title: Membrane-Anchoring, Comb-Like Pseudopeptides for Efficient, pH-Mediated Membrane Destabilization and Intracellular Delivery.
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.
authors.affiliation: Department of Chemical Engineering, Imperial College London , South Kensington Campus, London SW7 2AZ, United Kingdom.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Chemical Engineering, Imperial College London , South Kensington Campus, London SW7 2AZ, United Kingdom.
authors.forename: Shiqi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Chemical Engineering, Imperial College London , South Kensington Campus, London SW7 2AZ, United Kingdom.
authors.forename: Michal
authors.initials: M
authors.lastname: Kopytynski
authors.affiliation: Department of Chemical Engineering, Imperial College London , South Kensington Campus, London SW7 2AZ, United Kingdom.
authors.forename: Marie
authors.initials: M
authors.lastname: Bachelet
authors.affiliation: Department of Chemical Engineering, Imperial College London , South Kensington Campus, London SW7 2AZ, United Kingdom.
authors.forename: Rongjun
authors.identifier: http://orcid.org/0000-0002-8133-5472
authors.initials: R
authors.lastname: Chen
mesh_terms: D002462:Cell Membrane; D016503:Drug Delivery Systems; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D042541:Intracellular Space; D011108:Polymers
chemical_list: D011108:Polymers
keywords: comb-like polymer; drug delivery; endonsomal escape; pH-responsive; pseudopeptide