Although much progress is being made in understanding the molecular pathways in the placenta involved in the pathophysiology of pregnancy related disorders, a significant gap exists in utilizing this information for developing new drug therapies to improve pregnancy outcome. On March 5–6, 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health sponsored a two day workshop titled Placental Origins of Adverse Pregnancy Outcomes: Potential Molecular Targets to begin to address this gap. Particular emphasis was given in the identification of important molecular pathways that could serve as drug targets and the advantages and disadvantages of targeting these particular pathways. This article is a summary of the proceedings of this workshop. A broad number of topics were covered ranging from basic placental biology to clinical trials. This included research in the basic biology of placentation, such as trophoblast migration and spiral artery remodeling, and trophoblast sensing and response to infectious and non-infectious agents. Research findings in these areas will be critical for formulating developing future treatments and developing therapies for the prevention of a number of pregnancy disorders of placental origin including preeclampsia, fetal growth restriction, and uterine inflammation. Research was also presented summarizing ongoing clinical efforts in the U.S. and in Europe testing novel interventions for preeclampsia and fetal growth restriction, including agents such as oral arginine supplementation, sildenafil, pravastatin, gene therapy using virally-delivered vascular endothelial growth factor, and oxygen supplementation therapy. Strategies were also proposed to improve fetal growth by enhancing nutrient transport to the fetus by modulating their placental transporters, as well as targeting placental mitochondrial dysfunction and oxidative stress to improve placental health. The roles of microRNAs and placental-derived exosomes, as well as messenger RNAs, were also discussed in the context of their use for diagnostics and as drug targets. The workshop discussed the aspect of safety and pharmacokinetic profiles of potential existing and new therapeutics that will need to be determined especially in the context of the unique pharmacokinetic properties of pregnancy, as well as the hurdles and pitfalls of translating research findings into practice. The workshop also discussed novel methods of drug delivery and targeting during pregnancy using macromolecular carriers, such as nanoparticles and biopolymers, to minimize placental drug transfer and hence fetal drug exposure. In closing, a major theme that developed from the workshop was that the scientific community needs to change their thinking of the pregnant women and her fetus as a vulnerable patient population for which drug development should be avoided, but rather thought of as a deprived population in need of more effective therapeutic interventions.

Elastin-like polypeptides are biopolymers composed of the pentapeptide repeat Val-Pro-Gly-Xaa-Gly. Elastin-like polypeptides are soluble in aqueous solution below their transition temperature, but they hydrophobically collapse and aggregate when the temperature is raised above the transition temperature. Previous studies have suggested that the aggregation of these polypeptides in response to externally applied hyperthermia may be exploited in the use of elastin-like polypeptide for thermally targeted drug delivery. This work shows the application of elastin-like polypeptide as a delivery vehicle for a short peptide that can inhibit the transcriptional function of a specific oncogene. The coding sequence for elastin-like polypeptide was modified by the addition of the membrane translocating sequence penetratin and a peptide derived from helix 1 of the helix-loop-helix region of c-Myc (H1-S6A,F8A), known to inhibit c-Myc transcriptional function. The designed polypeptide (Pen-ELP-H1) was then expressed and purified from Escherichia coli. Cellular uptake of Pen-ELP-H1 is enhanced by both the penetratin sequence and by the hyperthermia-induced phase transition as shown by flow cytometry studies. Using immunofluorescence and reverse transcription-PCR, we show that Pen-ELP-H1 is able to disrupt the nuclear localization of c-Myc and inhibit transcriptional activation by c-Myc. Cell proliferation studies showed that Pen-ELP-H1 inhibits growth of MCF-7 cells. Furthermore, the use of hyperthermia increased the antiproliferative effect of a thermally responsive Pen-ELP-H1 f2-fold compared with a nonthermally responsive control polypeptide. These studies show that genetically engineered elastin-like polypeptide carriers may provide a new way to thermally target specific oncogene inhibitors to solid tumors. [Mol Cancer Ther 2005;4(7):1076 -85]

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