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Imran Ahmed Bhutto, Alexander J Clunies-Ross, Siva P Kambhampati, Manoj K Mishra, Scott D McLeod, Rangaramanujam Kannan, Gerard A Lutty; Transport and microglia uptake of dendrimers in normal and ischemia/reperfusion injury retina. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1448.
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Microglial activation in retina is a common response to various neurodegenerative diseases. A hydroxyl-terminated polyamidoamine (PAMAM) dendrimer-drug conjugate has been used to target microglia and attenuate neuroinflammation in degenerated rat retina when injected intravitreally. The aim of this study was to develop a dendrimer that targets activated microglia in retina and can be administered intravitreally as well as intravenously.
The dendrimer-Cy5 (D-Cy5) was evaluated in normal mouse and in a mouse model of retinal ischemia/reperfusion (I/R) injury. Transient ischemia was induced in one eye of Balb/c mice by raising intraocular pressure to 90 mm Hg for 90 minutes followed by retinal reperfusion which restores normal pressure. The fellow eye served as a non-I/R control eye. After 6 days post I/R, D-Cy5, free Cy5 or PBS was administered intravitreally or intravenously. Mice were then sacrificed at 24 hours, 3 days, and 21 days post injection. Eyecups were cryopreserved and 8um thick sections used for IHC using rabbit IBA-1 antibody (macrophage/microglia specific) and GSA lectin-FITC. D-Cy5 or Cy5 was assessed on the Zeiss 710 confocal microscope and autofluorescence was assessed in the sections of PBS injected eyes.
In I/R eyes at 24 hours after intravitreal injection, there was uptake of D-Cy5 at the level of ILM and co-localization with IBA-1+ microglia cells in sensory retina. Where as free Cy5 was diffuse and intense in retinal blood vessels and appeared to cleared within 72hr. This distinctive D-Cy5 pattern declined over 21 days in I/R eyes, less D-Cy5 and more IBA-1+ microglia cells in retina. On the other hand, intravenous administration showed continuous uptake of D-Cy5 and more colocalization with IBA-1+ microglia cells in retina and choroid even at 21 days post injection in I/R eyes. The pattern of enhanced uptake of D-Cy5 was not seen in the non-I/R retinas and choroids after either injection.
The nontoxic PAMAM dendrimers appear to be an excellent drug delivery system to activated microglia. In eyes with activated microglia after I/R injury, intravenous and intravitreal D-Cy5 was retained by microglia (IBA+). This approach may yield a dendrimer-based therapy to decrease inflammation in diseases associated with microglia activation.
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