title: Effect of hyaluronic acid-binding to lipoplexes on intravitreal drug delivery for retinal gene therapy.
abstract: Intravitreal administration of nanomedicines could be valuable for retinal gene therapy, if their mobility in the vitreous and therapeutic efficacy in the target cells can be guaranteed. Hyaluronic acid (HA) as an electrostatic coating of polymeric gene nanomedicines has proven to be beneficial on both accounts. While electrostatic coating provides an easy way of coating cationic nanoparticles, the stability of electrostatic complexes in vivo is uncertain. In this study, therefore, we compare electrostatic with covalent coating of gene nanocarriers with HA for retinal gene therapy via intravitreal administration. Specifically, DOTAP:DOPE/plasmid DNA lipoplexes coated with HA are evaluated in terms of intravitreal mobility using a previously optimized ex vivo model. We find that both electrostatic and covalent HA coating considerably improve the mobility of the lipoplexes in the vitreous humor of excised bovine eyes. In addition we evaluate in vitro uptake and transfection efficiency in ARPE-19 cells. Contrary to PEGylated lipoplexes it is found that HA coated lipoplexes are efficiently internalized into ARPE-19 cells. Covalent HA-coated lipoplexes had an 8-fold increase of transgene expression compared to the uncoated lipoplexes. We conclude that covalent HA-coating of gene nanomedicines is a promising approach for retinal gene therapy by intravitreal administration.
authors.affiliation: Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium; Center for Nano-and Biophotonics (NB-Photonics), Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Martens
authors.affiliation: Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
authors.forename: Karen
authors.initials: K
authors.lastname: Peynshaert
authors.affiliation: Institut Galien Paris-Sud, CNRS UMR 8612, Univ Paris-Sud, Faculté de Pharmacie, 5, rue J.B. Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Thaís Leite
authors.initials: TL
authors.lastname: Nascimento
authors.affiliation: Institut Galien Paris-Sud, CNRS UMR 8612, Univ Paris-Sud, Faculté de Pharmacie, 5, rue J.B. Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Elias
authors.initials: E
authors.lastname: Fattal
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Karlstetter
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Langmann
authors.affiliation: Institut de la Vision, INSERM, Université Pierre et Marie Curie-Paris 6, 17 rue Moreau, 75 012 Paris, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Picaud
authors.affiliation: Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Demeester
authors.affiliation: Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
authors.forename: Stefaan C
authors.initials: SC
authors.lastname: De Smedt
authors.affiliation: Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Remaut
authors.affiliation: Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium; Center for Nano-and Biophotonics (NB-Photonics), Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium. Electronic address: Kevin.Braeckmans@Ugent.be.
authors.forename: Kevin
authors.initials: K
authors.lastname: Braeckmans
mesh_terms: D000818:Animals; D002412:Cations; D002417:Cattle; D002460:Cell Line; D002470:Cell Survival; D004247:DNA / Q000008:administration & dosage; D016503:Drug Delivery Systems; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry*; D005456:Fluorescent Dyes / Q000737:chemistry; D015316:Genetic Therapy; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D058449:Intravitreal Injections; D008081:Liposomes; D053758:Nanoparticles; D010714:Phosphatidylethanolamines / Q000737:chemistry; D010957:Plasmids; D011092:Polyethylene Glycols; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*; D012160:Retina / Q000187:drug effects*; D055672:Static Electricity; D013499:Surface Properties; D014162:Transfection; D014822:Vitreous Body / Q000378:metabolism
chemical_list: D002412:Cations; D005229:Fatty Acids, Monounsaturated; D005456:Fluorescent Dyes; D008081:Liposomes; D010714:Phosphatidylethanolamines; D000644:Quaternary Ammonium Compounds; D011092:Polyethylene Glycols; C020888:1,2-dielaidoylphosphatidylethanolamine; D006820:Hyaluronic Acid; D004247:DNA; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane
keywords: Hyaluronic acid; Intravitreal administration; Lipoplexes; Nanoparticle mobility; Retinal gene therapy