Development of sustained and targeted ocular drug delivery systems using dendrimers

Nine-million Americans suffer progressive vision loss due to retinal neurodegenerative diseases such as age-related macular degeneration (AMD), diabetic retinopathy, glaucoma and retinitis pigmentosa. Number will grow by an estimated 200,000 new cases per year as the aged population in the society increases. An emerging body of literature has identified that retinal neuroinflammation plays a key role in the pathogenesis of photoreceptor and retinal pigment epithelial cell loss in these diseases. Though some of the neuroprotective drugs like fluocinolone acetonide (FA) and minocycline are available for treatment, it is difficult to deliver therapeutic amount of drug to the diseased site for a sustained period. We have developed polyamidoamine (PAMAM) dendrimer based nanodevices (size ≈ 5 nm) for sustained delivery of neuroprotectants. A single intravitreal injection of the nanodevice appears to prevent the neurodegeneration up to one month in the retinal degeneration model of RCS rats. In Vivo retinal biodistribution measurements of FITC-labeled PAMAM dendrimers suggested that dendrimers localized in the activated microglial cells, retinal astrocytes and Mueller glial cells which are responsible for neuroinflammation. To understand the release of drug from the dendrimer nanodevices, in vitro release of drug from the nanodevice at different pH conditions were conducted for a period of three months. Nearly zero-order release kinetics was observed in the release profile over a 90 day period.;To enable sustained delivery for six months from a single injection, dendrimer-FITC (model drug) nanodevices are encapsulated into a nanoparticle (size ≈ 600 nm) made up of FDA approved biomaterial which can release dendrimer-drug nanodevices for longer period. In vitro release profile of the nanodevices from the nanoparticles was characterized at physiological pH conditions.