Structure-Activity Relationship of PEGylated Polylysine Peptides as Scavenger Receptor Inhibitors for Non-Viral Gene Delivery

Nicholas J Baumhover; Jason T Duskey; Sanjib Khargharia; Christopher W White; Samuel T Crowley; Rondine J Allen; Kevin G Rice

doi:10.1021/acs.molpharmaceut.5b00513

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Structure-Activity Relationship of PEGylated Polylysine Peptides as Scavenger Receptor Inhibitors for Non-Viral Gene Delivery

Journal article

Open access

Peer reviewed

Structure-Activity Relationship of PEGylated Polylysine Peptides as Scavenger Receptor Inhibitors for Non-Viral Gene Delivery

Nicholas J Baumhover, Jason T Duskey, Sanjib Khargharia, Christopher W White, Samuel T Crowley, Rondine J Allen and Kevin G Rice

Molecular pharmaceutics, Vol.12(12), pp.4321-4328

12/07/2015

DOI: 10.1021/acs.molpharmaceut.5b00513

PMCID: PMC4837691

PMID: 26485572

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Abstract

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.

Gene Transfer Techniques

Nanoparticles - chemistry

Peptides - chemistry

Gene Expression - genetics

Liver - metabolism

Polylysine - administration & dosage

Polyethylene Glycols - chemistry

Polylysine - chemistry

Structure-Activity Relationship

Receptors, Scavenger - antagonists & inhibitors

Peptides - administration & dosage

Polyethylene Glycols - administration & dosage

DNA - genetics

Animals

Transfection - methods

Plasmids - genetics

Mice

Nanoparticles - administration & dosage

Genetic Therapy - methods

Details

Title: Subtitle: Structure-Activity Relationship of PEGylated Polylysine Peptides as Scavenger Receptor Inhibitors for Non-Viral Gene Delivery
Creators: Nicholas J Baumhover - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa , Iowa City, Iowa 52242, United States
Jason T Duskey - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa , Iowa City, Iowa 52242, United States
Sanjib Khargharia - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa , Iowa City, Iowa 52242, United States
Christopher W White - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa , Iowa City, Iowa 52242, United States
Samuel T Crowley - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa , Iowa City, Iowa 52242, United States
Rondine J Allen - 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.12(12), pp.4321-4328
DOI: 10.1021/acs.molpharmaceut.5b00513
PMID: 26485572
PMCID: PMC4837691
NLM abbreviation: Mol Pharm
ISSN: 1543-8384
eISSN: 1543-8392
Publisher: United States
Grant note: T32 GM067795 / NIGMS NIH HHS R01 GM097093 / NIGMS NIH HHS GM097093 / NIGMS NIH HHS T32 GM008365 / NIGMS NIH HHS T32 HL080070 / NHLBI NIH HHS R01 GM087653 / NIGMS NIH HHS
Language: English
Date published: 12/07/2015
Academic Unit: Radiology; Pharmaceutical Sciences and Experimental Therapeutics; Craniofacial Anomalies Research Center; Medicinal and Natural Products Chemistry
Record Identifier: 9984065312802771

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