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

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• 作者：Nicholas J. Baumhover ; Jason T. Duskey ; Sanjib Khargharia ; Christopher W. White ; Samuel T. Crowley ; Rondine J. Allen ; Kevin G. Rice
• 刊名：Molecular Pharmaceutics
• 出版年：2015
• 出版时间：December 7, 2015
• 年：2015
• 卷：12
• 期：12
• 页码：4321-4328
• 全文大小：373K
• ISSN：1543-8392

文摘

PEGylated polylysine peptides of the general structure PEG_30聽kDa-Cys-Trp-Lys_N (N = 10 to 30) were used to form fully condensed plasmid DNA (pGL3) polyplexes at a ratio of 1 nmol of peptide per 渭g 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 ¹²⁵I-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 PEG_30聽kDa-Cys-Trp-Lys₁₀ (IC₅₀ of 20.2 渭M) with PEG_30聽kDa-Cys-Trp-Lys₂₅ (IC₅₀ of 2.1 渭M). 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.