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Membrane-anchoring, comb-like pseudopeptides for efficient, pH-mediated membrane destabilization and intracellular delivery

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Chen et al, 2017, ACS Appl Mater Interfaces_accepted manuscript.pdfAccepted version1.83 MBAdobe PDFView/Open
Title: Membrane-anchoring, comb-like pseudopeptides for efficient, pH-mediated membrane destabilization and intracellular delivery
Authors: Chen, S
Wang, S
Kopytynski, M
Bachelet, M
Chen, R
Item Type: Journal Article
Abstract: Endosomal release has been identified as a rate-limiting step for intracellular delivery of therapeutic agents, in particular macromolecular drugs. Herein, we report a series of synthetic pH-responsive, membrane-anchoring polymers exhibiting dramatic endosomolytic activity for efficient intracellular delivery. The comb-like pseudopeptidic polymers were synthesized by grafting different amounts of decylamine (NDA), which act as hydrophobic membrane anchors, onto the pendant carboxylic acid groups of a pseudopeptide, poly(l-lysine iso-phthalamide). The effects of the hydrophobic relatively long alkyl side chains on aqueous solution properties, cell membrane destabilization activity, and in-vitro cytotoxicity were investigated. The optimal polymer containing 18 mol % NDA exhibited limited hemolysis at pH 7.4 but induced nearly complete membrane destabilization at endosomal pH within only 20 min. The mechanistic investigation of membrane destabilization suggests the polymer-mediated pore formation. It has been demonstrated that the polymer with hydrophobic side chains displayed a considerable endosomolytic ability to release endocytosed materials into the cytoplasm of various cell lines, which is of critical importance for intracellular drug delivery applications.
Issue Date: 8-Mar-2017
Date of Acceptance: 13-Feb-2017
URI: http://hdl.handle.net/10044/1/45335
DOI: 10.1021/acsami.7b00498
ISSN: 1944-8244
Publisher: American Chemical Society
Start Page: 8021
End Page: 8029
Journal / Book Title: ACS Applied Materials & Interfaces
Volume: 9
Issue: 9
Copyright Statement: © 2017 American Chemical Society
Sponsor/Funder: Commission of the European Communities
Biotechnology and Biological Sciences Research Council
MedImmune
Funder's Grant Number: 608184
BB/L016044/1
Ralph Minter
Keywords: comb-like polymer
drug delivery
endonsomal escape
pH-responsive
pseudopeptide
Science & Technology
Technology
Nanoscience & Nanotechnology
Materials Science, Multidisciplinary
Science & Technology - Other Topics
Materials Science
pH-responsive
pseudopeptide
endonsomal escape
drug delivery
comb-like polymer
RESPONSIVE PSEUDO-PEPTIDES
DRUG-DELIVERY
HYDROPHOBIC POLYELECTROLYTE
DISRUPTIVE ACTIVITY
LIPID-BILAYERS
POLYMERS
MACROMOLECULES
FUSION
ACID)
HEMAGGLUTININ
comb-like polymer
drug delivery
endonsomal escape
pH-responsive
pseudopeptide
Cell Membrane
Drug Delivery Systems
Hydrogen-Ion Concentration
Hydrophobic and Hydrophilic Interactions
Intracellular Space
Polymers
Cell Membrane
Intracellular Space
Polymers
Drug Delivery Systems
Hydrogen-Ion Concentration
Hydrophobic and Hydrophilic Interactions
03 Chemical Sciences
09 Engineering
Nanoscience & Nanotechnology
Publication Status: Published
Conference Place: United States
Online Publication Date: 2017-02-22
Appears in Collections:Chemical Engineering
Faculty of Engineering