Development of PEG-peptide scavenger receptor inhibitors for non-viral gene delivery

Abstract

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. Radio‐iodinated PEG‐peptides were used to study the pharmacokinetics and biodistribution to understand the structural properties which influence transfection competency and potency. We hypothesized that the in vivo potency and activity is influenced by the stability of protein nanoparticles formed in the blood. Results show that peptides featuring both hydrophobic and positively charged residues are able to potently inhibit scavenger receptor uptake of non viral gene delivery systems. Support or Funding Information This work was supported by the Iowa Biosciences Academy and University of Iowa Pharmacological Sciences T32 training grant. 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, the Pharmacological Sciences Training grant T32 GM067795 and NIH grant R01 GM087653. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Metabolic stability and persistence of expression of mRNA for nonviral gene delivery

“…Nevertheless, the successful scavenger receptor inhibition experiment demonstrated that a significant amount (about 20-fold) of the expression loss after 5 minutes of circulation is strictly due to Kupffer cell uptake and degradation (compare 40 µg/32 nmol decoy 5-minute stimulation to 0 µg/0 nmol 5-minute stimulation in Figure 4 -14). Work toward a potent, non-toxic scavenger receptor inhibitor that does not compete for binding nucleic acids is being pursued in earnest in our lab 234 .…”