title: Six month delivery of GDNF from PLGA/vitamin E biodegradable microspheres after intravitreal injection in rabbits.
abstract: Local long-term delivery of glial cell line derived neurotrophic factor (GDNF) from vitamin E/poly-lactic-co-glycolic acid microspheres (MSs) protects retinal ganglion cells in an animal model of glaucoma for up to 11weeks. However, the pharmacokinetics of GDNF after intravitreal injection of MSs is not known. We evaluated the GDNF levels after a single intravitreal injection of GDNF/VitE MSs. Biodegradable MSs were prepared by the solid-oil-in-water emulsion-solvent evaporation technique and characterized. Rabbits received a single intravitreal injection (50μL) of GDNF/VitE MSs (4%w/v; 24 right eyes; 74.85ng GDNF), blank MSs (4%w/v; 24 left eyes), and balanced salt solution (4 eyes). Two controls eyes received no injections. At 24h, 1, 4, 6, 8, 12, 18, and 24weeks after injection, the eyes were enucleated, and the intravitreal GDNF levels were quantified. Pharmacokinetic data were analysed according to non-compartmental model. Intraocular GDNF levels of 717.1±145.1pg/mL were observed at 24h for GDNF-loaded MSs, followed by a plateau (745.3±25.5pg/mL) until day 28. After that, a second plateau (17.4±3.7pg/mL) occurred from 8 to 24weeks post-injection, significantly higher than the basal levels. Eyes injected with GDNF/vitE and Blank-MSs did not show any abnormalities during the six-months follow up after administration. The single injection of GDNF/VitE MSs provided a sustained controlled release of the neurotrophic factor in a controlled fashion for up to six months.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: García-Caballero
authors.affiliation: Ophthalmology Department of Miguel Servet Hospital, Zaragoza, Spain; Sanitary Reseach Institute IIS- Aragón, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Prieto-Calvo
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Checa-Casalengua
authors.affiliation: Ophthalmology Department of Miguel Servet Hospital, Zaragoza, Spain; Sanitary Reseach Institute IIS- Aragón, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: García-Martín
authors.affiliation: Ophthalmology Department of Miguel Servet Hospital, Zaragoza, Spain; Sanitary Reseach Institute IIS- Aragón, Spain; Pharmarceutical Innovation in Ophthalmology Research Group, Sanitary Research Institute of San Carlos Clinical Hospital (IdISSC), Madrid, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Polo-Llorens
authors.affiliation: Pharmarceutical Innovation in Ophthalmology Research Group, Sanitary Research Institute of San Carlos Clinical Hospital (IdISSC), Madrid, Spain; Ophthalmology department of Clinic San Carlos Hospital, Madrid, Spain.
authors.forename: Julián
authors.initials: J
authors.lastname: García-Feijoo
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain; Pharmarceutical Innovation in Ophthalmology Research Group, Sanitary Research Institute of San Carlos Clinical Hospital (IdISSC), Madrid, Spain; Ocular Pathology National Net OFTARED, Madrid, Spain.
authors.forename: Irene Teresa
authors.initials: IT
authors.lastname: Molina-Martínez
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain; Pharmarceutical Innovation in Ophthalmology Research Group, Sanitary Research Institute of San Carlos Clinical Hospital (IdISSC), Madrid, Spain; Ocular Pathology National Net OFTARED, Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Bravo-Osuna
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain; Pharmarceutical Innovation in Ophthalmology Research Group, Sanitary Research Institute of San Carlos Clinical Hospital (IdISSC), Madrid, Spain; Ocular Pathology National Net OFTARED, Madrid, Spain. Electronic address: rociohv@ucm.es.
authors.forename: Rocío
authors.initials: R
authors.lastname: Herrero-Vanrell
mesh_terms: D000818:Animals; D004337:Drug Carriers; D065546:Drug Liberation; D005260:Female; D005901:Glaucoma / Q000188:drug therapy*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D058449:Intravitreal Injections; D019344:Lactic Acid; D008863:Microspheres; D010316:Particle Size; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011817:Rabbits; D014810:Vitamin E
chemical_list: D004337:Drug Carriers; D051100:Glial Cell Line-Derived Neurotrophic Factor; D014810:Vitamin E; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
keywords: Glial cell line-derived neurotrophic factor (GDNF); Intravitreal injection; Pharmacokinetics; Poly (lactic-co-glycolic acid) microspheres; Protein delivery; Vitamin E