389190 Targeted Intravenous Nanotherapies for Retinal Degeneration
Purpose: Choroidal neovascularization (CNV) is a major complication of age-related macular degeneration (AMD) and results in devastating damage to the retina. Increasing evidence suggests inflammation may play a critical role in the development and the progression of AMD. Polyamidoamine (PAMAM) dendrimers have been shown to localize in activated microglia cells associated with neuroinflammation. The purpose of this study was to investigate whether intravenously injected dendrimers would accumulate and deliver drugs in a lipid-induced CNV rat model.
Methods: Dendrimer-Cy5 (D-Cy5) and Dendrimer-N-acetyl cysteine (D-NAC) conjugates were evaluated in lipid-induced rat CNV model. A single dose of D-NAC+D-Cy5 was administered intravenously on day 3 post lipid injection. Rats injected with D-Cy5 alone and PBS served as controls. Rats were sacrificed 7 days post dendrimer injection, retina and choroid was prepared for flat-mount IHC. Immunolabeled flat-mounts were imaged under Zeiss 710 confocal microscope. The co-localization of D-Cy5 was assessed using IBA-1 antibody (macrophage/microglia) and GSA lectin-FITC (blood vessels and microglia). The CNV areas, and the microglial counts in the CNV area were assessed.
Results: Subretinal lipid injection produced blebs that stimulated migration of IBA-1 positive microglial/macrophages and formation of CNV. Intravenous administration of D-Cy5 was co-localized specifically in activated microglia/macrophages in the CNV/RNV areas. Image analysis showed that D-NAC + D-Cy5 treated rats had a ~68% reduction in the CNV area and a significant reduction in the number of microglial cells (~63%) in CNV area compared to CNV control rats. Moreover, D-NAC treated choroids and retinas showed significant reduction inflammatory cytokines. The dendrimers did not show any signs of toxicity and was mostly cleared (~ 62% of injected dose) intact within 24 hours after systemic administration.
Conclusions: D-Cy5 selectively co-localized with activated macrophages and microglial cells and, therefore, is promising for delivering anti-inflammatory drugs to retina via systemic administration. The efficacy of D-NAC in reduction of microglia numbers and CNV regression opens a new therapeutic window for delivering a combination of intravenous anti-angiogenic and anti-inflammatory drugs as an effective treatment option for early stages of AMD and other ocular inflammatory diseases.