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A Two-stage Poly(ethylenimine)-mediated Cytotoxicity: Implications For Gene Transfer/therapy.

S. Moghimi, P. Symonds, J. C. Murray, A. C. Hunter, G. Dȩbska, A. Szewczyk
Published 2005 · Biology, Medicine

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Poly(ethylenimine) (PEI) is a cationic macromolecule commonly used in gene transfer/therapy protocols with high transfection efficiency both in vitro and in vivo. PEI is also cytotoxic, but the molecular basis of its cytotoxicity is poorly understood. Here, we have demonstrated that branched (25 kDa) and linear (750 kDa) PEI can both induce membrane damage and initiate apoptosis in three clinically relevant human cell lines (Jurkat T cells, umbilical vein endothelial cells, and THLE3 hepatocyte-like cells). We have defined Phase I toxicity as early necrotic-like changes (30 min) resulting from compromised membrane integrity, assessed by considerable lactate dehydrogenase release and phosphatidylserine translocation from the inner plasma membrane to the outer cell surface. Phase II cytotoxicity (24 h) was due to activation of a "mitochondrially mediated apoptotic program," resulting from PEI-induced channel formation in the outer mitochondrial membrane. This led to the release of proapoptotic cytochrome c, subsequent activation of caspase 3, and alteration in mitochondrial membrane potential as a result of caspase translocation into the mitochondria. The reported observations have important implications for the design and execution of gene therapy protocols as well for controlling intracellular distribution of drugs with cationic-based polymer-delivery systems.
This paper references
Redistribution of cytochrome c precedes the caspase-dependent formation of ultracondensed mitochondria, with a reduced inner membrane potential, in apoptotic monocytes.
D. Dinsdale (1999)
Cellular Distribution of Nonionic Micelles
S. M. Moghimi (2004)
Toxicogenomics of Non-viral Vectors for Gene Therapy: A Microarray Study of Lipofectin- and Oligofectamine-induced Gene Expression Changes in Human Epithelial Cells
Y. Omidi (2003)
Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics.
A. Letai (2002)
Monitoring of the formation and dissociation of polyethylenimine/DNA complexes by two photon fluorescence correlation spectroscopy.
J. P. Clamme (2003)
Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl
S. J. Martin (1995)
Gene transfer with modified polyethylenimines
A. Kichler (2004)
The future of gene therapy
M. Cavazzana‐Calvo (2004)
Nanomedicine: current status and future prospects
S. Moghimi (2005)
Disruption of Mitochondrial Function during Apoptosis Is Mediated by Caspase Cleavage of the p75 Subunit of Complex I of the Electron Transport Chain
Jean-Ehrland Ricci (2004)
Evidence for the role of proteoglycans in cation-mediated gene transfer.
K. A. Mislick (1996)
Polycation‐based DNA complexes for tumor‐targeted gene delivery in vivo
R. Kircheis (1999)
Non-viral and hybrid vectors in human gene therapy: an update.
Gabriele D Schmidt-Wolf (2003)
Release of apoptogenic proteins from the mitochondrial intermembrane space during the mitochondrial permeability transition
J. Scarlett (1997)
Caspase Independent/Dependent Regulation of K+, Cell Shrinkage, and Mitochondrial Membrane Potential during Lymphocyte Apoptosis*
C. Bortner (1999)
Cytochrome c Release Occurs via Ca2+-dependent and Ca2+-independent Mechanisms That Are Regulated by Bax*
V. Gogvadze (2001)
Intracellular dynamics of the gene delivery vehicle polyethylenimine during transfection: investigation by two-photon fluorescence correlation spectroscopy.
Jean-Pierre Clamme (2003)
Phosphatidylserine Externalization during CD95-induced Apoptosis of Cells and Cytoplasts Requires ICE/CED-3 Protease Activity*
S. J. Martin (1996)
Effects of polyethyleneimine on endocytosis and lysosome stability.
A. Klemm (1998)
A Novel Non-Viral Vector for DNA Delivery Based on Low Molecular Weight, Branched Polyethylenimine: Effect of Molecular Weight on Transfection Efficiency and Cytotoxicity
D. Fischer (2004)
Spermine oxidation leads to necrosis with plasma membrane phosphatidylserine redistribution in mouse leukemia cells.
M. J. Bonneau (2000)
Tracking the intracellular path of poly(ethylenimine)/DNA complexes for gene delivery.
W. Godbey (1999)
CNS gene transfer mediated by a novel controlled release system based on DNA complexes of degradable polycation PPE-EA: a comparison with polyethylenimine/DNA complexes
Y. Li (2004)
Increased cell surface exposure of phosphatidylserine on propidium iodide negative thymocytes undergoing death by necrosis
P. Waring (1999)
Polymer-based gene delivery with low cytotoxicity by a unique balance of side-chain termini.
D. Putnam (2001)
pDMAEMA is internalised by endocytosis but does not physically disrupt endosomes.
R. Jones (2004)
Semi-automated synthesis and screening of a large library of degradable cationic polymers for gene delivery.
D. Anderson (2003)
Hierarchical self-assembly of F-actin and cationic lipid complexes: stacked three-layer tubule networks.
G. C. Wong (2000)
A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine.
O. Boussif (1995)

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J. Green (2008)
Novel biodegradable gene carriers based on oligomerized polyamines
J. Kloeckner (2006)
Visualizing the localization of transfection complexes during graphene nanoparticle-based transfection.
Filip ten Bruggencate (2013)
Direct reprogramming of mouse fibroblasts into neural cells via Porphyra yezoensis polysaccharide based high efficient gene co-delivery
Qingtong Yu (2017)
Strategies for short hairpin RNA delivery in cancer gene therapy
S. Wang (2009)
Identification of possible cytotoxicity mechanism of polyethylenimine by proteomics analysis
M. Khansarizadeh (2016)
A multifunctional nanocomplex for enhanced cell uptake, endosomal escape and improved cancer therapeutic effect.
Patrick V. Almeida (2017)
Proton-sensing transistor systems for detecting ion leakage from plasma membranes under chemical stimuli.
Y. Imaizumi (2017)
Interleukin-12 plasmid DNA delivery using l-thyroxine-conjugated polyethylenimine nanocarriers
A. Dehshahri (2014)
Polymer-Lipid Nanoparticles for Systemic Delivery of mRNA to the Lungs.
James C. Kaczmarek (2016)
Comb-like oligoaminoethane carriers: change in topology improves pDNA delivery.
Claudia Scholz (2014)
Redox-Sensitive Polymer/SPIO Nanocomplexes for Efficient Magnetofection and MR Imaging of Human Cancer Cells.
Rih-Yang Huang (2015)
Complexity in the therapeutic delivery of RNAi medicines: an analytical challenge
S. Colombo (2014)
Polymeric biomaterials with engineered degradation
Stephanie Deshayes (2013)
Synthesis of an ethyleneimine/tetrahedral DNA nanostructure complex and its potential application as a multi-functional delivery vehicle.
T. Tian (2017)
Ratio of Polycation and Serum Is a Crucial Index for Determining the RNAi Efficiency of Polyplexes.
W. Zhang (2017)
Effective pulmonary delivery of an aerosolized plasmid DNA vaccine via surface acoustic wave nebulization
Anushi Rajapaksa (2014)
Generation of magnetic nonviral gene transfer agents and magnetofection in vitro
O. Mykhaylyk (2007)
Evaluation and comparison of cytotoxicity, genotoxicity, and apoptotic effects of poly-l-lysine/plasmid DNA micro- and nanoparticles
E. Alinejad-Mofrad (2019)
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