{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T15:40:10Z","timestamp":1790696410777,"version":"4.1.0"},"reference-count":75,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T00:00:00Z","timestamp":1640217600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007393","name":"French Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["project n\u00b015628AFM"],"award-info":[{"award-number":["project n\u00b015628AFM"]}],"id":[{"id":"10.13039\/100007393","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>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\u2019s 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.<\/jats:p>","DOI":"10.3390\/pharmaceutics14010025","type":"journal-article","created":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T21:40:21Z","timestamp":1640295621000},"page":"25","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Aerosol-Mediated Non-Viral Lung Gene Therapy: The Potential of Aminoglycoside-Based Cationic Liposomes"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5922-5683","authenticated-orcid":false,"given":"Tony","family":"Le Gall","sequence":"first","affiliation":[{"name":"Univ Brest, INSERM, EFS, UMR 1078, GGB-GTCA, F-29200 Brest, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Berchel","sequence":"additional","affiliation":[{"name":"Univ Brest, CNRS, CEMCA UMR 6521, 6 Avenue Victor Le Gorgeu, 29238 Brest, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee","family":"Davies","sequence":"additional","affiliation":[{"name":"Gene Medicine Group, Radcliffe Department of Medicine (Clinical Laboratory Sciences), John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3343-8872","authenticated-orcid":false,"given":"Ang\u00e9lique","family":"Mottais","sequence":"additional","affiliation":[{"name":"Univ Brest, INSERM, EFS, UMR 1078, GGB-GTCA, F-29200 Brest, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3336-6629","authenticated-orcid":false,"given":"Rosy","family":"Ghanem","sequence":"additional","affiliation":[{"name":"Univ Brest, INSERM, EFS, UMR 1078, GGB-GTCA, F-29200 Brest, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Fautrel","sequence":"additional","affiliation":[{"name":"Univ Rennes, INSERM, CNRS, UMS Biosit, France-BioImaging, Core Facility H2P2, F-35000 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Gill","sequence":"additional","affiliation":[{"name":"Gene Medicine Group, Radcliffe Department of Medicine (Clinical Laboratory Sciences), John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Hyde","sequence":"additional","affiliation":[{"name":"Gene Medicine Group, Radcliffe Department of Medicine (Clinical Laboratory Sciences), John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Lehn","sequence":"additional","affiliation":[{"name":"Univ Brest, INSERM, EFS, UMR 1078, GGB-GTCA, F-29200 Brest, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8981-4593","authenticated-orcid":false,"given":"Jean-Marie","family":"Lehn","sequence":"additional","affiliation":[{"name":"Laboratoire de Chimie des Interactions Mol\u00e9culaires, Coll\u00e8ge de France, Place Marcelin Berthelot, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6622-171X","authenticated-orcid":false,"given":"Lo\u00efc","family":"Lemi\u00e8gre","sequence":"additional","affiliation":[{"name":"Univ Rennes, Ecole Nationale Sup\u00e9rieure de Chimie de Rennes, CNRS, ISCR-UMR 6226, 11 all\u00e9e de Beaulieu, CS 50837, CEDEX 7, 35708 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1613-9990","authenticated-orcid":false,"given":"Thierry","family":"Benvegnu","sequence":"additional","affiliation":[{"name":"Univ Rennes, Ecole Nationale Sup\u00e9rieure de Chimie de Rennes, CNRS, ISCR-UMR 6226, 11 all\u00e9e de Beaulieu, CS 50837, CEDEX 7, 35708 Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul-Alain","family":"Jaffr\u00e8s","sequence":"additional","affiliation":[{"name":"Univ Brest, CNRS, CEMCA UMR 6521, 6 Avenue Victor Le Gorgeu, 29238 Brest, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Pitard","sequence":"additional","affiliation":[{"name":"Univ Nantes, CNRS ERL6001, INSERM 1232, CRCINA, F-44000 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0452-6395","authenticated-orcid":false,"given":"Tristan","family":"Montier","sequence":"additional","affiliation":[{"name":"Univ Brest, INSERM, EFS, UMR 1078, GGB-GTCA, F-29200 Brest, France"},{"name":"CHRU de Brest, Service de G\u00e9n\u00e9tique M\u00e9dicale et de Biologie de la Reproduction, Centre de R\u00e9f\u00e9rence des Maladies Rares \u201cMaladies Neuromusculaires\u201d, F-29200 Brest, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nrg3849","article-title":"Cystic Fibrosis Genetics: From Molecular Understanding to Clinical Application","volume":"16","author":"Cutting","year":"2015","journal-title":"Nat. Rev. