title: Modulation of cell membrane disruption by pH-responsive pseudo-peptides through grafting with hydrophilic side chains.
abstract: The effect of grafting an amphiphilic pseudo-peptide, poly (L-lysine iso-phthalamide), with poly (ethylene glycol) or a hydrophilic poly (ethylene glycol) analogue, Jeffamine M-1000, on the pH-dependent erythrolytic activity and in vitro cytotoxicity have been studied together with the concentration-dependent haemolysis of the polymers with different degrees of grafting. PEGylated polymers showed pH-dependent membrane-disruptive ability similar to the parent poly (L-lysine iso-phthalamide). The polymers showed a better ability to haemolyse the erythrocyte membrane at mildly acidic pHs with increasing degree of PEGylation (up to 17.0 wt.%). Further increasing the degree of PEGylation resulted in a decrease in haemolytic ability. Grafting poly (L-lysine iso-phthalamide) with the lower molecular weight Jeffamine M-1000 had little effect on the haemolytic ability. Finally, the in vitro cytotoxicity of the grafted polymers was assessed by MTT assay, LDH assay and viable cell counts. At pH 7.4, these polymers were well tolerated by a range of mammalian cell lines and grafting reduced the cytotoxicity of polymers. However, at pH 5.5, relative to poly (L-lysine iso-phthalamide), the grafted polymers displayed a better ability to rupture the outer membranes of these cells.
authors.affiliation: Department of Chemical Engineering, University of Cambridge, Pembroke Street, Cambridge, CB2 3RA, UK.
authors.forename: Rongjun
authors.initials: R
authors.lastname: Chen
authors.forename: Zhilian
authors.initials: Z
authors.lastname: Yue
authors.forename: Mark E
authors.initials: ME
authors.lastname: Eccleston
authors.forename: Sharon
authors.initials: S
authors.lastname: Williams
authors.forename: Nigel K H
authors.initials: NK
authors.lastname: Slater
mesh_terms: D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004910:Erythrocyte Membrane / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects*; D006367:HeLa Cells; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010795:Phthalic Acids / Q000737:chemistry / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology*; D011107:Polylysine / Q000737:chemistry / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology*; D012756:Sheep
chemical_list: D010795:Phthalic Acids; D011108:Polymers; C507264:poly(L-lysine iso-phthalamide); D011107:Polylysine; D011092:Polyethylene Glycols