Effect of hyaluronic acid-binding to lipoplexes on intravitreal drug delivery for retinal gene therapy

• DOI: 10.1016/j.ejps.2017.02.027
• Publication Date: 2017-02-21T02:30:18Z
• Authors: Thomas F Martens; Karen Peynshaert; Thaís Leite Nasci...; Elias Fattal; Marcus Karlstetter; Thomas Langmann; Serge Picaud; Jo Demeester; Stefaan C De Smedt; Katrien Remaut; Kevin Braeckmans
• Keywords: PIGMENT EPITHELIUM; 0301 basic medicine; Cell Survival; Hyaluronic acid; LIPOSOMES; OCULAR DISEASES; SINGLE-PARTICLE TRACKING; Retina; Cell Line; Polyethylene Glycols; Fatty Acids, Monounsaturated; 03 medical and health sciences; Drug Delivery Systems; Cations; Medicine and Health Sciences; Animals; Humans; Hyaluronic Acid; Fluorescent Dyes; Phosphatidylethanolamines; Biology and Life Sciences; CD44 RECEPTOR; DNA; Genetic Therapy; SOLID LIPID NANOPARTICLES; Lipoplexes; Quaternary Ammonium Compounds; MOLECULAR-WEIGHT; CELLS; Intravitreal Injections; Liposomes; INTRACELLULAR TRAFFICKING; Nanoparticles; Cattle; Nanopartide mobility; Intravitreal administration; EXTRACELLULAR GLYCOSAMINOGLYCANS; Retinal gene therapy; Plasmids

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.