(303a) Ocular Nanotherapeutics for Targeting Neuroinflammation for the Treatment of Retinal Degeneration
Therapeutic approaches for the back of the eye to treat neurodegenerative diseases such as retinitis pigmentosa and age related macular degeneration are difficult because of the complex barriers to reach the retina, which is part of the central nervous system. Though neuroprotective drugs such as fluocinolone acetonide (FA) are available for treatment and are being explored in clinical trials, sustained, targeted delivery is a challenge. We have discovered that PAMAM dendrimers (generation 4) are able to selectively localize in the cells associated with the neuroinflammation process, upon intravitreal delivery in two different animal models of retinal degenration. These dendrimers, without any targeting ligands, localize in the activated microglia and astrocytes in the outer retina, only in animals with the disease, but not in age-matched controls. Building on this, we have developed polyamidoamine (PAMAM) dendrimer based nanodevices for sustained delivery of neuroprotectants, such as fluocinolone acetonide. The drug release from the ester-bonded conjugates reveals a nearly zero-order profile over a two month period. The in vivo evaluation in a RCS rat model of retinal degeneration was performed using electroretinography (ERG) measurements of the overall health of the retina, and at the tissue level using microglial and activated microglial, and outer nuclear cell counts. The dendrimer-based formulation was significantly more effective than the free drug, and a drug release implant undergoing clinical trials. One injection of 0.1 microgram of the drug containing 0.7 microgram of the dendrimer was able to arrest retinal degeneration, and preserve cell counts for an entire month. The mechanism of dendrimer-based sustained intracellular delivery, and the detailed in vivo biodistribution, efficacy, and in vitro release results will be presented.