Systemic and Intravitreal Delivery of Dendrimers to Activated Microglia/Macrophage in Ischemia/Reperfusion Mouse Retina.

Dendrimers are tree-like, nanostructured polymers that are emerging as good candidates for drug and gene delivery vehicles for a wide range of applications. Dendrimers possess a high density of surface functional groups that can modulate the local environment to enable unique tissue interactions, which can be advantageous when developing novel therapies.1 Generation-4 hydroxyl polyamidoamine (PAMAM-G4-OH) dendrimers have shown high levels of cellular uptake in previous studies2 and are noncytotoxic and nonimmunogenic.3 Balakrishnan et al.4 and Kannan et al.5 have shown the therapeutic utility of dendrimer-based delivery systems in producing motor function improvements in a rabbit model of cerebral palsy. Targeting neuroinflammation, even in the postnatal period for a prenatal injury, was effective in improving motor function. Other related studies have identified activated microglia as one of the targets of the dendrimers in brain and demonstrated that dendrimers can be effective in treating neuroinflammation.6 Targeting activated microglia may have significant implications in retinal diseases. Microglia are the resident macrophages of the brain and retina, and they play an important role in immune defense against pathogens in the central nervous system.7 They become activated in diseases such as diabetes and retinal degeneration, where cells die and microglia phagocytose cellular debris.8,9 Activation of retinal microglia occurs in a mouse model of ischemia/reperfusion injury (I/R), as well as in glaucoma,10 diabetic retinopathy,11 and branch vein occlusion.12 Retinal vascular occlusion, whether by high intraocular pressure in the I/R model or by thrombus in branch vein occlusion (BVO), causes a decrease in blood flow within the eye, resulting in retinal ischemia. This causes death of neurons, initiating further activation of microglia.9 This study explores the unique retinal biodistribution of systemically and intravitreally administered fluorescently labeled generation-4 hydroxyl polyamidoamine (D-Cy5) dendrimers. The ability of intravenously and intravitreally delivered dendrimers to target activated microglia in retina was investigated in normal and ischemic retinas. Activation of microglia was induced by I/R injury to retina, which damages neurons and blood vessels. Presently there are no systemic treatments available for ischemic retinopathies or age-related macular degeneration (AMD), and systemic delivery would have advantages beyond current treatments, including broader adaptation, reduced cost, and better patient compliance. The standard of care for exudative AMD is intravitreal injections of antibody against VEGF, as frequently as monthly, so intravenous (IV) administration would avoid injections directly in the eye. Furthermore, this study demonstrates long-term retention of the dendrimer in activated microglia, which may reduce the frequency of injection. Using activated microglia as a target for the attenuation of inflammation may be an effective way to treat a number of diseases of the eye, including AMD, where inflammation plays a large part in the degeneration of photoreceptors, destroying the delicate environment of the retina and choroid.13–15