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1. Aerosol-Mediated Non-Viral Lung Gene Therapy: The Potential of Aminoglycoside-Based Cationic Liposomes

Author

Tony Le Gall, Mathieu Berchel, Lee Davies, Angélique Mottais, Rosy Ghanem, Alain Fautrel, Deborah Gill, Steve Hyde, Pierre Lehn, Jean-Marie Lehn, Loïc Lemiègre, Thierry Benvegnu, Paul-Alain Jaffrès, Bruno Pitard, and Tristan Montier

Subjects
aminoglycoside-based cationic lipids, cystic fibrosis, lipidic formulations, lung gene therapy, nebulization, structure-activity, Pharmacy and materia medica, RS1-441
Abstract

Aerosol lung gene therapy using non-viral delivery systems represents a credible therapeutic strategy for chronic respiratory diseases, such as cystic fibrosis (CF). Progress in CF clinical setting using the lipidic formulation GL67A has demonstrated the relevance of such a strategy while emphasizing the need for more potent gene transfer agents. In recent years, many novel non-viral gene delivery vehicles were proposed as potential alternatives to GL67 cationic lipid. However, they were usually evaluated using procedures difficult or even impossible to implement in clinical practice. In this study, a clinically-relevant administration protocol via aerosol in murine lungs was used to conduct a comparative study with GL67A. Diverse lipidic compounds were used to prepare a series of formulations inspired by the composition of GL67A. While some of these formulations were ineffective at transfecting murine lungs, others demonstrated modest-to-very-efficient activities and a series of structure-activity relationships were unveiled. Lipidic aminoglycoside derivative-based formulations were found to be at least as efficient as GL67A following aerosol delivery of a luciferase-encoding plasmid DNA. A single aerosol treatment with one such formulation was found to mediate long-term lung transgene expression, exceeding half the animal’s lifetime. This study clearly supports the potential of aminoglycoside-based cationic lipids as potent GL67-alternative scaffolds for further enhanced aerosol non-viral lung gene therapy for diseases such as CF.

Published
2021
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2. Temperature‐Sensitive Amphiphilic Non‐Ionic Triblock Copolymers for Enhanced In Vivo Skeletal Muscle Transfection

Author

Pierre Lehn, Philippe Guégan, Tristan Montier, Jérôme Mathe, Nicolas Illy, Bazoly Rasolonjatovo, Cécile Huin, Patrick Midoux, Bruno Pitard, Véronique Bennevault, Thomas Haudebourg, Tony Le Gall, Hervé Cheradame, Laboratoire Analyse, Modélisation et Matériaux pour la Biologie et l'Environnement (LAMBE - UMR 8587), Université d'Évry-Val-d'Essonne (UEVE)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Institut Parisien de Chimie Moléculaire (IPCM), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Host-Pathogen Interactions in the Regulation of Immune Responses (CRCINA-ÉQUIPE 5), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and HAL-SU, Gestionnaire

Subjects
[CHIM.POLY] Chemical Sciences/Polymers, Phase transition, Polymers and Plastics, poly(2‐methyl‐2‐oxazoline), in vivo transfection, Bioengineering, 02 engineering and technology, Transfection, 010402 general chemistry, 01 natural sciences, Lower critical solution temperature, Biomaterials, Mice, In vivo, LCST, Amphiphile, Materials Chemistry, Copolymer, medicine, Animals, skeletal muscle, Muscle, Skeletal, Lipid bilayer, Chemistry, Skeletal muscle, DNA, 021001 nanoscience & nanotechnology, 0104 chemical sciences, medicine.anatomical_structure, [CHIM.POLY]Chemical Sciences/Polymers, Biophysics, amphiphilic copolymers, Female, 0210 nano-technology, Plasmids, Biotechnology
Abstract

