Interaction of dequalinium chloride with phosphatidylcholine bilayers: A biophysical study with consequences on the development of lipid-based mitochondrial nanomedicines

Félix Sauvage; François Xavier Legrand; Michel Roux; Ivan Rajkovic; Thomas M. Weiss; Zoltán Varga; Luc Augis; Guillaume Nugue; Jean Claude Debouzy; Juliette Vergnaud-Gauduchon; Gillian Barratt

doi:10.1016/j.jcis.2018.11.059

Interaction of dequalinium chloride with phosphatidylcholine bilayers: A biophysical study with consequences on the development of lipid-based mitochondrial nanomedicines

Félix Sauvage, François Xavier Legrand, Michel Roux, Ivan Rajkovic, Thomas M. Weiss, Zoltán Varga, Luc Augis, Guillaume Nugue, Jean Claude Debouzy, Juliette Vergnaud-Gauduchon, Gillian Barratt

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

Dequalinium (DQ) has been proposed as a mitochondrial targeting ligand for nanomedicines, including liposomes, given the implication of these organelles in many diseases. This original study focuses on the interactions of DQ with phosphatidylcholine bilayers during the formation of liposomes. Firstly, PEGylated liposomes suitable for drug delivery were studied and were found to be more stable when made in water than in phosphate-buffered saline, emphasizing the role of electrostatic interactions between positive charges on DQ and the polar head groups of the lipids. To gain more information, differential scanning calorimetry, small- and wide-angle X-ray scattering and diffraction, ³¹P and ²H NMR spectroscopy and freeze-fracture electron microscopy were performed on dimyristoylphosphatidylcholine (DMPC) model membranes in the presence of DQ. This molecule was shown to be located at the level of polar head groups and to induce electrostatic repulsions between adjacent lipid bilayers leading to membrane budding in water. These findings indicate that DQ is not completely inert towards lipid membranes and therefore is not an ideal candidate for encapsulation in liposomes. Overall, our work stresses the necessity for thorough physico-chemical characterization to better understand the mechanisms underlying the development of nanomedicines.

Original language	English (US)
Pages (from-to)	704-715
Number of pages	12
Journal	Journal of Colloid And Interface Science
Volume	537
DOIs	https://doi.org/10.1016/j.jcis.2018.11.059
State	Published - Mar 1 2019
Externally published	Yes

Bibliographical note

Funding Information:
Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. Félix Sauvage received a Ph.D. grant from the MESR, France. The authors thank Dr Georg Pabst (University of Graz, Graz, Austria) for providing GAP code to analyze SAXS data, Dr Benjamin Abecassis (LPS, UMR CNRS 8502, France) for his help in acquiring the preliminary SWAXS profiles, Frédéric Bourbon (IRBA) for the acquisition of ESR spectra, Teréz Kiss (RCNS, HAS) for FF-TEM investigations, Dr Sylviane Lesieur (IGPS, UMR CNRS 8612, France) for her advice about the determination of pKa, Pr Bernard Masereel (University of Namur, Belgium) for his attempt to determine the pKa of DQ, Dr Claudie Bourgaux (IGPS, UMR CNRS 8612, France) for fruitful discussions.

Funding Information:
Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory , is supported by the U.S. Department of Energy , Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515 . The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research , and by the National Institutes of Health , National Institute of General Medical Sciences (including P41GM103393 ). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH . Félix Sauvage received a Ph.D. grant from the MESR, France. The authors thank Dr Georg Pabst (University of Graz, Graz, Austria) for providing GAP code to analyze SAXS data, Dr Benjamin Abecassis (LPS, UMR CNRS 8502, France) for his help in acquiring the preliminary SWAXS profiles, Frédéric Bourbon (IRBA) for the acquisition of ESR spectra, Teréz Kiss (RCNS, HAS) for FF-TEM investigations, Dr Sylviane Lesieur (IGPS, UMR CNRS 8612, France) for her advice about the determination of pKa, Pr Bernard Masereel (University of Namur, Belgium) for his attempt to determine the pKa of DQ, Dr Claudie Bourgaux (IGPS, UMR CNRS 8612, France) for fruitful discussions.

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

Bilayers
Calorimetry
Dequalinium
Drug delivery
Liposomes
Mitochondria
NMR spectroscopy
X-ray scattering

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10.1016/j.jcis.2018.11.059

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Sauvage, F., Legrand, F. X., Roux, M., Rajkovic, I., Weiss, T. M., Varga, Z., Augis, L., Nugue, G., Debouzy, J. C., Vergnaud-Gauduchon, J., & Barratt, G. (2019). Interaction of dequalinium chloride with phosphatidylcholine bilayers: A biophysical study with consequences on the development of lipid-based mitochondrial nanomedicines. Journal of Colloid And Interface Science, 537, 704-715. https://doi.org/10.1016/j.jcis.2018.11.059

Interaction of dequalinium chloride with phosphatidylcholine bilayers: A biophysical study with consequences on the development of lipid-based mitochondrial nanomedicines. / Sauvage, Félix; Legrand, François Xavier; Roux, Michel et al.
In: Journal of Colloid And Interface Science, Vol. 537, 01.03.2019, p. 704-715.

