Alternative Administration Routes of a Biopolymer‐Stabilized VEGF Chimera to Optimize Therapeutic Efficacy in Treating a Rodent Model of Placental Ischemia

Abstract

Preeclampsia is a form of gestational hypertension that complicates 5–8% of pregnancies in the United States. The unknown etiology originates from abnormal remodeling of the maternal spiral arteries, creating an ischemic placenta that releases factors that drive the pathophysiology. One of these pathogenic factors, soluble fms‐like tyrosine kinase‐1 (sFlt‐1), causes angiogenic imbalance by sequestering vascular endothelial growth factor (VEGF), leading to endothelial dysfunction and hypertension. Apart from delivery of the ischemic placenta, no effective therapy exists to treat preeclampsia. Innovative treatments are needed not only to reduce the morbidity and mortality rates during the preeclamptic index pregnancy, but also to decrease the incidence of later life cardiovascular‐renal and metabolic risk factors that are associated with the systemic endothelial dysfunction.In order to develop treatments that are safe for both the mother and fetus, we are testing novel therapies that target sFlt‐1 and other pathogenic factors in a preclinical model of placental ischemia, the reduced uterine perfusion pressure (RUPP) surgery. Previously, we demonstrated in timed pregnant Sprague‐Dawley rats that the biopolymer drug carrier elastin‐like polypeptide (ELP) fused to human VEGF‐A121 (ELP‐VEGF) prevents VEGF from crossing the placental barrier and thus ameliorates the risk of fetal exposure. Furthermore, in pregnant rats that had undergone the RUPP surgery, chronic administration of ELP‐VEGF at 5 mg/kg/day via intraperitoneal minipump blocked hypertension, significantly enhanced renal nitric oxide signaling, and had no deleterious effect on fetal weight or placental efficiency. However, dams also experienced dose‐dependent adverse events likely attributed to the continuous intraperitoneal infusion method, including ascites production, neovascular tissue encapsulation around the minipump, and, at the 10 mg/kg/day dose, fetal loss.With the aim of minimizing 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 with Alexa Fluor 633 succinimidyl ester. In a repeated intravenous dosing cohort, a 5 mg/kg IV bolus of fluorescent labeled ELP‐VEGF was delivered via jugular catheter once daily for 5 days. In a parallel controlled‐release dosing study, rats received a single 5 mg/kg bolus subcutaneously between the scapulae. In vivo imaging and blood draws were conducted at specific time points in order to assess ELP‐VEGF biodistribution and plasma clearance rates, respectively. Mean fluorescence radiant efficiency was averaged, levels were corrected for autofluorescence, and data were fit to the standard curve of the injected protein. We report that whereas a single subcutaneous bolus yields a slow absorption and release of ELP‐VEGF, repeated intravenous dosing can replicate tissue levels comparable to the therapeutic levels achieved by the intraperitoneal osmotic pumps, and free of any peritoneal ascites. Plasma clearance rates and terminal half‐life of ELP‐VEGF determined from these studies are being employed in ongoing experiments to test the therapeutic efficacy of these administration routes in the RUPP model of placental ischemia.Support or Funding InformationSupported by NIH NHLBI grant R01HL121527 (GLB), NIH grant T32HL105324 (OCL) and AHA fellowship 17POST3346012 (OCL).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.