title: Dendrimer-based targeted intravitreal therapy for sustained attenuation of neuroinflammation in retinal degeneration.
abstract: Retinal neuroinflammation, mediated by activated microglia, plays a key role in the pathogenesis of photoreceptor and retinal pigment epithelial cell loss in age-related macular degeneration and retinitis pigmentosa. Targeted drug therapy for attenuation of neuroinflammation in the retina was explored using hydroxyl-terminated polyamidoamine (PAMAM) dendrimer-drug conjugate nanodevices. We show that, upon intravitreal administration, PAMAM dendrimers selectively localize within activated outer retinal microglia in two rat models of retinal degeneration, but not in the retina of healthy controls. This pathology-dependent biodistribution was exploited for drug delivery, by covalently conjugating fluocinolone acetonide to the dendrimer. The conjugate released the drug in a sustained manner over 90 days. In vivo efficacy was assessed using the Royal College of Surgeons (RCS) rat retinal degeneration model over a four-week period when peak retinal degeneration occurs. One intravitreal injection of 1 μg of FA conjugated to 7 μg of the dendrimer was able to arrest retinal degeneration, preserve photoreceptor outer nuclear cell counts, and attenuate activated microglia, for an entire month. These studies suggest that PAMAM dendrimers (with no targeting ligands) have an intrinsic ability to selectively localize in activated microglia, and can deliver drugs inside these cells for a sustained period for the treatment of retinal neuroinflammation.
authors: Ligon Research Center of Vision, Wayne State University, Detroit, MI, USA.
authors: Raymond
authors: R
authors: Iezzi
authors: Bharath R
authors: BR
authors: Guru
authors: Inna V
authors: IV
authors: Glybina
authors: Manoj K
authors: MK
authors: Mishra
authors: Alexander
authors: A
authors: Kennedy
authors: Rangaramanujam M
authors: RM
authors: Kannan
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000627:therapeutic use*; D050091:Dendrimers / Q000737:chemistry*; D004596:Electroretinography; D005446:Fluocinolone Acetonide / Q000737:chemistry* / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy; D058449:Intravitreal Injections; D015213:Neuroimmunomodulation / Q000187:drug effects; D051381:Rats; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000276:immunology*
chemical_list: D000893:Anti-Inflammatory Agents; D050091:Dendrimers; C104700:PAMAM Starburst; D005446:Fluocinolone Acetonide