Background:
Preeclampsia is a major obstetrical health concern, affecting 5-8% of all pregnancies. Hallmarked by hypertension and endothelial dysfunction the origin of the disease remains obscure, though it is generally accepted that placental insufficiency/ischemia is a central cause. In response, the placenta secretes pathogenic factors, in particular the anti-angiogenic protein sFlt-1. Currently, there is no effective therapy for the management of the preeclampsia patient. We have recently produced a novel synthetic peptide based on placental growth factor (PlGF) which is maternally restricted by fusion to the synthetic carrier elastin like polypeptide (ELP). Here, we describe its in vivo pharmacokinetics and biodistribution.
Methods:
Fluorescently labeled ELP-PLGF was administered i.v. and blood sampled serially to determine clearance kinetics. Long-term pharmacokinetics and biodistribution was performed after subcutaneous administration of labeled peptide. Measurements were made on serially drawn blood, and in the whole animal by in vivo imaging.
Results:
ELP-PlGF exhibited markedly more favorable pharmacokinetics than the normal half life of PlGF, with a terminal half-life of ~10 hours as opposed to ~30 minutes for PlGF alone. Chronic administration found highest levels accumulating in placenta and kidney (two favorable targets for preeclampsia) and liver. A single subcutaneous administration at 100mg/kg resulted in sustained therapeutic plasma concentrations for over 10 days.
Conclusion:
These data demonstrate that ELP-PlGF has favorable pharmacokinetic and biodistribution profiles. Previous data suggest ELP-PlGF directly antagonizes sFlt-1 in culture. Future studies to assess the in vivo effectiveness of ELP-PlGF in managing placental ischemia induced hypertension and endothelial dysfunction are currently in progress.
Acknowledgment:
This work was supported by NIH grants R0121527 (GLB), T32HL105324 (OCL), P01HL51971, P20GM104357 (EMG), and R00HL116774 (EMG)
Mild-to-moderate hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentrations of asymmetric dimethylarginine