Research output: Contribution to journal › Article › peer-review

Sauvage, F, Legrand, FX, Roux, M, Rajkovic, I, Weiss, TM, Varga, Z, Augis, L, Nugue, G, Debouzy, JC, Vergnaud-Gauduchon, J & Barratt, G 2019, 'Interaction of dequalinium chloride with phosphatidylcholine bilayers: A biophysical study with consequences on the development of lipid-based mitochondrial nanomedicines', Journal of Colloid And Interface Science, vol. 537, pp. 704-715. https://doi.org/10.1016/j.jcis.2018.11.059

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title = "Interaction of dequalinium chloride with phosphatidylcholine bilayers: A biophysical study with consequences on the development of lipid-based mitochondrial nanomedicines",

abstract = "Dequalinium (DQ) has been proposed as a mitochondrial targeting ligand for nanomedicines, including liposomes, given the implication of these organelles in many diseases. This original study focuses on the interactions of DQ with phosphatidylcholine bilayers during the formation of liposomes. Firstly, PEGylated liposomes suitable for drug delivery were studied and were found to be more stable when made in water than in phosphate-buffered saline, emphasizing the role of electrostatic interactions between positive charges on DQ and the polar head groups of the lipids. To gain more information, differential scanning calorimetry, small- and wide-angle X-ray scattering and diffraction, 31P and 2H NMR spectroscopy and freeze-fracture electron microscopy were performed on dimyristoylphosphatidylcholine (DMPC) model membranes in the presence of DQ. This molecule was shown to be located at the level of polar head groups and to induce electrostatic repulsions between adjacent lipid bilayers leading to membrane budding in water. These findings indicate that DQ is not completely inert towards lipid membranes and therefore is not an ideal candidate for encapsulation in liposomes. Overall, our work stresses the necessity for thorough physico-chemical characterization to better understand the mechanisms underlying the development of nanomedicines.",

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author = "F{\'e}lix Sauvage and Legrand, {Fran{\c c}ois Xavier} and Michel Roux and Ivan Rajkovic and Weiss, {Thomas M.} and Zolt{\'a}n Varga and Luc Augis and Guillaume Nugue and Debouzy, {Jean Claude} and Juliette Vergnaud-Gauduchon and Gillian Barratt",

note = "Funding Information: Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. F{\'e}lix Sauvage received a Ph.D. grant from the MESR, France. The authors thank Dr Georg Pabst (University of Graz, Graz, Austria) for providing GAP code to analyze SAXS data, Dr Benjamin Abecassis (LPS, UMR CNRS 8502, France) for his help in acquiring the preliminary SWAXS profiles, Fr{\'e}d{\'e}ric Bourbon (IRBA) for the acquisition of ESR spectra, Ter{\'e}z Kiss (RCNS, HAS) for FF-TEM investigations, Dr Sylviane Lesieur (IGPS, UMR CNRS 8612, France) for her advice about the determination of pKa, Pr Bernard Masereel (University of Namur, Belgium) for his attempt to determine the pKa of DQ, Dr Claudie Bourgaux (IGPS, UMR CNRS 8612, France) for fruitful discussions. Funding Information: Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory , is supported by the U.S. Department of Energy , Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515 . The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research , and by the National Institutes of Health , National Institute of General Medical Sciences (including P41GM103393 ). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH . F{\'e}lix Sauvage received a Ph.D. grant from the MESR, France. The authors thank Dr Georg Pabst (University of Graz, Graz, Austria) for providing GAP code to analyze SAXS data, Dr Benjamin Abecassis (LPS, UMR CNRS 8502, France) for his help in acquiring the preliminary SWAXS profiles, Fr{\'e}d{\'e}ric Bourbon (IRBA) for the acquisition of ESR spectra, Ter{\'e}z Kiss (RCNS, HAS) for FF-TEM investigations, Dr Sylviane Lesieur (IGPS, UMR CNRS 8612, France) for her advice about the determination of pKa, Pr Bernard Masereel (University of Namur, Belgium) for his attempt to determine the pKa of DQ, Dr Claudie Bourgaux (IGPS, UMR CNRS 8612, France) for fruitful discussions. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

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doi = "10.1016/j.jcis.2018.11.059",

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AU - Legrand, François Xavier

AU - Roux, Michel

AU - Rajkovic, Ivan

AU - Weiss, Thomas M.