International audience; It is reported that low concentration of amphiphilic triblock copolymers of pMeOx‐b‐pTHF‐b‐pMeOx structure (TBCPs) improves gene expression in skeletal muscle upon intramuscular co‐injection with plasmid DNA. Physicochemical studies carried out to understand the involved mechanism show that a phase transition of TBCPs under their unimer state is induced when the temperature is elevated from 25 to 37 °C, the body temperature. Several lines of evidences suggest that TBCP insertion in a lipid bilayer causes enough lipid bilayer destabilization and even pore formation, a phenomenon heightened during the phase transition of TBCPs. Interestingly, this property allows DNA translocation across the lipid bilayer model. Overall, the results indicate that TBCPs exhibiting a phase transition at the body temperature is promising to favor in vivo pDNA translocation in skeletal muscle cells for gene therapy applications.

Published
2020
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3. Targeting different binding sites in the CFTR structures allows to synergistically potentiate channel activity

Author

Sandra Mirval, Nesrine Baatallah, Jean-Paul Mornon, Julien Alliot, Isabelle Callebaut, Wael Zeinyeh, Arnaud Billet, Brice Hoffmann, Pierre Lehn, Ahmad Elbahnsi, Frédéric Becq, Renaud Zelli, Christophe Simard, Jean-Luc Décout, Romain Haudecoeur, Antoine Fortuné, Benjamin Boucherle, Benoit Chevalier, Alexandre Hinzpeter, Lionel Froux, Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Grenoble Alpes (UGA), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Université de Poitiers-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité (UPCité), HAL-SU, Gestionnaire, UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)

Subjects
Mutant, Modulator, Cystic Fibrosis Transmembrane Conductance Regulator, Quinolones, Aminophenols, 3D structure, Cystic fibrosis, Combinatorial therapies, Ivacaftor, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Drug Discovery, medicine, Humans, Binding site, CFTR, 030304 developmental biology, Pharmacology, Ussing chamber, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Forskolin, Binding Sites, biology, Organic Chemistry, Drug Synergism, General Medicine, Potentiator, medicine.disease, Small molecule, Cystic fibrosis transmembrane conductance regulator, 3. Good health, Cell biology, Molecular Docking Simulation, chemistry, Purines, 030220 oncology & carcinogenesis, Benzamides, Mutation, biology.protein, Halide-sensitive fluorescence, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug, HeLa Cells, Protein Binding
Abstract

International audience; Recent evidence shows that combination of correctors and potentiators, such as the drug ivacaftor (VX-770), can significantly restore the functional expression of mutated Cystic Fibrosis Transmembrane conductance Regulator (CFTR), an anion channel which is mutated in cystic fibrosis (CF). The success of these combinatorial therapies highlights the necessity of identifying a broad panel of specific binding mode modulators, occupying several distinct binding sites at structural level. Here, we identified two small molecules, SBC040 and SBC219, which are two efficient cAMP-independent potentiators, acting at low concentration of forskolin with EC50 close to 1 μM and in a synergic way with the drug VX-770 on several CFTR mutants of classes II and III. Molecular dynamics simulations suggested potential SBC binding sites at the vicinity of ATP-binding sites, distinct from those currently proposed for VX-770, outlining SBC molecules as members of a new family of potentiators.

Published
2020
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4. Combining theoretical and experimental data to decipher CFTR 3D structures and functions

Author

Jean-Paul Mornon, Isabelle Callebaut, Fabio Pietrucci, Brice Hoffmann, Pierre Lehn, Jean-Luc Décout, Ahmad Elbahnsi, Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Génétique moléculaire et génétique épidémiologique, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pharmacochimie moléculaire (DPM ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, 0301 basic medicine, Cryo-electron microscopy, Cystic Fibrosis Transmembrane Conductance Regulator, Closed conformation, Filamin, 03 medical and health sciences, Cellular and Molecular Neuroscience, Protein Domains, Animals, Humans, Amino Acid Sequence, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, ComputingMilieux_MISCELLANEOUS, Pharmacology, biology, Chemistry, Cryoelectron Microscopy, Metadynamics, Experimental data, Cell Biology, Cystic fibrosis transmembrane conductance regulator, Protein Structure, Tertiary, 3. Good health, 030104 developmental biology, biology.protein, Biophysics, Molecular Medicine, Sequence Alignment
Abstract

