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Structure Activity Relationship of PEG‐Peptide Scavenger Receptor Inhibitors
Author(s) -
Allen Rondine,
Rice Kevin
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb609
Subject(s) - scavenger receptor , biodistribution , in vivo , chemistry , peg ratio , transfection , peptide , gene delivery , polylysine , ethylene glycol , biochemistry , in vitro , pharmacology , biophysics , biology , gene , lipoprotein , microbiology and biotechnology , organic chemistry , finance , cholesterol , economics
The rapid capture and degradation of viral and non‐viral gene delivery nanoparticles by scavenger receptors (SR) on Kupffer cells and fenestrated endothelial cells in the liver results in a decreased half life of all nanoparticles in an in vivo system, as well as a lower percentage of the dose available for delivery to the target organ. Current attempts to achieve SR inhibition involves co‐administering high molecular weight, polyanionic inhibitors. Polyinosinic acid (Poly‐I), the most widely used and potent inhibitor, competes for SR binding and successfully inhibits the uptake and metabolism of viral gene delivery nanoparticles in the liver. However, Poly‐I also activates the immune system, resulting in toxicity in mice, making Poly‐I clinically unacceptable. We have discovered peptide based SR inhibitors that block SR uptake of DNA nanoparticles and improves their metabolic half‐life by forming protein nanoparticles in the blood. These Poly (ethylene) glycol (PEG) polylysine peptides potently inhibit SR and allow DNA to transfect hepatocytes up to 12 hours after administration in mice. Radio‐iodinated PEG‐peptides were used to study the pharmacokinetics and biodistribution to understand the structural properties which influence transfection competency and potency. We hypothesize that the in vivo potency and activity is influenced by the stability of protein nanoparticles formed in the blood. Peptides which are able to form stable nanoparticles are able to effectively block liver uptake of DNA nanoparticles by saturating SRs on Kupffer cells in the liver. The results of this study provide a framework for the design and synthesis of future PEG‐peptide scavenger receptor inhibitors, as well as an assay to quickly determine the activity of each inhibitor. Support or Funding Information The Iowa Biosciences Academy is supported by the National Institute Of General Medical Sciences of the National Institutes of Health under Award Number R25GM058939, the University of Iowa (UI) Office of the Vice President for Research and the UI Chief Diversity Office. This work was also supported by the NIH Pharmacological Sciences Training Grant T32 GM067795 and NIH grant R01 GM087653.