AU - Varga, Zoltán

AU - Augis, Luc

AU - Nugue, Guillaume

AU - Debouzy, Jean Claude

AU - Vergnaud-Gauduchon, Juliette

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N1 - Funding Information: Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. Félix Sauvage received a Ph.D. grant from the MESR, France. The authors thank Dr Georg Pabst (University of Graz, Graz, Austria) for providing GAP code to analyze SAXS data, Dr Benjamin Abecassis (LPS, UMR CNRS 8502, France) for his help in acquiring the preliminary SWAXS profiles, Frédéric Bourbon (IRBA) for the acquisition of ESR spectra, Teréz Kiss (RCNS, HAS) for FF-TEM investigations, Dr Sylviane Lesieur (IGPS, UMR CNRS 8612, France) for her advice about the determination of pKa, Pr Bernard Masereel (University of Namur, Belgium) for his attempt to determine the pKa of DQ, Dr Claudie Bourgaux (IGPS, UMR CNRS 8612, France) for fruitful discussions. Funding Information: Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory , is supported by the U.S. Department of Energy , Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515 . The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research , and by the National Institutes of Health , National Institute of General Medical Sciences (including P41GM103393 ). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH . Félix Sauvage received a Ph.D. grant from the MESR, France. The authors thank Dr Georg Pabst (University of Graz, Graz, Austria) for providing GAP code to analyze SAXS data, Dr Benjamin Abecassis (LPS, UMR CNRS 8502, France) for his help in acquiring the preliminary SWAXS profiles, Frédéric Bourbon (IRBA) for the acquisition of ESR spectra, Teréz Kiss (RCNS, HAS) for FF-TEM investigations, Dr Sylviane Lesieur (IGPS, UMR CNRS 8612, France) for her advice about the determination of pKa, Pr Bernard Masereel (University of Namur, Belgium) for his attempt to determine the pKa of DQ, Dr Claudie Bourgaux (IGPS, UMR CNRS 8612, France) for fruitful discussions. Publisher Copyright: © 2018 Elsevier Inc.

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N2 - Dequalinium (DQ) has been proposed as a mitochondrial targeting ligand for nanomedicines, including liposomes, given the implication of these organelles in many diseases. This original study focuses on the interactions of DQ with phosphatidylcholine bilayers during the formation of liposomes. Firstly, PEGylated liposomes suitable for drug delivery were studied and were found to be more stable when made in water than in phosphate-buffered saline, emphasizing the role of electrostatic interactions between positive charges on DQ and the polar head groups of the lipids. To gain more information, differential scanning calorimetry, small- and wide-angle X-ray scattering and diffraction, 31P and 2H NMR spectroscopy and freeze-fracture electron microscopy were performed on dimyristoylphosphatidylcholine (DMPC) model membranes in the presence of DQ. This molecule was shown to be located at the level of polar head groups and to induce electrostatic repulsions between adjacent lipid bilayers leading to membrane budding in water. These findings indicate that DQ is not completely inert towards lipid membranes and therefore is not an ideal candidate for encapsulation in liposomes. Overall, our work stresses the necessity for thorough physico-chemical characterization to better understand the mechanisms underlying the development of nanomedicines.

AB - Dequalinium (DQ) has been proposed as a mitochondrial targeting ligand for nanomedicines, including liposomes, given the implication of these organelles in many diseases. This original study focuses on the interactions of DQ with phosphatidylcholine bilayers during the formation of liposomes. Firstly, PEGylated liposomes suitable for drug delivery were studied and were found to be more stable when made in water than in phosphate-buffered saline, emphasizing the role of electrostatic interactions between positive charges on DQ and the polar head groups of the lipids. To gain more information, differential scanning calorimetry, small- and wide-angle X-ray scattering and diffraction, 31P and 2H NMR spectroscopy and freeze-fracture electron microscopy were performed on dimyristoylphosphatidylcholine (DMPC) model membranes in the presence of DQ. This molecule was shown to be located at the level of polar head groups and to induce electrostatic repulsions between adjacent lipid bilayers leading to membrane budding in water. These findings indicate that DQ is not completely inert towards lipid membranes and therefore is not an ideal candidate for encapsulation in liposomes. Overall, our work stresses the necessity for thorough physico-chemical characterization to better understand the mechanisms underlying the development of nanomedicines.

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KW - Liposomes

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Interaction of dequalinium chloride with phosphatidylcholine bilayers: A biophysical study with consequences on the development of lipid-based mitochondrial nanomedicines

Abstract

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Keywords

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