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1164\/rccm.201910-1943SO","article-title":"Cystic Fibrosis: Emergence of Highly Effective Targeted Therapeutics and Potential Clinical Implications","volume":"201","author":"Mall","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1089\/hum.2020.142","article-title":"Gene Therapy for Respiratory Diseases: Progress and a Changing Context","volume":"31","author":"Alton","year":"2020","journal-title":"Hum. Gene Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/S2213-2600(15)00245-3","article-title":"Repeated Nebulisation of Non-Viral CFTR Gene Therapy in Patients with Cystic Fibrosis: A Randomised, Double-Blind, Placebo-Controlled, Phase 2b Trial","volume":"3","author":"Alton","year":"2015","journal-title":"Lancet Respir. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1136\/thoraxjnl-2016-208406","article-title":"Preparation for a First-in-Man Lentivirus Trial in Patients with Cystic Fibrosis","volume":"72","author":"Alton","year":"2017","journal-title":"Thorax"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1089\/humc.2014.019","article-title":"Aerosol Delivery of DNA\/Liposomes to the Lung for Cystic Fibrosis Gene Therapy","volume":"25","author":"Davies","year":"2014","journal-title":"Hum. Gene Ther. Clin. Dev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"R52","DOI":"10.1093\/hmg\/ddt372","article-title":"Moving Forward: Cystic Fibrosis Gene Therapy","volume":"22","author":"Griesenbach","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.ijpharm.2017.11.022","article-title":"Antibacterial Effect and DNA Delivery Using a Combination of an Arsonium-Containing Lipophosphoramide with an N-Heterocyclic Carbene-Silver Complex-Potential Benefits for Cystic Fibrosis Lung Gene Therapy","volume":"536","author":"Mottais","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"118500","DOI":"10.1016\/j.ijpharm.2019.118500","article-title":"Antibacterial and Transfection Activities of Nebulized Formulations Incorporating Long N-Alkyl Chain Silver N-Heterocyclic Carbene Complexes","volume":"567","author":"Mottais","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1089\/hum.1996.7.14-1701","article-title":"Detailed Analysis of Structures and Formulations of Cationic Lipids for Efficient Gene Transfer to the Lung","volume":"7","author":"Lee","year":"1996","journal-title":"Hum. Gene Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/sj.gt.3301663","article-title":"Pegylated GL67 Lipoplexes Retain Their Gene Transfection Activity after Exposure to Components of CF Mucus","volume":"9","author":"Sanders","year":"2002","journal-title":"Gene Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1038\/gt.2011.55","article-title":"Pre-Clinical Evaluation of Three Non-Viral Gene Transfer Agents for Cystic Fibrosis after Aerosol Delivery to the Ovine Lung","volume":"18","author":"McLachlan","year":"2011","journal-title":"Gene Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10267","DOI":"10.1016\/j.biomaterials.2013.09.023","article-title":"The Safety Profile of a Cationic Lipid-Mediated Cystic Fibrosis Gene Transfer Agent Following Repeated Monthly Aerosol Administration to Sheep","volume":"34","author":"Alton","year":"2013","journal-title":"Biomaterials"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/gt.2013.61","article-title":"Toxicology Study Assessing Efficacy and Safety of Repeated Administration of Lipid\/DNA Complexes to Mouse Lung","volume":"21","author":"Alton","year":"2014","journal-title":"Gene Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1136\/thoraxjnl-2013-203309","article-title":"A Randomised, Double-Blind, Placebo-Controlled