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.

Neurotrophin-conjugated nanoparticles prevent retina damage induced by oxidative stress

“…The use of IVT injected nanoformulations has also been explored, such as the injection of basic fibroblast growth factor (FGF)-impregnated nanoparticles (NP) [ 4 ] or poly-lactic- co -glycolic acid (PLGA) microspheres containing NTs [ 18 ]. A single IVT injection of the glial cell-derived neurotrophic factor (GDNF) encapsulated in vitamin E/PLGA microspheres was found to protect RGCs in animal models of glaucoma for up to 11 weeks by providing the sustained controlled release of GDNF in a controlled fashion for up to 6 months [ 19 , 20 ].…”

Retinal Cell Protection in Ocular Excitotoxicity Diseases. Possible Alternatives Offered by Microparticulate Drug Delivery Systems and Future Prospects

“…Recent studies confirmed this system to be safe. These MS did not show abnormalities during a six-month follow up after intravitreal administration on adult female New Zealand albino rabbits [32].…”

“…Nowadays, it is known that preservation of adequate protein folding, mitochondrial function, inflammation process and scavenging pathways directly avoids programmed cell death and irreversible damage of the neuronal cells [32]. Also, inhibition of retinal microglial and Müller glia activation via sigma-1 receptor agonism with neurosteroids (e.g., dehydroepiandrosterone, that has anti-inflammatory functions as well) has been described recently as an innovative and viable strategy [28].…”

Nanotechnology for Medical and Surgical Glaucoma Therapy—A Review

“…10% GDNF-microsphere emulsion resulted in a significant reduction of optic nerve head excavation, and increased RGC survival, compared with 2% GDNF-microspheres, blank microspheres, and saline solution [205]. In order to evaluate the pharmacokinetics of GDNF, García-Caballero et al [206] analyzed its levels after a single intravitreal injection of GDNF/vitamin E microspheres in rabbits. This method allowed a sustained controlled release of GDNF for up to 6 months.…”