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

Rondine J Allen; Basil Mathew; Kevin G Rice

doi:10.1021/acs.molpharmaceut.8b00355

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

Journal article

Peer reviewed

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

Rondine J Allen, Basil Mathew and Kevin G Rice

Molecular pharmaceutics, Vol.15(9), pp.3881-3891

09/04/2018

DOI: 10.1021/acs.molpharmaceut.8b00355

PMCID: PMC6413502

PMID: 30052459

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https://www.ncbi.nlm.nih.gov/pmc/articles/6413502View

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Abstract

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 (IC ) was dependent on both the length of a polylysine repeat and PEG molecular weight. PEG -Cys-Tyr-Lys was confirmed to be a high molecular weight (33.5 kDa) scavenger receptor inhibitor with an IC of 18 μM. Incorporation of multiple Leu residues improved potency, allowing a decrease in PEG MW and Lys repeat, resulting in PEG -Cys-Tyr-Lys-(Leu-Lys ) -Leu-Lys that inhibited scavenger receptors with an IC = 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 IC 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.

Peptides - chemistry

Liver - metabolism

Peptides - pharmacokinetics

Polyethylene Glycols - pharmacokinetics

Male

Polyethylene Glycols - chemistry

Structure-Activity Relationship

Kupffer Cells - drug effects

Peptides - pharmacology

Polylysine - metabolism

Animals

Nanoparticles - metabolism

Biological Transport - drug effects

Kupffer Cells - metabolism

Mice

Receptors, Scavenger - metabolism

Details

Title: Subtitle: PEG-Peptide Inhibition of Scavenger Receptor Uptake of Nanoparticles by the Liver
Creators: Rondine J Allen - Division of Medicinal and Natural Products Chemistry, College of Pharmacy , University of Iowa , Iowa City , Iowa 52242 , United States
Basil Mathew - Division of Medicinal and Natural Products Chemistry, College of Pharmacy , University of Iowa , Iowa City , Iowa 52242 , United States
Kevin G Rice - Division of Medicinal and Natural Products Chemistry, College of Pharmacy , University of Iowa , Iowa City , Iowa 52242 , United States
Resource Type: Journal article
Publication Details: Molecular pharmaceutics, Vol.15(9), pp.3881-3891
DOI: 10.1021/acs.molpharmaceut.8b00355
PMID: 30052459
PMCID: PMC6413502
NLM abbreviation: Mol Pharm
ISSN: 1543-8384
eISSN: 1543-8392
Publisher: United States
Grant note: T32 GM067795 / NIGMS NIH HHS R25 GM058939 / NIGMS NIH HHS R01 GM117785 / NIGMS NIH HHS P30 DK054759 / NIDDK NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 09/04/2018
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; Craniofacial Anomalies Research Center; Medicinal and Natural Products Chemistry
Record Identifier: 9984065698702771

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