Phase IIB Clinical Trial of Repeated Application of Gene Therapy in Patients with Cystic Fibrosis","volume":"68","author":"Alton","year":"2013","journal-title":"Thorax"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1136\/thoraxjnl-2014-205835","article-title":"Delivery of Genes into the CF Airway","volume":"69","author":"Gill","year":"2014","journal-title":"Thorax"},{"key":"ref_17","first-page":"3124","article-title":"Novel Neutral Imidazole-Lipophosphoramides for Transfection Assays","volume":"27","author":"Neveu","year":"2008","journal-title":"Chem. Comm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1002\/adhm.201200478","article-title":"Arsonium-Containing Lipophosphoramides, Poly-Functional Nano-Carriers for Simultaneous Antibacterial Action and Eukaryotic Cell Transfection","volume":"2","author":"Berchel","year":"2013","journal-title":"Adv. Healthc. Mater."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1039\/C3OB42270D","article-title":"Cationic Lipophosphoramidates with Two Different Lipid Chains: Synthesis and Evaluation as Gene Carriers","volume":"12","author":"Berchel","year":"2014","journal-title":"Org. Biomol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1021\/bc050097k","article-title":"Cationic Lipophosphoramidates and Lipophosphoguanidines Are Very Efficient for in Vivo DNA Delivery","volume":"16","author":"Picquet","year":"2005","journal-title":"Bioconjug. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1021\/jm900897a","article-title":"A Novel Cationic Lipophosphoramide with Diunsaturated Lipid Chains: Synthesis, Physicochemical Properties, and Transfection Activities","volume":"53","author":"Loizeau","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6240","DOI":"10.1016\/j.biomaterials.2012.05.014","article-title":"The Gene Transfection Properties of a Lipophosphoramidate Derivative with Two Phytanyl Chains","volume":"33","author":"Lindberg","year":"2012","journal-title":"Biomaterials"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2973","DOI":"10.1021\/mp4006276","article-title":"Effects of a Novel Archaeal Tetraether-Based Colipid on the in Vivo Gene Transfer Activity of Two Cationic Amphiphiles","volume":"11","author":"Barbeau","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1902","DOI":"10.1021\/mp500807k","article-title":"Cationic Lipophosphoramidates Containing a Hydroxylated Polar Headgroup for Improving Gene Delivery","volume":"12","author":"Berchel","year":"2015","journal-title":"Mol. Pharm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biomaterials.2015.04.024","article-title":"Efficient in Vivo Transfection and Safety Profile of a CpG-Free and Codon Optimized Luciferase Plasmid Using a Cationic Lipophosphoramidate in a Multiple Intravenous Administration Procedure","volume":"59","author":"Lindberg","year":"2015","journal-title":"Biomaterials"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1165\/rcmb.2009-0075OC","article-title":"Limitations of the Murine Nose in the Development of Nonviral Airway Gene Transfer","volume":"43","author":"Griesenbach","year":"2010","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.ijpharm.2013.11.005","article-title":"Lipopolyplexes Comprising Imidazole\/Imidazolium Lipophosphoramidate, Histidinylated Polyethyleneimine and SiRNA as Efficient Formulation for SiRNA Transfection","volume":"460","author":"Berchel","year":"2014","journal-title":"Int. J. Pharm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"16534","DOI":"10.1073\/pnas.0707431104","article-title":"Self-Assembled Lamellar Complexes of SiRNA with Lipidic Aminoglycoside Derivatives Promote Efficient SiRNA Delivery and Interference","volume":"104","author":"Desigaux","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.jconrel.2011.12.019","article-title":"Paromomycin and Neomycin B Derived Cationic Lipids: Synthesis and Transfection Studies","volume":"158","author":"Sainlos","year":"2012","journal-title":"J. Control Release"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.omtn.2018.11.002","article-title":"Proximity Ligation Assays for In Situ Detection of Innate Immune Activation: Focus on In Vitro-Transcribed MRNA","volume":"14","author":"Blanchard","year":"2019","journal-title":"Mol. Ther. Nucleic. Acids"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.biomaterials.2018.01.010","article-title":"Unifying in Vitro and in Vivo IVT MRNA Expression Discrepancies in Skeletal Muscle via Mechanotransduction","volume":"159","author":"Bhosle","year":"2018","journal-title":"Biomaterials"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/s41551-019-0378-3","article-title":"Visualization of Early Events in MRNA Vaccine Delivery in Non-Human Primates via PET-CT and near-Infrared Imaging","volume":"3","author":"Lindsay","year":"2019","journal-title":"Nat. Biomed. Eng."