Structure-Activity Relationship of PEGylated Polylysine Peptides as Scavenger Receptor Inhibitors for Non-Viral Gene Delivery.
PEGylated polylysine peptides of the general structure PEG30 kDa-Cys-Trp-LysN (N = 10 to 30) were used to form fully condensed plasmid DNA (pGL3) polyplexes at a ratio of 1 nmol of peptide per μg of DNA (ranging from N:P 3:1 to 10:1 depending on Lys repeat). Co-administration of 5 to 80 nmols of excess PEG-peptide with fully formed polyplexes inhibited the liver uptake of (125)I-pGL3-polyplexes. The percent inhibition was dependent on the PEG-peptide dose and was saturable, consistent with inhibition of scavenger receptors. The scavenger receptor inhibition potency of PEG-peptides was dependent on the length of the Lys repeat, which increased 10-fold when comparing PEG30 kDa-Cys-Trp-Lys10 (IC50 of 20.2 μM) with PEG30 kDa-Cys-Trp-Lys25 (IC50 of 2.1 μM). We hypothesize that PEG-peptides inhibit scavenger receptors by spontaneously forming small 40 to 60 nm albumin nanoparticles that bind to and saturate the receptor. Scavenger receptor inhibition delayed the metabolism of pGL3-polyplexes, resulting in efficient gene expression in liver hepatocytes following delayed hydrodynamic dosing. PEG-peptides represent a new class of scavenger inhibitors that will likely have broad utility in blocking unwanted liver uptake and metabolism of a variety of nanoparticles.
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa , Iowa City, Iowa 52242, United States.
Nicholas J
NJ
Baumhover
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa , Iowa City, Iowa 52242, United States.
Jason T
JT
Duskey
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa , Iowa City, Iowa 52242, United States.
Sanjib
S
Khargharia
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa , Iowa City, Iowa 52242, United States.
Christopher W
CW
White
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa , Iowa City, Iowa 52242, United States.
Samuel T
ST
Crowley
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa , Iowa City, Iowa 52242, United States.
Rondine J
RJ
Allen
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa , Iowa City, Iowa 52242, United States.
Kevin G
KG
Rice
D000818:Animals; D004247:DNA / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D008099:Liver / Q000378:metabolism; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry*; D010957:Plasmids / Q000235:genetics; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry*; D011107:Polylysine / Q000008:administration & dosage* / Q000737:chemistry*; D051116:Receptors, Scavenger / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014162:Transfection / Q000379:methods
D010455:Peptides; D051116:Receptors, Scavenger; D011107:Polylysine; D011092:Polyethylene Glycols; D004247:DNA
liver biodistribution; nonviral gene delivery; polyethylene glycol peptide; polyplex; scavenger receptor inhibition