Project Details
Projekt
Nanoparticles for the Treatment of Neovascularizations in the Eye
Subject Area
Pharmacy
Ophthalmology
Ophthalmology
Term
from 2015 to 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 269235691
Age-related macular degeneration (AMD) and diabetic retinopathy are among the leading causes of blindness and affect together worldwide more than 100 million people. The wet form of AMD and proliferative diabetic retinopathy (PDR) share pathogenic mechanisms of endothelial cell hyperproliferation and blood vessel hyperpermeability. Since vascular endothelial growth factor (VEGF) drives both processes, intraocular injections of VEGF antibodies evolved as a highly successful therapeutic strategy. However, since VEGF is a pivotal factor for retinal tissue maintenance its unspecific elimination triggers severe adverse effects. The goal of this project will be to develop nanoparticles for more selective therapeutic strategies. A first approach is a retinal and choroidal endothelium-specific anti-VEGF strategy and based on our discovery that integrin receptor-targeted nanoparticles accumulate in retinal blood vessels upon intravenous injection. We will design lipid nanoparticles that are able to transport cyclosporin A and itraconazole, two potent and synergistic VEGF signaling inhibitors, to retinal and choroidal endothelial cells following systemic administration. The second strategy is a VEGF-signaling independent intervention and rests on our finding that ligand-decorated nanoparticles bind to cell surface receptors in a way that is superior to that of a free ligand. With such multivalent binding nanoparticles we will silence the angiotensin II receptor type 1 (AT1R) which exhibits pro-inflammatory effects in wet AMD as well as PDR. We will, thereby, attach AT1R antagonists either to quantum dots to identify the tissue binding sites of such particles, or branched polymers for therapeutic purposes. Such constructs can either be administered systemically or via intravitreal injection. Both, drug loaded therapeutic lipid particles and multivalent binding AT1R antagonists, will first be tested and optimized in vitro for their cell binding behavior in cell culture. The biodistribution of both will be tested and further refined in healthy mice. The efficacy of drug loaded lipid nanoparticles and multivalent AT1R antagonists with a particularly favorable distribution into the retinal and choroidal endothelium will be finally tested in a mouse model of oxygen-induced neovascularization.
DFG Programme
Research Grants
Co-Investigators
Professorin Dr. Antje Grosche; Professor Dr. Herbert Jägle
