Cytotoxicity of Polycations: Relationship of Molecular Weight and the Hydrolytic Theory of the Mechanism of Toxicity

Bryn D. Monnery, Michael Wright, Rachel Cavill, Richard Hoogenboom, Sunil Shaunak, Joachim H.G. Steinke, Maya Thanou

Research output: Contribution to journalArticlepeer-review

146 Citations (Scopus)
574 Downloads (Pure)

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 synthesized uniform (near monodisperse) linear polyethylenimines, commercially available poly(L-lysine)s and two commonly used PEI-based transfectants (broad 22 kDa linear and 25 kDa 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.
Original languageEnglish
Pages (from-to)249-258
JournalINTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume521
Issue number1-2
Early online date21 Feb 2017
DOIs
Publication statusPublished - Apr 2017

Keywords

  • Cytotoxicity
  • Gene therapy
  • Hydrolysis
  • Molecular weight
  • MTT assay
  • Phospholipids

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