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

TY - JOUR

T1 - Cytotoxicity of Polycations: Relationship of Molecular Weight and the Hydrolytic Theory of the Mechanism of Toxicity

AU - Monnery, Bryn D.

AU - Wright, Michael

AU - Cavill, Rachel

AU - Hoogenboom, Richard

AU - Shaunak, Sunil

AU - Steinke, Joachim H.G.

AU - Thanou, Maya

PY - 2017/4

Y1 - 2017/4

N2 - 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.

AB - 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.

KW - Cytotoxicity

KW - Gene therapy

KW - Hydrolysis

KW - Molecular weight

KW - MTT assay

KW - Phospholipids

U2 - 10.1016/j.ijpharm.2017.02.048

DO - 10.1016/j.ijpharm.2017.02.048

M3 - Article

SN - 0378-5173

VL - 521

SP - 249

EP - 258

JO - INTERNATIONAL JOURNAL OF PHARMACEUTICS

JF - INTERNATIONAL JOURNAL OF PHARMACEUTICS

IS - 1-2

ER -