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.
authors.affiliation: University of Michigan, College of Engineering, Department of Biomedical Engineering, Cellular Engineering & Nano-Therapeutics Laboratory, Ann Arbor, MI 48109, USA.
authors.forename: Yen-Ling
authors.initials: YL
authors.lastname: Lin
authors.forename: Guohua
authors.initials: G
authors.lastname: Jiang
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Birrell
authors.forename: Mohamed E H
authors.initials: ME
authors.lastname: El-Sayed
mesh_terms: D045744:Cell Line, Tumor; D004355:Drug Stability; D005822:Genetic Vectors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D009696:Nucleic Acids / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D014162:Transfection / Q000379:methods*
chemical_list: D009696:Nucleic Acids; D011108:Polymers