June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Retinal biodistribution and therapeutic efficacy of systemic dendrimer-drug therapy for choroidal neovascularization
Author Affiliations & Notes
  • Siva Pramodh Kambhampati
    Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD
  • Imran Ahmed Bhutto
    Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD
  • Manoj K Mishra
    Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD
  • Katie Ho
    Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD
  • Gerard A Lutty
    Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD
  • Kannan M Rangaramanujam
    Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD
  • Footnotes
    Commercial Relationships Siva Pramodh Kambhampati, None; Imran Bhutto, None; Manoj Mishra, None; Katie Ho, None; Gerard Lutty, None; Kannan Rangaramanujam, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 2285. doi:
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      Siva Pramodh Kambhampati, Imran Ahmed Bhutto, Manoj K Mishra, Katie Ho, Gerard A Lutty, Kannan M Rangaramanujam; Retinal biodistribution and therapeutic efficacy of systemic dendrimer-drug therapy for choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2285.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Inflammation and choroidal neovascularization (CNV) are two major pathological characteristics of age-related macular degeneration (AMD). Therapies that can target both can be highly beneficial for advanced stages of AMD. Current treatments for wet AMD involves localized intravitreal injections of biologics, for CNV suppression. Systemic therapies for retinal degeneration could increase therapeutic option, improve compliance and reduce costs. We have shown that PAMAM dendrimer can target and localize in activated retinal microglia/macrophages (mi/ma) and RPE upon intravenous injections (IV). The purpose of this study was to evaluate the efficacy of intravenously injected dendrimers drug conjugates in a lipid-induced CNV rat model.

Methods: Dendrimer-Cy5 (D-Cy5) was used to evaluate biodistribution. Dendrimer-N-acetyl cysteine (D-NAC) and Dendrimer-Triamcinolone acetonide (D-TA) conjugates were used for therapy. For early CNV, D-NAC was administered IV on day 3 post lipid injection, and assessed on Day 10. For late CNV, combination therapy with D-NAC+D-TA was administered on day 10, and assessed on Day 21. Rats were sacrificed, retina and choroid was prepared for flat-mount IHC and imaged under confocal microscope for CNV area, volume and mi/ma counts. RT-PCR and western blot were used to analyze inflammatory cytokines and adhesion molecules.

Results: Subretinal lipid injection produced blebs that stimulated migration of mi/ma and formation of CNV. D-Cy5 exhibited pathology dependent, selective biodistribution in activated mi/ma in CNV/RNV areas. D-NAC treatment suppressed CNV growth (~78%), reduced in mi/ma accumulation (~63%) and attenuated inflammation by suppressing cytokine production. D-NAC+D-TA treatment promotes CNV regression (~72 %), reduced CNV volume, enhanced adhesion molecules expression and reduced leakage in late stages of CNV than compared to controls. Dendrimer-drug therapy did not lead to ocular toxicity.

Conclusions: Targeting and selectively co-localization of dendrimers, in activated mi/ma of dendrimers, makes them excellent carriers for systemic drug delivery to the choroid/retina. The efficacy of D-NAC and D-TA in CNV suppression/regression and attenuation of retinal/choroidal inflammation may offer an effective treatment option for early and late stages of AMD and other ocular inflammatory diseases.

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