Trophoblast-Targeted Nanomedicine Modulates Placental sFLT1 for Preeclampsia Treatment.

Lei Li,Huijun Yang,Dan Wei,Tao Xin,Qian Zhou,Pengzheng Chen,Shan Wang,Yanan Zhang

doi:10.3389/fbioe.2020.00064

Abstract

The overexpressed soluble fms-like tyrosine kinase 1 (sFLT-1) in placenta is considered to be a potential therapeutic target for preeclampsia (PE). How to achieve efficient intervention of sFLT1 expression in the placenta is an urgent problem to be solved. PEG-PLA nanoparticle generated by double-emulsion methods is a novel siRNA delivery system. Synthetic placental CSA binding peptide (P-CSA-BP) is effective for targeting lipid-polymer nanoparticle to the placenta. We conjugated P-CSA-BP to the surface of PEG-PLA nanoparticle to create a novel placenta specific sFLT1 siRNA delivery system for the therapy of PE. Nanoparticles were synthesized using double emulsion method and characterized by dynamic light scattering and transmission electron microscopy (TEM). RT-PCR was employed to evaluate mRNA level and protein level was analyzed by ELISA kit. The tissue distribution of nanoparticles was observed through ex vivo images. The concentrations of nanoparticles in organs were measured using high-performance liquid chromatography. T-NPsisFLT1 had higher efficiency than NPsisFLT1 in accumulating in HTR-8/SVneo cells and significantly decreased the expression of sFLT1. Intravenously administered T-NPsisFLT1 specifically accumulated in placentas of mice. sFLT1 mRNA level in placenta and protein level in serum were declined by T-NPsisFLT1. T-NPsisFLT1 shown no obvious toxic effect on both mother and fetus. The utility of T-NPsisFLT1 nanoparticles as a sFLT1 siRNA placenta specific delivery system significantly silenced sFLT1 in mice and is safe for both mother and fetus. This nanoparticle is a novel potential therapeutic strategy for PE.

Highlights

Preeclampsia is a special type of hypertensive disorders complicating pregnancy (HDCP) which is characterized by hypertension, proteinuria, hematological complications, and uteroplacental dysfunction
dynamic light scattering (DLS) results shown that the resulted nanoparticles T-NPsisFLT1 had a relative larger particle size than NPsisFLT1 (Figure 1B)
The P-Chondroitin sulfate A (CSA)-BP could be observed on the surface of T-NPsisFLT1

Summary

Introduction

Preeclampsia is a special type of hypertensive disorders complicating pregnancy (HDCP) which is characterized by hypertension, proteinuria, hematological complications, and uteroplacental dysfunction (von Dadelszen and Magee, 2014). The fetal development is significantly influenced by the pathogenesis of PE, such as amniotic fluid reduction, oxygenation defect, and Abbreviations: sFLT-1, fms-like tyrosine kinase 1; P-CSA-BP, Synthetic placental CSA binding peptide; PE, preeclampsia. During the pathogenesis of PE, the dysfunction in maternal vascular system and the abnormal activation of maternal-fetal immune system are proved to be the two main factors (Laresgoiti-Servitje, 2013). The primary prevention of PE is mainly performed through the treatment of aspirin, vitamin D, and low-dose calcium (Henderson et al, 2014). The termination of pregnancy or fetus delivery is thought to be the only definitive treatment for PE (World Health Organization [WHO], 2011). There has been great progress in the study of PE, the prediction and prevention of PE development is still a big challenge

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