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3046","DOI":"10.1021\/acs.jmedchem.5b01679","article-title":"Design of Ionizable Lipids to Overcome the Limiting Step of Endosomal Escape: Application in the Intracellular Delivery of MRNA, DNA, and SiRNA","volume":"59","author":"Habrant","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_34","first-page":"2054","article-title":"Archaeosomes Based on Synthetic Tetraether-like Lipids as Novel Versatile Gene Delivery Systems","volume":"20","author":"Montier","year":"2007","journal-title":"Chem. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.ijpharm.2017.03.080","article-title":"Efficient Transfection of Xenobiotic Responsive Element-Biosensor Plasmid Using Diether Lipid and Phosphatidylcholine Liposomes in Differentiated HepaRG Cells","volume":"524","author":"Demazeau","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/nbt1399","article-title":"CpG-Free Plasmids Confer Reduced Inflammation and Sustained Pulmonary Gene Expression","volume":"26","author":"Hyde","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"21759","DOI":"10.1074\/jbc.273.34.21759","article-title":"Membrane Trafficking of the Cystic Fibrosis Gene Product, Cystic Fibrosis Transmembrane Conductance Regulator, Tagged with Green Fluorescent Protein in Madin-Darby Canine Kidney Cells","volume":"273","author":"Moyer","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1002\/jgm.1472","article-title":"The ARRIVE Guidelines, a Welcome Improvement to Standards for Reporting Animal Research","volume":"12","author":"Danos","year":"2010","journal-title":"J. Gene Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1126\/science.257.5073.1083","article-title":"An Animal Model for Cystic Fibrosis Made by Gene Targeting","volume":"257","author":"Snouwaert","year":"1992","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5616","DOI":"10.1021\/bi9602019","article-title":"Mechanism of DNA Release from Cationic Liposome\/DNA Complexes Used in Cell Transfection","volume":"35","author":"Xu","year":"1996","journal-title":"Biochemistry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2096","DOI":"10.1016\/S0006-3495(02)73970-2","article-title":"Phase Behavior of Cationic Amphiphiles and Their Mixtures with Helper Lipid Influences Lipoplex Shape, DNA Translocation, and Transfection Efficiency","volume":"83","author":"Zuhorn","year":"2002","journal-title":"Biophys. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1126\/science.281.5373.78","article-title":"An Inverted Hexagonal Phase of Cationic Liposome-DNA Complexes Related to DNA Release and Delivery","volume":"281","author":"Koltover","year":"1998","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/BF01200214","article-title":"Cholesterol Enhances Cationic Liposome-Mediated DNA Transfection of Human Respiratory Epithelial Cells","volume":"15","author":"Bennett","year":"1995","journal-title":"Biosci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.biomaterials.2014.12.051","article-title":"Evaluation of Tetrafunctional Block Copolymers as Synthetic Vectors for Lung Gene Transfer","volume":"45","author":"Hervouet","year":"2015","journal-title":"Biomaterials"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.omtn.2019.02.016","article-title":"Tetrafunctional Block Copolymers Promote Lung Gene Transfer in Newborn Piglets","volume":"16","author":"Caballero","year":"2019","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.biomaterials.2015.02.017","article-title":"Efficient in Vitro and in Vivo Pulmonary Delivery of Nucleic Acid by Carbon Dot-Based