Cryo-electron microscopy (cryo-EM) has recently provided invaluable experimental data about the full-length cystic fibrosis transmembrane conductance regulator (CFTR) 3D structure. However, this experimental information deals with inactive states of the channel, either in an apo, quiescent conformation, in which nucleotide-binding domains (NBDs) are widely separated or in an ATP-bound, yet closed conformation. Here, we show that 3D structure models of the open and closed forms of the channel, now further supported by metadynamics simulations and by comparison with the cryo-EM data, could be used to gain some insights into critical features of the conformational transition toward active CFTR forms. These critical elements lie within membrane-spanning domains but also within NBD1 and the N-terminal extension, in which conformational plasticity is predicted to occur to help the interaction with filamin, one of the CFTR cellular partners.

Published
2018
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5. Molecular modelling and molecular dynamics of CFTR

Author

Jean-Paul Mornon, Pierre Lehn, Isabelle Callebaut, and Brice Hoffmann

Subjects
0301 basic medicine, Cystic Fibrosis, Protein Conformation, In silico, Cystic Fibrosis Transmembrane Conductance Regulator, ATP-binding cassette transporter, Context (language use), Computational biology, Molecular Dynamics Simulation, Biology, Ligands, Bioinformatics, Cystic fibrosis, 03 medical and health sciences, Cellular and Molecular Neuroscience, medicine, Animals, Humans, Molecular Biology, Pharmacology, Drug discovery, Cell Biology, medicine.disease, Precision medicine, Cystic fibrosis transmembrane conductance regulator, Molecular Docking Simulation, 030104 developmental biology, Drug Design, Mutation, biology.protein, Molecular Medicine, Function (biology)
Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) protein is a member of the ATP-binding cassette (ABC) transporter superfamily that functions as an ATP-gated channel. Considerable progress has been made over the last years in the understanding of the molecular basis of the CFTR functions, as well as dysfunctions causing the common genetic disease cystic fibrosis (CF). This review provides a global overview of the theoretical studies that have been performed so far, especially molecular modelling and molecular dynamics (MD) simulations. A special emphasis is placed on the CFTR-specific evolution of an ABC transporter framework towards a channel function, as well as on the understanding of the effects of disease-causing mutations and their specific modulation. This in silico work should help structure-based drug discovery and design, with a view to develop CFTR-specific pharmacotherapeutic approaches for the treatment of CF in the context of precision medicine.

Published
2016
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6. Polynucleotide transport through lipid membrane in the presence of starburst cyclodextrin-based poly(ethylene glycol)s

Author

Philippe Guégan, Cécile Huin, Tristan Montier, Loïc Auvray, Pierre Lehn, Zahra Eskandani, Fabien Montel, Tony Le Gall, Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Saclay (COmUE), Université de Bretagne Occidentale - UFR Médecine et Sciences de la Santé (UBO UFR MSS), Université de Brest (UBO), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Parisien de Chimie Moléculaire (IPCM), Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Matière et Systèmes Complexes (MSC), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Lipid Bilayers, Polynucleotides, Biophysics, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Polyethylene Glycols, chemistry.chemical_compound, Polymer chemistry, Amphiphile, [CHIM]Chemical Sciences, General Materials Science, Lipid bilayer, chemistry.chemical_classification, Cyclodextrins, Molar mass, Cyclodextrin, Base Sequence, Cell Membrane, Biological Transport, Surfaces and Interfaces, General Chemistry, Polymer, DNA, 021001 nanoscience & nanotechnology, 0104 chemical sciences, Nanopore, [CHIM.POLY]Chemical Sciences/Polymers, chemistry, Polynucleotide, 0210 nano-technology, Ethylene glycol, Biotechnology
Abstract

International audience; Symmetrical cyclodextrin-based 14-arm star polymers with poly(ethylene glycol) PEG branches were synthesized and characterized. Interactions of the star polymers with lipid bilayers were studied by the “black lipid membrane” technique in order to demonstrate the formation of monomolecular artificial channels. The conditions for the insertion are mainly based on dimensions and amphiphilic properties of the star polymers, in particular the molar mass of the water-soluble polymer branches. Translocation of single-strand DNA (ssDNA) through those synthetic nanopores was investigated, and the close dimension between the cross-section of ssDNA and the cyclodextrin cavity led to an energy barrier that slowed down the translocation process.

