Polymer Size Affects Biodistribution and Placental Accumulation of the Drug Delivery Biopolymer Elastin‐Like Polypeptide in a Rodent Pregnancy Model

Abstract

Pregnancy has been a limiting factor in drug development, and pregnant females are often excluded from clinical trials. Developmental and reproductive toxicology studies are often done in mice, rats and rabbits during the drug development process for a novel therapeutic, however very little drug development occurs for disorders specific to pregnancy due to the risk of deleterious effects on the developing fetus. Nevertheless, there is still a need for drug administration during pregnancy and for development of treatments for pregnancy – specific conditions. We have approached this problem by developing a novel drug delivery system that prevents placental drug transfer. In the emerging field of biologics, the effects during pregnancy are variable. While some protein therapeutics are too large to cross the placental barrier, many biologics are monoclonal antibodies or Fc domain fusion proteins that are substrates for the placental antibody transport machinery, and these agents can be actively shuttled into the fetal circulation. Our lab has developed a drug delivery system based on a biopolymer called elastin‐like polypeptide (ELP) that does not cross the placental barrier. ELPs consist of a repetitive five amino acid motif. ELPs can be easily modified to attach therapeutic proteins or peptides, and small drugs can be chemically attached to them. Previous studies have showed that little to no ELP crosses the placental barrier, and ELPs can be safely used as carriers to prevent placental drug transfer. However, all previous work in pregnancy models has been done with a single ELP molecule of 60 kDa. Recently, we have studied the effect of molecular weight (MW) on the pharmacokinetics, biodistribution and renal deposition of ELPs in mice. However, given that pharmacokinetics could change during pregnancy and that placental transfer may be size dependent, the goal of this study was to measure the effects of polymer size on pharmacokinetics, biodistribution, and placental transfer of ELP in a rodent pregnancy model. Three ELP proteins, 25, 50 and 86 kDa, were fluorescently labeled and administered via bolus intravenous injection to timed pregnant Sprague Dawley rats on gestational day 14. Plasma clearance was determined to define the plasma pharmacokinetics. The biodistribution of each ELP construct was determined by whole‐organ ex vivo fluorescence imaging. Placental distribution was determined in feto‐amnio‐placental units by quantitative fluorescence and histological analysis. Increasing MW resulted in an increase in organ ELP levels, except in the kidneys where an opposite effect was observed. Kidney levels were 6.7, 5, and 1.7 μM for 25, 50 and 86 kDa ELP following an intravenous dose of 1.5 μmol/kg. Placental levels increased with an increase in MW from 0.05, 0.26 to 0.5 μM for 25, 50 and 86 kDa ELP, while in the pups, little to no ELP was detected. Plasma clearance rate was inversely related to MW, and terminal half‐life increased with an increase in MW. Pharmacokinetics and biodistribution of ELPs are size dependent, but they do not affect placental transfer.Support or Funding InformationSupported by NIH NHLBI Grant R01HL121527 (GLB).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.