Nanocarriers","volume":"51","author":"Pierrat","year":"2015","journal-title":"Biomaterials"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"8720","DOI":"10.1073\/pnas.1502281112","article-title":"Highly Compacted Biodegradable DNA Nanoparticles Capable of Overcoming the Mucus Barrier for Inhaled Lung Gene Therapy","volume":"112","author":"Mastorakos","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1089\/hum.2004.15.1255","article-title":"Compacted DNA Nanoparticles Administered to the Nasal Mucosa of Cystic Fibrosis Subjects Are Safe and Demonstrate Partial to Complete Cystic Fibrosis Transmembrane Regulator Reconstitution","volume":"15","author":"Konstan","year":"2004","journal-title":"Hum. Gene Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.1016\/j.biomaterials.2010.12.001","article-title":"Secreted Gaussia Luciferase as a Sensitive Reporter Gene for in Vivo and Ex Vivo Studies of Airway Gene Transfer","volume":"32","author":"Griesenbach","year":"2011","journal-title":"Biomaterials"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1038\/mt.2008.96","article-title":"Enhanced Lung Gene Expression after Aerosol Delivery of Concentrated PDNA\/PEI Complexes","volume":"16","author":"Davies","year":"2008","journal-title":"Mol. Ther."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1002\/cbic.200700727","article-title":"Synthesis and Transfection Activity of New Cationic Phosphoramidate Lipids: High Efficiency of an Imidazolium Derivative","volume":"9","author":"Breuzard","year":"2008","journal-title":"ChemBioChem"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Dezanet, C., Kempf, J., Mingeot-Leclercq, M.-P., and D\u00e9cout, J.-L. (2020). Amphiphilic Aminoglycosides as Medicinal Agents. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197411"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Bellucci, M.C., and Volonterio, A. (2020). Aminoglycosides: From Antibiotics to Building Blocks for the Synthesis and Development of Gene Delivery Vehicles. Antibiotics, 9.","DOI":"10.3390\/antibiotics9080504"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1002\/jgm.297","article-title":"Aminoglycoside-Derived Cationic Lipids as Efficient Vectors for Gene Transfection in Vitro and in Vivo","volume":"4","author":"Belmont","year":"2002","journal-title":"J. Gen Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2764","DOI":"10.1002\/ejoc.200300164","article-title":"Aminoglycoside-Derived Cationic Lipids for Gene Transfection: Synthesis of Kanamycin A Derivatives","volume":"2003","author":"Sainlos","year":"2003","journal-title":"Eur. J. Org. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1002\/cbic.200400344","article-title":"Kanamycin A-Derived Cationic Lipids as Vectors for Gene Transfection","volume":"6","author":"Sainlos","year":"2005","journal-title":"ChemBioChem"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.1021\/bc900062z","article-title":"Synthesis and Transfection Properties of a Series of Lipidic Neamine Derivatives","volume":"20","author":"Baussanne","year":"2009","journal-title":"Bioconjug. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.3389\/fphys.2019.01037","article-title":"Oral Delivery of MiRNA With Lipidic Aminoglycoside Derivatives in the Breastfed Rat","volume":"10","author":"Beuzelin","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e244","DOI":"10.1038\/mtna.2015.17","article-title":"Liposome-Based Formulation for Intracellular Delivery of Functional Proteins","volume":"4","author":"Chatin","year":"2015","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.nano.2017.09.005","article-title":"Single Lipoaminoglycoside Promotes Efficient Intracellular Antibody Delivery: A Comprehensive Insight into the Mechanism of Action","volume":"14","author":"Dallet","year":"2018","journal-title":"Nanomedicine"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.jconrel.2017.01.041","article-title":"Self-Assembling Complexes between Binary Mixtures of Lipids with Different Linkers and Nucleic Acids Promote Universal MRNA, DNA and SiRNA Delivery","volume":"249","author":"Colombani","year":"2017","journal-title":"J. Control Release"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/jgm.2869","article-title":"Important Role of Phosphoramido Linkage in Imidazole-Based Dioleyl Helper