Published
2018
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7. Important role of phosphoramido linkage in imidazole-based dioleyl helper lipids for liposome stability and primary cell transfection

Author

Thibault Colombani, Paul-Alain Jaffrès, Pierre Lehn, Bruno Pitard, Olivier Lambert, Benoît Chatin, Mathieu Berchel, Laurence Dallet, Mathieu Mével, Pauline Peuziat, Tristan Montier, and Thomas Haudebourg

Subjects
0301 basic medicine, Liposome, Stereochemistry, HEK 293 cells, 02 engineering and technology, Transfection, 021001 nanoscience & nanotechnology, Molecular biology, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, chemistry, Amide, Drug Discovery, Genetics, Molecular Medicine, Imidazole, lipids (amino acids, peptides, and proteins), 0210 nano-technology, Lipid bilayer, Molecular Biology, Linker, Genetics (clinical), DNA
Abstract

BACKGROUND To optimize synthetic gene delivery systems, there is a need to develop more efficient lipid formulations. Most cationic lipid formulations contain 'helper' neutral lipids because of their ability to increase DNA delivery, in particular by improving endosomal escape of DNA molecules via the pH-buffering effect of protonatable groups and/or fusion with the lipid bilayer of endosomes. METHODS We evaluated the influence of the linker structure between the two oleyl chains in the helper lipid on transfection efficiency in cell lines, as well as in primary cells (hepatocytes/cardiomyocytes). We reported the synthesis of two new pH-buffering imidazole helper lipids characterized by a polar headgroup containing one (compound 6) or two (compound 5) imidazole groups and two oleyl chains linked by an amide group. We studied their association with the aminoglycoside lipidic derivative dioleylsuccinylparomomycin (DOSP), which contains two oleyl chains linked to the aminoglycoside polar headgroup via an amide function. We compared the morphology and transfection properties of such binary liposomes of DOSP/5 and DOSP/6 with those of liposomes combining DOSP with another imidazole-based dioleyl helper lipid (MM27) in which a phosphoramido group acts as a linker between the two oleyl chains and imidazole function. RESULTS The phosphoramido linker in the helper lipid induces a major difference in terms of morphology and resistance to decomplexation at physical pH for DOSP/helper lipid complexes. CONCLUSIONS This hybrid dioleyl linker composition of DOSP/MM27 led to higher transfection efficiency in cell lines and in primary cells compared to complexes with homogeneous dioleyl linker.

Published
2016
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8. Synthetic vectors for gene delivery: An overview of their evolution depending on routes of administration

Author

Nawal Belmadi, Catherine Passirani, Pierre Lehn, Tony Le Gall, Tristan Montier, Pascal Loyer, Patrick Midoux, Chantal Pichon, Paul-Alain Jaffrès, Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université européenne de Bretagne - European University of Brittany (UEB), Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Pôle de recheche et d'enseignement supérieur (UNAM), PRES Université Nantes Angers Le Mans (UNAM), Chimie, Electrochimie Moléculaires et Chimie Analytique (CEMCA), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Brest (UBO)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), and EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM)

