PROJECT SUMMARY Age-related macular degeneration (AMD) is the third leading cause of blindness in the US and one of the leading causes of blindness worldwide. Initially, dry AMD results from inflammation caused by excess reactive oxygen species (ROS), and has no cure. When it progresses to wet AMD, the disease is characterized by abnormal growth of leaky blood vessels caused by excess expression of vascular endothelial growth factor (VEGF), which permanently damages the retina and causes severe vision loss. Anti-VEGF therapeutics are the current standard treatment for wet AMD. However, the requirement of frequent intravitreal injections is associated with high treatment costs, patient burden, and risk of complications including pain. This also does not address the inflammatory component of early stages of the disease. There is a clinical need to reduce injection frequency and treat underlying inflammation causing the disease. The overall objective of this project is to develop and validate an injectable, biodegradable, stimuli-responsive nanoparticle delivery system that can sustain release of a new therapeutic to treat inflammation for several months. In Aim 1, an investigational therapeutic will be synthesized and characterized. Stimuli-responsive polydopamine nanoparticles that release more therapeutic in the presence of reactive oxygen species (ROS) will be synthesized and loaded with the new therapeutic. Therapeutic and nanoparticles will be evaluated for in vitro cellular uptake in human retinal pigment epithelial cells using flow cytometry. Short-term biocompatibility of both the therapeutic and nanoparticles will be evaluated in vivo in a mouse model over 2 weeks. In Aim 2, in vivo biocompatibility and efficacy of the proposed treatments will be evaluated in the sodium iodate mouse model of dry AMD over 2 months. Structural and functional assessments of the eye will include intraocular pressure, fundus imaging, spectral domain optical coherence tomography, histology, and immunohistochemistry. Biocompatibility and biodegradation will be assessed concurrently. Therapeutic concentrations in ocular tissues will be validated by ELISA after 2 months. ELISA will also be used to evaluate retinal expression levels of HO-1 in the disease model to investigate the mechanism of action of the proposed therapeutic. These aims will evaluate a ROS-responsive drug delivery system to sustain release of an anti-inflammatory therapeutic in the eye. This has potential to treat underlying disease pathways associated with AMD and reduce intravitreal injections, improving the quality of life for patients with AMD and other ocular or inflammatory diseases.

PROJECT NARRATIVE In this project, we will investigate a new therapeutic and drug delivery system to treat the two key disease pathways associated with age-related macular degeneration (AMD), inflammation and oxidative stress. Anti- VEGF therapeutics are currently used to mitigate neovascularization, but this does not treat the inflammatory pathway of the disease, and the need for frequent intravitreal injections results in high costs and burdens the patients and health care system. The objective of this work is to perform in vivo validation of an injectable, biodegradable, stimuli-responsive nanoparticle delivery system that can sustain release of an investigational therapeutic to treat retinal inflammation for several months.