coding RNA sequences that regulate multiple downstream genes; miR-145 and miR675 have previously been identified as negative regulators of placental growth. In this proof of principle study, we explored the feasibility of delivering miRNA inhibitors to the placentas of pregnant mice and developed novel placental homing peptide-microRNA inhibitor conjugates for targeted enhancement of intrinsic placental growth signalling. Scrambled-, miR-145- or miR-675 inhibitor sequences were synthesised from peptide nucleic acids and conjugated to the placental homing peptide CCGKRK. Intravenous administration of the miR-145- and miR-675 conjugates to pregnant C57BL/6J mice significantly increased fetal and placental weights compared to controls; the miR-675 conjugate significantly reduced placental miR-675 expression. When applied to human first trimester placental explants, the miR-145 conjugate significantly reduced placental miR-145 expression, and both conjugates induced significant enhancement of cytotrophoblast proliferation; no effect was observed in term placental explants. This study demonstrates that homing peptide-miRNA inhibitor conjugates can be exploited to promote placental growth; these novel therapeutics may represent an innovative strategy for targeted treatment of compromised placental development.

中文翻译：

胎盘归巢肽-microRNA 抑制剂偶联物用于靶向增强内在胎盘生长信号传导

胎盘生长发育不理想是许多妊娠并发症的根本原因。没有可用的治疗方法，主要是由于有导致胎儿致畸的风险。microRNA (miRNA) 是调节多个下游基因的短的非编码 RNA 序列；miR-145 和 miR675 先前已被确定为胎盘生长的负调节剂。在这项原理验证研究中，我们探索了将 miRNA 抑制剂递送至怀孕小鼠胎盘的可行性，并开发了新型胎盘归巢肽-microRNA 抑制剂偶联物，用于靶向增强内在胎盘生长信号传导。从肽核酸合成加扰、miR-145 或 miR-675 抑制剂序列，并与胎盘归巢肽 CCGKRK 缀合。与对照组相比，向妊娠 C57BL/6J 小鼠静脉注射 miR-145-和 miR-675 偶联物显着增加了胎儿和胎盘重量；miR-675 偶联物显着降低了胎盘 miR-675 的表达。当应用于人类妊娠早期胎盘外植体时，miR-145 偶联物显着降低了胎盘 miR-145 的表达，并且两种偶联物均显着增强了细胞滋养层的增殖；在足月胎盘外植体中未观察到效果。该研究表明，归巢肽-miRNA 抑制剂偶联物可用于促进胎盘生长；这些新疗法可能代表了一种针对胎盘发育受损的靶向治疗的创新策略。miR-675 偶联物显着降低了胎盘 miR-675 的表达。当应用于人类妊娠早期胎盘外植体时，miR-145 偶联物显着降低了胎盘 miR-145 的表达，并且两种偶联物均显着增强了细胞滋养层的增殖；在足月胎盘外植体中未观察到效果。该研究表明，归巢肽-miRNA 抑制剂偶联物可用于促进胎盘生长；这些新疗法可能代表了一种针对胎盘发育受损的靶向治疗的创新策略。miR-675 偶联物显着降低了胎盘 miR-675 的表达。当应用于人类妊娠早期胎盘外植体时，miR-145 偶联物显着降低了胎盘 miR-145 的表达，并且两种偶联物均显着增强了细胞滋养层的增殖；在足月胎盘外植体中未观察到效果。该研究表明，归巢肽-miRNA 抑制剂偶联物可用于促进胎盘生长；这些新疗法可能代表了一种针对胎盘发育受损的靶向治疗的创新策略。并且两种缀合物均诱导细胞滋养层增殖的显着增强；在足月胎盘外植体中未观察到效果。该研究表明，归巢肽-miRNA 抑制剂偶联物可用于促进胎盘生长；这些新疗法可能代表了一种针对胎盘发育受损的靶向治疗的创新策略。并且两种缀合物均诱导细胞滋养层增殖的显着增强；在足月胎盘外植体中未观察到效果。该研究表明，归巢肽-miRNA 抑制剂偶联物可用于促进胎盘生长；这些新疗法可能代表了一种针对胎盘发育受损的靶向治疗的创新策略。

更新日期：2017-11-01

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