Subjects
Drug, Biodistribution, Routes of administration, [SDV]Life Sciences [q-bio], media_common.quotation_subject, Genetic Vectors, Cellular barriers, 02 engineering and technology, Computational biology, Pharmacology, Biology, Gene delivery, Applied Microbiology and Biotechnology, Cell Line, Mice, 03 medical and health sciences, Cations, Sense (molecular biology), Animals, Humans, Tissue Distribution, 030304 developmental biology, media_common, 0303 health sciences, Synthetic vectors, Gene Transfer Techniques, Genetic Therapy, General Medicine, Active protein, 021001 nanoscience & nanotechnology, Lipids, 3. Good health, Nucleic acid, Molecular Medicine, Synthetic Biology, 0210 nano-technology, Function (biology), Potential toxicity
Abstract

International audience; Nucleic acid delivery constitutes an emerging therapeutic strategy to cure various human pathologies. This therapy consists of introducing genetic material into the whole body or isolated cells to correct a cellular abnormality or disfunction. As with any drug, the main objective of nucleic acid delivery is to establish optimal balance between efficacy and tolerance. The methods of administration and the vectors used are selected depending on whether the goal of treatment is the production of an active protein; the replacement of a missing or inactive gene; or the combat of acquired diseases, such as cancer or AIDS. In that sense, synthetic vectors represent a valuable solution because they are well characterized, their structure can be fine tuned, and their potential toxicity can be reduced, since toxicity depends on the composition of the formulations. Here we review various synthetic vectors for gene delivery and address the question of their biodistribution as a function of the route of administration. We highlight the modifications to vectors structure and formulations necessary to overcome the major hurdles limiting the effectiveness of nucleic acid therapies

Published
2015
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9. Synthetic Phospholipids for pDNA Delivery and Antibacterial Action

Author

Pierre Lehn, Tony Le Gall, Hélène Couthon-Gourvès, Damien Afonso, Stéphanie S. Le Corre, Mathieu Berchel, Paul-Alain Jaffrès, and Tristan Montier

Subjects
Inorganic Chemistry, Chemistry, Organic Chemistry, Supramolecular chemistry, Organic chemistry, Antibacterial action, Gene delivery, Biochemistry, Combinatorial chemistry
Published
2015
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10. Cationic Lipophosphoramidates Containing a Hydroxylated Polar Headgroup for Improving Gene Delivery

Author

Paul-Alain Jaffrès, Pierre Lehn, Jean-Pierre Haelters, Mathieu Berchel, Tristan Montier, Tony Le Gall, Chimie, Electrochimie Moléculaires et Chimie Analytique (CEMCA), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Département Universitaire de Médecine Générale (DUMG), and Université de Brest (UBO)

Subjects
liposomes, Stereochemistry, Pharmaceutical Science, Gene delivery, Hydroxylation, cationic lipids, 010402 general chemistry, 01 natural sciences, In vivo, Cations, Drug Discovery, Amphiphile, [CHIM]Chemical Sciences, Moiety, Cationic liposome, gene delivery, amphiphiles, Drug Carriers, Liposome, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 010405 organic chemistry, Chemistry, Gene Transfer Techniques, Cationic polymerization, DNA, Transfection, Lipids, 0104 chemical sciences, Quaternary Ammonium Compounds, Molecular Medicine
Abstract

International audience; The structure of the cationic moiety of amphiphiles is a key factor which directly influences their transfection efficacy. Accordingly, in the present work, we have synthesized three new lipophosphoramide-based amphiphilic compounds incorporating a methoxy 5, hydroxyl 6, or dihydroxyl 7 functional group in their cationic part. Gene delivery efficacies of these novel vectors were compared to our benchmark compound, the arsenolipophosphoramidate KLN47, and to its trimethylammonium (TMA) analogue 4. We next studied the characteristics (size, ζ potential) of the nanometric assemblies formed (liposomes and lipid/DNA complexes), and the DNA binding ability of the cationic liposomes was characterized at the physicochemical level. In vitro, all of the cationic lipids evaluated were efficient not only to condense plasmids but also to transfect two types of human airway epithelial cells. Interestingly, in vivo administration to mice (via simple tail vein injection) showed that compound 6 was the most efficient in transfecting the lungs when compared to that of the other cationic lipids studied, including compound KLN47. All of these results suggest that a hydroxyethyldimethylammonium (HE-DMA) polar head could be a valuable alternative to a trimethylarsonium (TMAs) polar head and that they also invite further evaluation of the in vivo potential of compound 6 using more clinically relevant delivery procedures.

