Membrane-anchoring, comb-like pseudopeptides for efficient, pH-mediated membrane destabilization and intracellular delivery
File(s)
Author(s)
Chen, S
Wang, S
Kopytynski, M
Bachelet, M
Chen, R
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.
Date Issued
2017-03-08
Date Acceptance
2017-02-13
Citation
ACS Applied Materials & Interfaces, 2017, 9 (9), pp.8021-8029
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
Commission of the European Communities
Biotechnology and Biological Sciences Research Council
MedImmune
Identifier
http://www.ncbi.nlm.nih.gov/pubmed/28225250
Grant Number
608184
BB/L016044/1
Ralph Minter
Subjects
comb-like polymer
drug delivery
endonsomal escape
pH-responsive
pseudopeptide
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2017-02-22