pH-responsive pseudo-peptides for cell membrane disruption.

We describe pseudo-peptides obtained by the copolymerisation of L-lysine and L-lysine ethyl-ester with various hydrophobic dicarboxylic acid moieties. In aqueous solution, when the carboxylic acid groups are charged, the polymers dissolve. When they are fully neutralised the hydrophobic moieties cause the polymer to precipitate. The pH range over which reversible precipitation occurs can be adjusted by changing the intramolecular hydrophilic/hydrophobic balance, by using a carboxylic acid moiety with a different pK(a) value or by changing the apparent pK(a) value of the polymer through chemical modifications of the backbone. These bio-degradable materials are well tolerated by a range of mammalian cell lines at physiological pH but display an ability to associate with the outer membranes of these cells, which they rupture to varying degrees at pH 5.5. Relative to the degree of lysis displayed by poly(L-lysine iso-phthalamide), lysis was reduced by partial esterification and increased by replacing the aromatic iso-phthaloyl moiety with a long chain aliphatic dodecyl moiety. Similar behaviour was observed for the pH-dependent rupture of human erythrocytes, where poly(L-lysine dodecanamide) displayed enhanced cell lysis at pH values <7.0 relative to poly(L-lysine iso-phthalamide).