Published
2015
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11. Curcumin/poly(2-methyl-2-oxazoline-b-tetrahydrofuran-b-2-methyl-2-oxazoline) formulation: An improved penetration and biological effect of curcumin in F508del-CFTR cell lines

Author

Philippe Hulin, Cécile Huin, Cristine Gonçalves, Philippe Guégan, Tristan Montier, David Gosset, Pierre Lehn, Tony Le Gall, Chantal Pichon, Hervé Cheradame, Steven Nedellec, Bazoly Rasolonjatovo, Jean-Pierre Gomez, Patrick Midoux, William Même, Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Saclay (COmUE), Plateforme MicroPicell [Nantes], Université de Nantes (UN), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Cell Membrane Permeability, Curcumin, Stereochemistry, Drug Compounding, Pharmaceutical Science, Cystic Fibrosis Transmembrane Conductance Regulator, Respiratory Mucosa, Cystic fibrosis, Flow cytometry, law.invention, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Confocal microscopy, law, Amphiphile, medicine, Copolymer, Animals, Humans, CFTR, Furans, Oxazoles, Tetrahydrofuran, Active ingredient, medicine.diagnostic_test, Dose-Response Relationship, Drug, Chemistry, Amphiphilic polymer, General Medicine, 3. Good health, 030104 developmental biology, Membrane, [SDV.SP.PG]Life Sciences [q-bio]/Pharmaceutical sciences/Galenic pharmacology, 030220 oncology & carcinogenesis, Biophysics, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Triblock copolymer, Biotechnology
Abstract

International audience; Neutral amphiphilic triblock ABA copolymers are of great interest to solubilize hydrophobic drugs. We reported that a triblock ABA copolymer consisting of methyl-2-oxazoline (MeOx) and tetrahydrofuran (THF) (MeOx6-THF19-MeOx6) (TBCP2) can solubilize curcumin (Cur) a very hydrophobic molecule exhibiting multiple therapeutic effects but whose insolubility and low stability in water is a major drawback for clinical applications. Here, we provide evidences by flow cytometry and confocal microscopy that Cur penetration in normal and ΔF508-CFTR human airway epithelial cell lines is facilitated by TBCP2. When used on ΔF508-CFTR cell lines, the Cur/TBCP2 formulation promotes the restoration of the expression of the CFTR protein in the plasma membrane. Furthermore, patch-clamp and MQAE fluorescence experiments show that this effect is associated with a correction of a Cl− selective current at the membrane surface of F508del-CFTR cells. The results show the great potential of the neutral amphiphilic triblock copolymer MeOx6-THF19-MeOx6 as carrier for curcumin in a Cystic Fibrosis context. We anticipate that other MeOxn-THFm-MeOxn copolymers could have similar behaviours for other highly insoluble therapeutic drugs or cosmetic active ingredients.

Published
2017
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13. Important role of phosphoramido linkage in imidazole-based dioleyl helper lipids for liposome stability and primary cell transfection

Author

Mathieu, Mével, Thomas, Haudebourg, Thibault, Colombani, Pauline, Peuziat, Laurence, Dallet, Benoît, Chatin, Olivier, Lambert, Mathieu, Berchel, Tristan, Montier, Paul-Alain, Jaffrès, Pierre, Lehn, and Bruno, Pitard

Subjects
Primary Cell Culture, Imidazoles, DNA, Endosomes, Transfection, Lipids, Rats, Myoblasts, Mice, HEK293 Cells, Microscopy, Electron, Transmission, Cations, Liposomes, Hepatocytes, Animals, Humans, Phosphoramides
Abstract

