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The role of hydrophobic amino acid grafts in the enhancement of membrane-disruptive activity of pH-responsive pseudo-peptides
R. Chen, S. Khormaee, M. E. Eccleston and N. K.H. Slater, Biomaterials. 2009 30(10):1954-61

pH-responsive polymers have been synthesised by grafting l-valine (PV-75), l-leucine (PL-75) and l-phenylalanine (PP-75) onto the pendant carboxylic acid moieties of a pseudo-peptide, poly(l-lysine iso-phthalamide), at a stoichiometric degree of substitution of 75 mol%. The effect of such modification on the pH-, concentration- and time-dependent cell membrane-disruptive activity of the grafted polymers has been investigated using a haemolysis model. At 0.025 mg mL−1, the grafted polymers were almost non-haemolytic at pH 7.4, but mediated considerable membrane lysis after 60 min in the pH range characteristic of early endosomes, which ranked in the order: PP-75 > PL-75 > PV-75 > poly(l-lysine iso-phthalamide). PP-75 was 35-fold more lytic on a molar basis than the membrane-lytic peptide melittin. With increasing concentration, the grafted polymers showed an increased ability to lyse cell membranes and caused noticeable membrane disruption at physiological pH. The mechanism of the polymer-mediated membrane destabilisation has been investigated. The in-vitro cytotoxicity of the grafted polymers has been assessed using a propidium iodide fluorescence assay. It has been demonstrated by confocal microscopy that the grafted polymers can induce a significant release of endocytosed materials into the cytoplasm of HeLa cells, which is a feature critical for drug delivery applications.



Category: BioScience Engineering group, Cambridge | Added by: drug-delivery (04.10.2010)
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Molecular Simulation group, Tarragona [4]
Theory of Polymers at Interfaces group, Dresden [1]
BioScience Engineering group, Cambridge [2]
Membrane Biophysics Group, Copenhagen [0]
Membranes and Microforces Mcube group, Strasbourg [0]
Biological Physics group, Manchester [0]
Biomedical and Health Research Centre, Leeds [0]
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