pH-responsive pseudo-peptides for cell membrane disruption

We describe pseudo-peptides obtained by the copolymerisation of L-lysine an d L-lysine ethyl-ester with various hydrophobic dicarboxylic acid moieties. In aqueous solution, when the carboxylic acid groups are charged, the poly mers dissolve. When they are fully neutralised the hydrophobic moieties cau se the polymer to precipitate. The pH range over which reversible precipita tion occurs can be adjusted by changing the intramolecular hydrophilic/hydr ophobic balance, by using a carboxylic acid moiety with a different pK(a) v alue or by changing the apparent pK(a) value of the polymer through chemica l modifications of the backbone. These bio-degradable materials are well to lerated 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 disp layed by poly(L-lysine iso-phthalamide), lysis was reduced by partial ester ification 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 dodecan amide) displayed enhanced cell lysis at pH values <7.0 relative to poly(L-l ysine iso-phthalamide). (C) 2000 Elsevier Science B.V. All rights reserved.