Novel Technologies for Target Delivery of Therapeutics to the Placenta during Pregnancy: A Review.

Gerald J Pepe,Eugene D Albrecht

doi:10.3390/genes12081255

Gerald J Pepe, Eugene D Albrecht

Open Access

https://doi.org/10.3390/genes12081255

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Abstract

Uterine spiral artery remodeling is essential for placental perfusion and fetal growth and, when impaired, results in placental ischemia and pregnancy complications, e.g., fetal growth restriction, preeclampsia, premature birth. Despite the high incidence of adverse pregnancies, current treatment options are limited. Accordingly, research has shifted to the development of gene therapy technologies that provide targeted delivery of “payloads” to the placenta while limiting maternal and fetal exposure. This review describes the current strategies, including placental targeting peptide-bound liposomes, nanoparticle or adenovirus constructs decorated with specific peptide sequences and placental gene promoters delivered via maternal IV injection, directly into the placenta or the uterine artery, as well as noninvasive site-selective targeting of regulating genes conjugated with microbubbles via contrast-enhanced ultrasound. The review also provides a perspective on the effectiveness of these technologies in various animal models and their practicability and potential use for targeted placental delivery of therapeutics and genes in adverse human pregnancies affected by placental dysfunction.

Highlights

The establishment of the placenta and appropriate uteroplacental blood flow are critical for fetal development, maternal well-being, and the physiologic homeostasis of offspring
Failure of spiral artery remodeling (SAR) results in placental ischemia and poor perfusion, a condition that underpins a number of pregnancy complications, including fetal growth restriction (FGR), new-onset maternal hypertension, early-onset preeclampsia, premature birth, and placental abruption [6,7,8]
Summary It is apparent that significant progress has been made in the development of liposomal, engineered nanoparticle and adenovirus constructs in which sequences for various genes, e.g., IGF1, vascular endothelial growth factor (VEGF) as well as miRNA inhibitors, growth-promoting peptides, and drugs to control vascular tone, have been inserted

Summary

Introduction

The establishment of the placenta and appropriate uteroplacental blood flow are critical for fetal development, maternal well-being, and the physiologic homeostasis of offspring. Specific genetic modification of the rodent trophoblast lineage has been employed to gain a better understanding of the impact of genetic manipulation on placental development [26,27,28], applicability to the human remains unclear It is well-established that the placenta produces a number of physiologically active factors, e.g., vascular endothelial growth factor (VEGF), insulin-like growth factors; placental growth factor; placental lactogen, that regulates maternal vascular function and metabolism as well as the placental transfer of nutrients to the fetus [29]. Additional studies showed that IV injection on days 11.5, 13.5, 15.5, and 17.5 of gestation of liposomes containing the peptide CRGDKGPDC to which IGF-2 was attached enhanced placental but not fetal weight in wild type animals and restored fetal weight in mice with FGR elicited by deletion of the U2 exon within the IGF-2 gene. As indicated by King et al [23], peptide-directed targeting provides a novel platform for the development of placenta-specific therapeutics, including gene delivery

Trophoblast Targeted Nanoparticles

Findings

Adenovirus Mediated Intra-Placental Gene Therapy