The intracellular delivery of active biomacromolecules from endosomes into the cytoplasm generally requires a membrane-disrupting agent. Since endosomes have a slightly acidic pH, anionic carboxylated polymers could be potentially useful for this purpose because they can destabilize membrane bilayers by pH-triggered conformational change. In this study, different pH-sensitive 2-ethylacrylic acid and alkyl methacrylate [butyl methacrylate and hexyl methacrylate] copolymers were synthesized by reversible addition-fragmentation chain transfer polymerization with high yields. pH-dependent membrane disruptive activity was investigated with respect to their physicochemical and membrane lytic properties as a function of pH, concentration, and molecular weight. Hemolysis assays demonstrated that the presence of the hydrophobic monomer and sufficient protonation of the carboxylic acid groups were important parameters for efficient membrane destabilization. (C) 2009 Wiley Periodicals, Inc. J Appl Polym Sci 114: 2522-2527, 2009