Bioreducible liposomes for gene delivery: from the formulation to the mechanism of action.

<h4>Background</h4>A promising strategy to create stimuli-responsive gene delivery systems is to exploit the redox gradient between the oxidizing extracellular milieu and the reducing cytoplasm in order to disassemble DNA/cationic lipid complexes (lipoplexes). On these premises, we previ...

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Autores principales:	Gabriele Candiani, Daniele Pezzoli, Laura Ciani, Roberto Chiesa, Sandra Ristori
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1822ed1315c84a7192657baf8793dfe4
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spelling	oai:doaj.org-article:1822ed1315c84a7192657baf8793dfe42021-11-18T07:03:16ZBioreducible liposomes for gene delivery: from the formulation to the mechanism of action.1932-620310.1371/journal.pone.0013430https://doaj.org/article/1822ed1315c84a7192657baf8793dfe42010-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20976172/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>A promising strategy to create stimuli-responsive gene delivery systems is to exploit the redox gradient between the oxidizing extracellular milieu and the reducing cytoplasm in order to disassemble DNA/cationic lipid complexes (lipoplexes). On these premises, we previously described the synthesis of SS14 redox-sensitive gemini surfactant for gene delivery. Although others have attributed the beneficial effects of intracellular reducing environment to reduced glutathione (GSH), these observations cannot rule out the possible implication of the redox milieu in its whole on transfection efficiency of bioreducible transfectants leaving the determinants of DNA release largely undefined.<h4>Methodology/principal findings</h4>With the aim of addressing this issue, SS14 was here formulated into binary and ternary 100 nm-extruded liposomes and the effects of the helper lipid composition and of the SS14/helper lipids molar ratio on chemical-physical and structural parameters defining transfection effectiveness were investigated. Among all formulations tested, DOPC/DOPE/SS14 at 25:50:25 molar ratio was the most effective in transfection studies owing to the presence of dioleoyl chains and phosphatidylethanolamine head groups in co-lipids. The increase in SS14 content up to 50% along DOPC/DOPE/SS14 liposome series yielded enhanced transfection, up to 2.7-fold higher than that of the benchmark Lipofectamine 2000, without altering cytotoxicity of the corresponding lipoplexes at charge ratio 5. Secondly, we specifically investigated the redox-dependent mechanisms of gene delivery into cells through tailored protocols of transfection in GSH-depleted and repleted vs. increased oxidative stress conditions. Importantly, GSH specifically induced DNA release in batch and in vitro.<h4>Conclusions/significance</h4>The presence of helper lipids carrying unsaturated dioleoyl chains and phosphatidylethanolamine head groups significantly improved transfection efficiencies of DOPC/DOPE/SS14 lipoplexes. Most importantly, this study shows that intracellular GSH levels linearly correlated with transfection efficiency while oxidative stress levels did not, highlighting for the first time the pivotal role of GSH rather than oxidative stress in its whole in transfection of bioreducible vectors.Gabriele CandianiDaniele PezzoliLaura CianiRoberto ChiesaSandra RistoriPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 10, p e13430 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gabriele Candiani Daniele Pezzoli Laura Ciani Roberto Chiesa Sandra Ristori Bioreducible liposomes for gene delivery: from the formulation to the mechanism of action.
description	<h4>Background</h4>A promising strategy to create stimuli-responsive gene delivery systems is to exploit the redox gradient between the oxidizing extracellular milieu and the reducing cytoplasm in order to disassemble DNA/cationic lipid complexes (lipoplexes). On these premises, we previously described the synthesis of SS14 redox-sensitive gemini surfactant for gene delivery. Although others have attributed the beneficial effects of intracellular reducing environment to reduced glutathione (GSH), these observations cannot rule out the possible implication of the redox milieu in its whole on transfection efficiency of bioreducible transfectants leaving the determinants of DNA release largely undefined.<h4>Methodology/principal findings</h4>With the aim of addressing this issue, SS14 was here formulated into binary and ternary 100 nm-extruded liposomes and the effects of the helper lipid composition and of the SS14/helper lipids molar ratio on chemical-physical and structural parameters defining transfection effectiveness were investigated. Among all formulations tested, DOPC/DOPE/SS14 at 25:50:25 molar ratio was the most effective in transfection studies owing to the presence of dioleoyl chains and phosphatidylethanolamine head groups in co-lipids. The increase in SS14 content up to 50% along DOPC/DOPE/SS14 liposome series yielded enhanced transfection, up to 2.7-fold higher than that of the benchmark Lipofectamine 2000, without altering cytotoxicity of the corresponding lipoplexes at charge ratio 5. Secondly, we specifically investigated the redox-dependent mechanisms of gene delivery into cells through tailored protocols of transfection in GSH-depleted and repleted vs. increased oxidative stress conditions. Importantly, GSH specifically induced DNA release in batch and in vitro.<h4>Conclusions/significance</h4>The presence of helper lipids carrying unsaturated dioleoyl chains and phosphatidylethanolamine head groups significantly improved transfection efficiencies of DOPC/DOPE/SS14 lipoplexes. Most importantly, this study shows that intracellular GSH levels linearly correlated with transfection efficiency while oxidative stress levels did not, highlighting for the first time the pivotal role of GSH rather than oxidative stress in its whole in transfection of bioreducible vectors.
format	article
author	Gabriele Candiani Daniele Pezzoli Laura Ciani Roberto Chiesa Sandra Ristori
author_facet	Gabriele Candiani Daniele Pezzoli Laura Ciani Roberto Chiesa Sandra Ristori
author_sort	Gabriele Candiani
title	Bioreducible liposomes for gene delivery: from the formulation to the mechanism of action.
title_short	Bioreducible liposomes for gene delivery: from the formulation to the mechanism of action.
title_full	Bioreducible liposomes for gene delivery: from the formulation to the mechanism of action.
title_fullStr	Bioreducible liposomes for gene delivery: from the formulation to the mechanism of action.
title_full_unstemmed	Bioreducible liposomes for gene delivery: from the formulation to the mechanism of action.
title_sort	bioreducible liposomes for gene delivery: from the formulation to the mechanism of action.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/1822ed1315c84a7192657baf8793dfe4
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Bioreducible liposomes for gene delivery: from the formulation to the mechanism of action.

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