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Membrane-Anchoring, Comb-Like Pseudopeptides for Efficient, pH-Mediated Membrane Destabilization and Intracellular Delivery
journal contribution
posted on 2017-02-13, 00:00 authored by Siyuan Chen, Shiqi Wang, Michal Kopytynski, Marie Bachelet, Rongjun ChenEndosomal
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.
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alkyl side chainscell membrane destabilization activitypendant carboxylic acid groupsintracellular deliveryendosomolyticmembrane destabilizationIntracellular Delivery Endosomal releaseintracellular drug delivery applicationsNDApolymer-mediated pore formationpH-Mediated Membrane Destabilizationcomb-like pseudopeptidic polymersrelease endocytosed materials
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