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

Siva Pramodh Kambhampati, Alexander J M Clunies-Ross, Imran Bhutto, Manoj K. Mishra, Malia Edwards, D. Scott McLeod, Kannan Rangaramanujam, Gerard Anthony 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 - 2015

Fingerprint

Dendrimers
Microglia
Reperfusion
Retina
Ischemia
Macrophages
Retinal Degeneration
Retinal Diseases
Drug Compounding
Intravitreal Injections
Macrophage Activation
Antibodies
Fluorescence Spectrometry
Macular Degeneration
Diabetic Retinopathy
Virus Diseases
Reperfusion Injury
Intravenous Administration
Fluorescent Antibody Technique
Coloring Agents

Keywords

  • Choroid
  • Dendrimers
  • Ischemia
  • Microglia
  • Retina

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

@article{ec097af9732649c691d1b7e331840989,
title = "Systemic and intravitreal delivery of dendrimers to activated microglia/macrophage in ischemia/reperfusion mouse retina",
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.",
keywords = "Choroid, Dendrimers, Ischemia, Microglia, Retina",
author = "Kambhampati, {Siva Pramodh} and Clunies-Ross, {Alexander J M} and Imran Bhutto and Mishra, {Manoj K.} and Malia Edwards and McLeod, {D. Scott} and Kannan Rangaramanujam and Lutty, {Gerard Anthony}",
year = "2015",
doi = "10.1167/iovs.14-16250",
language = "English (US)",
volume = "56",
pages = "4413--4424",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "8",

}

TY - JOUR

T1 - Systemic and intravitreal delivery of dendrimers to activated microglia/macrophage in ischemia/reperfusion mouse retina

AU - Kambhampati, Siva Pramodh

AU - Clunies-Ross, Alexander J M

AU - Bhutto, Imran

AU - Mishra, Manoj K.

AU - Edwards, Malia

AU - McLeod, D. Scott

AU - Rangaramanujam, Kannan

AU - Lutty, Gerard Anthony

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Choroid

KW - Dendrimers

KW - Ischemia

KW - Microglia

KW - Retina

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U2 - 10.1167/iovs.14-16250

DO - 10.1167/iovs.14-16250

M3 - Article

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JO - Investigative Ophthalmology and Visual Science

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