Daily Subcutaneous Administration of a Biopolymer-Stabilized VEGF Chimera Optimizes Therapeutic Efficacy in Treating a Rodent Model of Placental Ischemia.

Preeclampsia (PE) complicates 3-5% of pregnancies with gestational hypertension, and programs later life outcomes in both mother and offspring. The unknown etiology arises from abnormal remodeling of the maternal spiral arteries, creating an ischemic placenta that releases pathogenic factors that drive the syndrome. One of these factors, soluble fms-like tyrosine kinase-1 (sFlt-1), contributes to the hypertensive response by sequestering vascular endothelial growth factor (VEGF). Currently, no effective pharmacological therapies exist for PE. With the goal of developing PE treatments that are safe for both the mother and fetus, novel therapies that target sFlt-1 are being tested in the reduced uterine perfusion pressure (RUPP) rodent model. Previously, we demonstrated that intraperitoneal administration of human VEGF-A121 fused to the bioengineered protein polymer drug carrier elastin-like polypeptide (ELP-VEGF), at a dose of 5 mg/kg/d, blocked hypertension by sequestering sFlt-1, enhanced renal nitric oxide signaling, and simultaneously prevented fetal exposure to VEGF. However, chronic intraperitoneal infusion was associated with adverse ascites production, and at the 10 mg/kg/day dose, fetal loss. In order to minimize dose-dependent side effects while retaining the therapeutic efficacy of ELP-VEGF, chronic biodistribution studies were conducted in non-pregnant female hairless Sprague-Dawley rats. ELP-VEGF was fluorescently labeled, and rats ( n =4) received a single 50 mg/kg bolus subcutaneously (SC) between the scapulae or intravenously (IV) by daily bolus injection (5 mg/kg/day) via jugular catheter. Blood draws and in vivo whole-animal imaging were conducted at specific timepoints to assess plasma levels and mean tissue polypeptide levels. Pharmacokinetic fits demonstrated a plasma half-life of 2.18 +/- 1.1 hours following IV administration, and the plasma clearance rate was consistent after each daily injection. Tissue levels accumulated over the five-day IV dosing time course. When administered SC, plasma levels peaked 3 hours after administration and cleared slowly over a 24 - 48 h period. Based on these data, the therapeutic efficacy of daily SC administration of ELP-VEGF (50 mg/kg/d) is being assessed in the RUPP model.