Systemic and intravitreal delivery of dendrimers to activated microglia/macrophage in ischemia/reperfusion mouse retina

Siva P. Kambhampati, Alexander J.M. Clunies-Ross, Imran Bhutto, Manoj K. Mishra, Malia Edwards, D. Scott McLeod, Rangaramanujam M. Kannan, Gerard Lutty

Research output: Contribution to journalArticle

Abstract

PURPOSE. Microglial activation and associated neuroinflammation play a key role in the pathogenesis of many diseases of the retina, including viral infection, diabetes, and retinal degeneration. Strategies to target activated microglia and macrophages and attenuate inflammation may be valuable in treating these diseases. We seek to develop dendrimerbased formulations that target retinal microglia and macrophages in a pathology-dependent manner, and deliver drugs, either intravenously or intravitreally. METHODS. Retinal uptake of cyanine dye (Cy5)-conjugated dendrimer (D-Cy5) was assessed in normal and ischemia/reperfusion (I/R) mouse eyes. Microglia/macrophage uptake of the dendrimer was assessed with immunofluorescence using rabbit Iba-1 antibody with Cy3- tagged secondary antibody (microglia/macrophage). Uptake in retina and other organs was quantified using fluorescence spectroscopy. RESULTS. Clearance of D-Cy5 from normal eyeswas almost complete by 72 hours after intravitreal injection and 24 hours after intravenous delivery. In eyes with activatedmicroglia after I/R injury, D-Cy5 was retained by activated microglia/macrophage (Iba1+ cells) up to 21 days after intravitreal and intravenous administration. In I/R eyes, the relative retention of intravitreal and intravenous D-Cy5 was comparable, if a 30-fold higher intravenous dose was used. CONCLUSIONS. Intravitreal and systemic dendrimers target activated microglia and show qualitatively similar retinal biodistribution when administered by either route. Results provide proof-of-concept insights for developing dendrimer drug formulations as treatment options for retinal diseases associated with microglia or macrophage activation such as age-related macular degeneration, diabetic retinopathy, and retinal degenerations.

Original languageEnglish (US)
Pages (from-to)4413-4424
Number of pages12
JournalInvestigative Ophthalmology and Visual Science
Volume56
Issue number8
DOIs
StatePublished - Jan 1 2015

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Keywords

  • Choroid
  • Dendrimers
  • Ischemia
  • Microglia
  • Retina

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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