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Opposing influence of intracellular and membrane thiols on the toxicity of reducible polycations

Toxicity of polycations has been recognized since their first use in gene delivery. Bioreducible polycations attract attention because of their improved safety due to selective intracellular degradation by glutathione (GSH). Here we present a systematic study of the toxicity of bioreducible poly(ami... Full description

Journal Title: Biomaterials November 2013, Vol.34(34), pp.8843-8850
Main Author: Wu, Chao
Other Authors: Li, Jing , Zhu, Yu , Chen, Jun , Oupický, David
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0142-9612 ; E-ISSN: 1878-5905 ; DOI: 10.1016/j.biomaterials.2013.07.095
Link: https://www.sciencedirect.com/science/article/pii/S014296121300923X
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recordid: elsevier_sdoi_10_1016_j_biomaterials_2013_07_095
title: Opposing influence of intracellular and membrane thiols on the toxicity of reducible polycations
format: Article
creator:
  • Wu, Chao
  • Li, Jing
  • Zhu, Yu
  • Chen, Jun
  • Oupický, David
subjects:
  • Non-Viral Gene Delivery
  • Polycations
  • Bioreducible Polycations
  • Glutathione
  • Toxicity
  • Medicine
  • Engineering
ispartof: Biomaterials, November 2013, Vol.34(34), pp.8843-8850
description: Toxicity of polycations has been recognized since their first use in gene delivery. Bioreducible polycations attract attention because of their improved safety due to selective intracellular degradation by glutathione (GSH). Here we present a systematic study of the toxicity of bioreducible poly(amido amine)s (PAA). PAA with increasing content of disulfide bonds were synthesized by Michael addition. Toxicity of PAA was evaluated in two cell lines with different innate levels of intracellular GSH. Increasing the content of disulfide bonds decreased the toxicity of PAA, with more significant decrease observed in cells with high GSH. Depleting intracellular GSH by diethyl maleate resulted in increased toxicity of bioreducible PAA. In contrast, increasing the GSH concentrations by growing cells in hypoxic conditions resulted in further decreased toxicity compared with cells grown in normoxic conditions. The presence of exofacial plasma membrane thiols selectively increased toxicity of bioreducible PAA while having no effect on non-degradable controls. These results improve our understanding of the cellular mechanisms of polycation toxicity. They also shed light on the opposing effects of different cellular thiol pools on the toxicity of bioreducible polycations.
language: eng
source:
identifier: ISSN: 0142-9612 ; E-ISSN: 1878-5905 ; DOI: 10.1016/j.biomaterials.2013.07.095
fulltext: fulltext
issn:
  • 0142-9612
  • 01429612
  • 1878-5905
  • 18785905
url: Link


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subjectNon-Viral Gene Delivery ; Polycations ; Bioreducible Polycations ; Glutathione ; Toxicity ; Medicine ; Engineering
descriptionToxicity of polycations has been recognized since their first use in gene delivery. Bioreducible polycations attract attention because of their improved safety due to selective intracellular degradation by glutathione (GSH). Here we present a systematic study of the toxicity of bioreducible poly(amido amine)s (PAA). PAA with increasing content of disulfide bonds were synthesized by Michael addition. Toxicity of PAA was evaluated in two cell lines with different innate levels of intracellular GSH. Increasing the content of disulfide bonds decreased the toxicity of PAA, with more significant decrease observed in cells with high GSH. Depleting intracellular GSH by diethyl maleate resulted in increased toxicity of bioreducible PAA. In contrast, increasing the GSH concentrations by growing cells in hypoxic conditions resulted in further decreased toxicity compared with cells grown in normoxic conditions. The presence of exofacial plasma membrane thiols selectively increased toxicity of bioreducible PAA while having no effect on non-degradable controls. These results improve our understanding of the cellular mechanisms of polycation toxicity. They also shed light on the opposing effects of different cellular thiol pools on the toxicity of bioreducible polycations.
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abstract

Toxicity of polycations has been recognized since their first use in gene delivery. Bioreducible polycations attract attention because of their improved safety due to selective intracellular degradation by glutathione (GSH). Here we present a systematic study of the toxicity of bioreducible poly(amido amine)s (PAA). PAA with increasing content of disulfide bonds were synthesized by Michael addition. Toxicity of PAA was evaluated in two cell lines with different innate levels of intracellular GSH. Increasing the content of disulfide bonds decreased the toxicity of PAA, with more significant decrease observed in cells with high GSH. Depleting intracellular GSH by diethyl maleate resulted in increased toxicity of bioreducible PAA. In contrast, increasing the GSH concentrations by growing cells in hypoxic conditions resulted in further decreased toxicity compared with cells grown in normoxic conditions. The presence of exofacial plasma membrane thiols selectively increased toxicity of bioreducible PAA while having no effect on non-degradable controls. These results improve our understanding of the cellular mechanisms of polycation toxicity. They also shed light on the opposing effects of different cellular thiol pools on the toxicity of bioreducible polycations.

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