To optimize synthetic gene delivery systems, there is a need to develop more efficient lipid formulations. Most cationic lipid formulations contain 'helper' neutral lipids because of their ability to increase DNA delivery, in particular by improving endosomal escape of DNA molecules via the pH-buffering effect of protonatable groups and/or fusion with the lipid bilayer of endosomes.We evaluated the influence of the linker structure between the two oleyl chains in the helper lipid on transfection efficiency in cell lines, as well as in primary cells (hepatocytes/cardiomyocytes). We reported the synthesis of two new pH-buffering imidazole helper lipids characterized by a polar headgroup containing one (compound 6) or two (compound 5) imidazole groups and two oleyl chains linked by an amide group. We studied their association with the aminoglycoside lipidic derivative dioleylsuccinylparomomycin (DOSP), which contains two oleyl chains linked to the aminoglycoside polar headgroup via an amide function. We compared the morphology and transfection properties of such binary liposomes of DOSP/5 and DOSP/6 with those of liposomes combining DOSP with another imidazole-based dioleyl helper lipid (MM27) in which a phosphoramido group acts as a linker between the two oleyl chains and imidazole function.The phosphoramido linker in the helper lipid induces a major difference in terms of morphology and resistance to decomplexation at physical pH for DOSP/helper lipid complexes.This hybrid dioleyl linker composition of DOSP/MM27 led to higher transfection efficiency in cell lines and in primary cells compared to complexes with homogeneous dioleyl linker.

Published
2015

14. Full-open and closed CFTR channels, with lateral tunnels from the cytoplasm and an alternative position of the F508 region, as revealed by molecular dynamics

Author

Brice Hoffmann, Pierre Lehn, Isabelle Callebaut, Slavica Jonic, Jean-Paul Mornon, Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique (CNRS), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Cytoplasm, Cystic Fibrosis, Molecular model, Stereochemistry, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Mutation, Missense, Cystic Fibrosis Transmembrane Conductance Regulator, Molecular modeling, Molecular Dynamics Simulation, Molecular dynamics, Protein Structure, Secondary, Cellular and Molecular Neuroscience, Protein structure, Animals, Humans, Amino Acid Sequence, Amino Acids, CFTR, Molecular Biology, Peptide sequence, Pharmacology, Binding Sites, Sequence Homology, Amino Acid, biology, Chemistry, Cell Biology, ABC exporters, Cystic fibrosis transmembrane conductance regulator, Protein Structure, Tertiary, Transmembrane domain, Chloride channel, biology.protein, Biophysics, Molecular Medicine, Mutant Proteins
Abstract

In absence of experimental 3D structures, several homology models, based on ABC exporter 3D structures, have provided significant insights into the molecular mechanisms underlying the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride channel whose defects are associated with cystic fibrosis (CF). Until now, these models, however, did not furnished much insights into the continuous way that ions could follow from the cytosol to the extracellular milieu in the open form of the channel. Here, we have built a refined model of CFTR, based on the outward-facing Sav1866 experimental 3D structure and integrating the evolutionary and structural information available today. Molecular dynamics simulations revealed significant conformational changes, resulting in a full-open channel, accessible from the cytosol through lateral tunnels displayed in the long intracellular loops (ICLs). At the same time, the region of nucleotide-binding domain 1 in contact with one of the ICLs and carrying amino acid F508, the deletion of which is the most common CF-causing mutation, was found to adopt an alternative but stable position. Then, in a second step, this first stable full-open conformation evolved toward another stable state, in which only a limited displacement of the upper part of the transmembrane helices leads to a closure of the channel, in a conformation very close to that adopted by the Atm1 ABC exporter, in an inward-facing conformation. These models, supported by experimental data, provide significant new insights into the CFTR structure–function relationships and into the possible impact of CF-causing mutations.

