PEG-Peptide Inhibition of Scavenger Receptor Uptake of Nanoparticles by the Liver

• Published in: Molecular pharmaceutics Vol. 15; no. 9; pp. 3881 - 3891
• Main Authors: Allen, Rondine J, Mathew, Basil, Rice, Kevin G
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 04-09-2018
• Subjects: Animals; Biological Transport - drug effects; Kupffer Cells - drug effects; Kupffer Cells - metabolism; Liver - metabolism; Male; Mice; Nanoparticles - metabolism; Peptides - chemistry; Peptides - pharmacokinetics; Peptides - pharmacology; Polyethylene Glycols - chemistry; Polyethylene Glycols - pharmacokinetics; Polylysine - metabolism; Receptors, Scavenger - metabolism; Structure-Activity Relationship; nanoparticle; scavenger receptor; biodistribution; inhibitor; liver
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.8b00355

PEGylated polylysine peptides represent a new class of scavenger receptor inhibitors that may find utility at inhibiting DNA nanoparticle uptake by Kupffer cells in the liver. PEG-peptides inhibit scavenger receptors in the liver by a novel mechanism involving in situ formation of albumin nanoparticles. The present study developed a new in vivo assay used to explore the structure–activity-relationships of PEG-peptides to find potent scavenger receptor inhibitors. Radio-iodinated PEG-peptides were dosed i.v. in mice and shown to saturate liver uptake in a dose-dependent fashion. The inhibition potency (IC50) was dependent on both the length of a polylysine repeat and PEG molecular weight. PEG30kda-Cys-Tyr-Lys25 was confirmed to be a high molecular weight (33.5 kDa) scavenger receptor inhibitor with an IC50 of 18 μM. Incorporation of multiple Leu residues improved potency, allowing a decrease in PEG MW and Lys repeat, resulting in PEG5kda-Cys-Tyr-Lys-(Leu-Lys4)3-Leu-Lys that inhibited scavenger receptors with an IC50 = 20 μM. A further decrease in PEG MW to 2 kDa increased potency further, resulting in a low molecular weight (4403 g/mol) PEG-peptide with an IC50 of 3 μM. Optimized low molecular weight PEG-peptides also demonstrated potency when inhibiting the uptake of radio-iodinated DNA nanoparticles by the liver. This study demonstrates an approach to discover low molecular weight PEG-peptides that serve as potent scavenger receptor inhibitors to block nanoparticle uptake by the liver.