Lipids for Liposome Stability and Primary Cell Transfection","volume":"18","author":"Haudebourg","year":"2016","journal-title":"J. Gene Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/s00249-015-1095-9","article-title":"Selective Condensation of DNA by Aminoglycoside Antibiotics","volume":"45","author":"Kopaczynska","year":"2016","journal-title":"Eur. Biophys. J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4516","DOI":"10.1039\/C6SM00609D","article-title":"Triggering Bilayer to Inverted-Hexagonal Nanostructure Formation by Thiol-Ene Click Chemistry on Cationic Lipids: Consequences on Gene Transfection","volume":"12","author":"Afonso","year":"2016","journal-title":"Soft Matter"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"L231","DOI":"10.1152\/ajplung.90209.2008","article-title":"Ciliated Epithelial Cell Lifespan in the Mouse Trachea and Lung","volume":"295","author":"Rawlins","year":"2008","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1089\/hum.2017.059","article-title":"Role of Basal Cells in Producing Persistent Lentivirus-Mediated Airway Gene Expression","volume":"29","author":"Farrow","year":"2018","journal-title":"Hum. Gene Ther."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1002\/jgm.178","article-title":"Time Course of Gene Expression after Plasmid DNA Gene Transfer to the Liver","volume":"3","author":"Herweijer","year":"2001","journal-title":"J. Gene Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1093\/hmg\/1.6.363","article-title":"Long-Term Persistence of Plasmid DNA and Foreign Gene Expression in Mouse Muscle","volume":"1","author":"Wolff","year":"1992","journal-title":"Hum. Mol. Genet."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.ymthe.2004.05.004","article-title":"A Facile Nonviral Method for Delivering Genes and SiRNAs to Skeletal Muscle of Mammalian Limbs","volume":"10","author":"Hagstrom","year":"2004","journal-title":"Mol. Ther."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Ghanem, R., Laurent, V., Roquefort, P., Haute, T., Ramel, S., Gall, T.L., Aubry, T., and Montier, T. (2020). Optimizations of In Vitro Mucus and Cell Culture Models to Better Predict In Vivo Gene Transfer in Pathological Lung Respiratory Airways: Cystic Fibrosis as an Example. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13010047"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Ghanem, R., Roquefort, P., Ramel, S., Laurent, V., Haute, T., Le Gall, T., Aubry, T., and Montier, T. (2021). Apparent Yield Stress of Sputum as a Relevant Biomarker in Cystic Fibrosis. Cells, 10.","DOI":"10.3390\/cells10113107"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1164\/rccm.201305-0912OC","article-title":"Poly-L-Lysine Compacts DNA, Kills Bacteria, and Improves Protease Inhibition in Cystic Fibrosis Sputum","volume":"188","author":"Dubois","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S2213-2600(14)70100-6","article-title":"Ataluren for the Treatment of Nonsense-Mutation Cystic Fibrosis: A Randomised, Double-Blind, Placebo-Controlled Phase 3 Trial","volume":"2","author":"Kerem","year":"2014","journal-title":"Lancet Respir. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.2165\/00003495-200363220-00015","article-title":"Inhaled Tobramycin (TOBI): A Review of Its Use in the Management of Pseudomonas Aeruginosa Infections in Patients with Cystic Fibrosis","volume":"63","author":"Cheer","year":"2003","journal-title":"Drugs"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"5618","DOI":"10.1016\/j.biomaterials.2012.04.019","article-title":"The Use of CpG-Free Plasmids to Mediate Persistent Gene Expression Following Repeated Aerosol Delivery of PDNA\/PEI Complexes","volume":"33","author":"Davies","year":"2012","journal-title":"Biomaterials"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/1\/25\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:51:56Z","timestamp":1760169116000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/1\/25"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,23]]},"references-count":75,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["pharmaceutics14010025"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14010025","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,23]]}}}