title: Cytotoxicity of polycations: Relationship of molecular weight and the hydrolytic theory of the mechanism of toxicity.
abstract: The mechanism of polycation cytotoxicity and the relationship to polymer molecular weight is poorly understood. To gain an insight into this important phenomenon a range of newly synthesised uniform (near monodisperse) linear polyethylenimines, commercially available poly(l-lysine)s and two commonly used PEI-based transfectants (broad 22kDa linear and 25kDa branched) were tested for their cytotoxicity against the A549 human lung carcinoma cell line. Cell membrane damage assays (LDH release) and cell viability assays (MTT) showed a strong relationship to dose and polymer molecular weight, and increasing incubation times revealed that even supposedly "non-toxic" low molecular weight polymers still damage cell membranes. The newly proposed mechanism of cell membrane damage is acid catalysed hydrolysis of lipidic phosphoester bonds, which was supported by observations of the hydrolysis of DOPC liposomes.
authors.affiliation: Chemical Biology Section, Department of Chemistry, Imperial College London, London SW7 2AZ, UK.
authors.forename: Bryn D
authors.initials: BD
authors.lastname: Monnery
authors.affiliation: Institute of Pharmaceutical Science, King's College London,Franklin-Wilkins Building, London, SE1 9NH, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Wright
authors.affiliation: Department of Data Science and Knowledge Engineering, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Rachel
authors.initials: R
authors.lastname: Cavill
authors.affiliation: Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281-S4, 9000 Gent, Belgium.
authors.forename: Richard
authors.initials: R
authors.lastname: Hoogenboom
authors.affiliation: Department of Infectious Diseases and Immunity, Faculty of Medicine, Imperial College London, Hammersmith Campus, London, W12 ONN, UK.
authors.forename: Sunil
authors.initials: S
authors.lastname: Shaunak
authors.affiliation: Chemical Biology Section, Department of Chemistry, Imperial College London, London SW7 2AZ, UK.
authors.forename: Joachim H G
authors.initials: JHG
authors.lastname: Steinke
authors.affiliation: Institute of Pharmaceutical Science, King's College London,Franklin-Wilkins Building, London, SE1 9NH, UK. Electronic address: Maya.thanou@kcl.ac.uk.
authors.forename: Maya
authors.initials: M
authors.lastname: Thanou
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008970:Molecular Weight; D010743:Phospholipids / Q000737:chemistry; D011073:Polyamines / Q000737:chemistry / Q000633:toxicity*; D000071228:Polyelectrolytes; D011094:Polyethyleneimine / Q000737:chemistry
chemical_list: D007770:L-Lactate Dehydrogenase; D010743:Phospholipids; D011073:Polyamines; D000071228:Polyelectrolytes; D011094:Polyethyleneimine
keywords: Cytotoxicity; Gene therapy; Hydrolysis; MTT assay; Molecular weight; Phospholipids