Published
2015
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15. Poly(2-methyl-2-oxazoline)-b-poly(tetrahydrofuran)-b-poly(2-methyl-2-oxazoline) Amphiphilic Triblock Copolymers: Synthesis, Physicochemical Characterizations, and Hydrosolubilizing Properties

Author

Cécile Huin, Bazoly Rasolonjatovo, Pierre Lehn, Philippe Guégan, Véronique Bennevault-Celton, Tristan Montier, William Même, Jean-Pierre Gomez, Cristine Gonçalves, Hervé Cheradame, Patrick Midoux, Tony Le Gall, Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), INSERM U613, IFR148, IFR148 ScInBioS, Université de Brest (UBO)-Université de Brest (UBO), Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE - UMR 8587), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), and Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
Curcumin, Polymers and Plastics, Polymers, [SDV]Life Sciences [q-bio], Bioengineering, Micelle, Ring-opening polymerization, Biomaterials, Surface-Active Agents, Amphiphile, Polymer chemistry, Materials Chemistry, Copolymer, Polyamines, Humans, Butylene Glycols, Micelles, Drug Carriers, Aggregation number, Chemistry, Cationic polymerization, Poloxamer, HEK293 Cells, Solubility, Critical micelle concentration, Hydrophobic and Hydrophilic Interactions, HeLa Cells
Abstract

International audience; Block copolymers assembled into micelles have gained a lot of attention to improve drug delivery. The recent drawbacks of the poly(ethylene oxide) blocks (PEO) contained in amphiphilic pluronics derivatives made of a central poly(propylene oxide) block surrounded by two PEO blocks were recently revealed, opening the way to the design of new amphiphilic block copolymers able to self-assemble in water and to entrap molecules of interest. Here, a family of p(methyloxazoline)-b-p(tetrahydrofuran)-b-p(methyloxazoline) triblock copolymers (called TBCP) is synthesized using cationic ring opening polymerization. Studies of micelle formation using dynamic light scattering, isothermal titration calorimetry (ITC), NMR diffusion-ordered spectroscopy (DOSY), and fluorescence experiments lead us to draw a relationship between copolymer structure and the physicochemical properties of the block copolymers (critical micellar concentration (CMC), Nagg, core diameter, shell thickness, etc.). The packing parameter of the block copolymers indicates the formation of a core–corona structure. Hydrosolubilizing properties of TBCPs were exemplified with curcumin selected as a highly insoluble drug model. Curcumin, a natural polyphenolic compound, has shown a large spectrum of biological and pharmacological activity, including anti-inflammatory, antimicrobial, antioxidant, and anticarcinogenic activities. An optimized formulation process reveals that the aggregation number is the parameter affecting drug encapsulation. Patch clamp experiments carried out to study the interaction of TBCP with the cell membrane demonstrate their permeation property suitable to promote the cellular internalization of curcumin.

Published
2015
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16. 167. Development of Non-Viral Gene Delivery Systems Deliverable Via Aerosol and Displaying Broad-Spectrum Antibacterial Activity for Cystic Fibrosis Gene Therapy

Author

Angélique Mottais, Tony Le Gall, Paul-Alain Jaffrès, Mathieu Berchel, Tristan Montier, and Pierre Lehn

Subjects
Pharmacology, biology, Pseudomonas aeruginosa, fungi, food and beverages, Transfection, Gene delivery, medicine.disease_cause, biology.organism_classification, medicine.disease, Cystic fibrosis, Microbiology, Staphylococcus aureus, Drug Discovery, medicine, Genetics, Molecular Medicine, Antibacterial activity, Molecular Biology, Bacteria, Gram
Abstract

In cystic fibrosis (CF) patients, bronchopulmonar infections are due to various micro-organisms including Gram(+) (e.g. Staphylococcus aureus) and Gram(-) (e.g. Pseudomonas aeruginosa) bacteria. These can alter CF gene transfer, especially by impairing the DNA to be delivered and the epithelial cells to be transfected. Gene delivery vectors can show some antibacterial activity, an additive property that could be useful for transfecting cells in spite of the presence of bacteria. To date, most of the vectors that we have evaluated can demonstrate strong antibacterial activity against Gram(+) bacteria but little or no against Gram(-) bacteria.

Published
2015
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