title: Systemic and Intravitreal Delivery of Dendrimers to Activated Microglia/Macrophage in Ischemia/Reperfusion Mouse Retina.
abstract: OBJECTIVE
  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 dendrimer-based 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 eyes was almost complete by 72 hours after intravitreal injection and 24 hours after intravenous delivery. In eyes with activated microglia 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.
authors.affiliation: Department of Ophthalmology Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, Maryland, United States 2Department of Biomedical Engineering, Wayne State University, Detroit, Michigan, United States.
authors.forename: Siva P
authors.initials: SP
authors.lastname: Kambhampati
authors.affiliation: Department of Ophthalmology Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, Maryland, United States.
authors.forename: Alexander J M
authors.initials: AJ
authors.lastname: Clunies-Ross
authors.affiliation: Department of Ophthalmology Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, Maryland, United States.
authors.forename: Imran
authors.initials: I
authors.lastname: Bhutto
authors.affiliation: Department of Ophthalmology Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, Maryland, United States.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Mishra
authors.affiliation: Department of Ophthalmology Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, Maryland, United States.
authors.forename: Malia
authors.initials: M
authors.lastname: Edwards
authors.affiliation: Department of Ophthalmology Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, Maryland, United States.
authors.forename: D Scott
authors.initials: DS
authors.lastname: McLeod
authors.affiliation: Department of Ophthalmology Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, Maryland, United States.
authors.forename: Rangaramanujam M
authors.initials: RM
authors.lastname: Kannan
authors.affiliation: Department of Ophthalmology Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, Maryland, United States.
authors.forename: Gerard
authors.initials: G
authors.lastname: Lutty
mesh_terms: D000818:Animals; D002232:Carbocyanines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D050091:Dendrimers / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D058449:Intravitreal Injections; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D018613:Microscopy, Confocal; D009757:Nylons / Q000493:pharmacokinetics; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012164:Retinal Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D055351:Retinal Neurons / Q000187:drug effects* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D002232:Carbocyanines; D050091:Dendrimers; D009757:Nylons; C520550:PAMAM-G4; C085321:cyanine dye 5