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Degradable, pH-sensitive, membrane-destabilizing, comb-like polymers for intracellular delivery of nucleic acids

Paper ID Volume ID Publish Year Pages File Format Full-Text
8360 587 2010 17 PDF Available
Title
Degradable, pH-sensitive, membrane-destabilizing, comb-like polymers for intracellular delivery of nucleic acids
Abstract

This report describes the design and synthesis of a new series of degradable, pH-sensitive, membrane-destabilizing, comb-like polymers that can enhance the intracellular delivery of therapeutic nucleic acids. These comb-like polymers are based on a diblock polymer backbone where the first block is a copolymer of pH-sensitive ethyl acrylic acid (EAA) monomers and hydrophobic butyl methacrylate (BMA) or hexyl methacrylate monomers. The second block is a homopolymer of N-acryloxy succinimide (NASI) or ß-benzyl l-aspartate N-carboxy-anhydride (BLA-NCA) monomers, which are functionalized to allow controlled grafting of hydrophobic HMA and cationic trimethyl aminoethyl methacrylate (TMAEMA) copolymers via acid-labile hydrazone linkages. These comb-like polymers displayed high hemolytic activity in acidic solutions, which increased with the increase in polymer concentration. All comb-like polymers degraded into small fragments upon incubation in an acidic solution (pH 5.8) due to hydrolysis of the hydrazone linkages connecting the hydrophobic/cationic grafts to the polymer backbone. Comb-like polymers successfully complexed anti-GAPDH siRNA molecules into serum- and nuclease-stable particles, which successfully silenced GAPDH expression at both the mRNA and protein levels. These results collectively indicate the potential of these new comb-like polymers to serve as vehicles for effective intracellular delivery of therapeutic nucleic acids.

Keywords
pH-sensitive polymers; Acid-labile linkage; Comb-like polymers; Endosomal escape; Intracellular siRNA delivery
First Page Preview
Degradable, pH-sensitive, membrane-destabilizing, comb-like polymers for intracellular delivery of nucleic acids
Publisher
Database: Elsevier - ScienceDirect
Journal: Biomaterials - Volume 31, Issue 27, September 2010, Pages 7150–7166
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering