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Kannan Rangaramanujam, Siva Pramodh Kambhampati, Imran Ahmed Bhutto, Gerard A Lutty; Systemic dendrimer-based combination therapies for AMD. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1942.
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© ARVO (1962-2015); The Authors (2016-present)
Oxidative stress and inflammation are early events in the development of exudative AMD, followed by choroidal neovascularization (CNV). Systemic therapies that target CNV and inflammation (microglia/macrophages, mi/ma) would be highly beneficial for delaying the progression to wet AMD. PAMAM dendrimers have been shown to localize in activated microglia cells in retina and choroid associated with neuro-inflammation. In this study, we evaluate the efficacy of systemic dendrimer combination therapy for early and late AMD in a lipid induced rat AMD model.
Dendrimer-N-acetyl cysteine (D-NAC) and dendrimer-triamcinolone acetonide (D-TA) conjugates were used for therapy. For early AMD, D-NAC was administered IV on day 3 post lipid injection, and assessed on Day 10. For late neovascular AMD, combination therapy (D-NAC+D-TA) was administered at day 10, and assessed on Day 21. CNV suppression and regression were evaluated using choroidal flat mount IHC. Attenuation of oxidative stress and inflammation were assessed using RT-PCR. Vascular leakage was evaluated using fluorescein angiography. Preservation of retinal health was accessed using ERG.
Subretinal lipid injection stimulated migration of mi/ma, oxidative stress and formation of CNV. D-NAC treatment suppressed CNV growth (~78%), reduction in mi/ma accumulation (~63%) and attenuated inflammation by suppressing pro-inflammatory cytokines and oxidative stress precursors. D-NAC+D-TA treatment promoted CNV regression (~72 %), reduced CNV volume, suppressed ICAM-1 expressiondecreased VEGF production and reduced leakage in late stages of AMD than compared to controls. Dendrimer-drug therapy did not lead to ocular toxicity nor increase in IOP.
The selective targeting of systemic dendrimers in activated mi/ma makes them excellent carriers for systemic drug delivery to the choroid/retina. The promising therapeutic efficacy of systemic D-NAC and D-TA in CNV suppression/regression, attenuation of retinal/choroidal inflammation may offer an effective treatment option for early and late stages of AMD and other ocular inflammatory diseases and it also also minimizes drug side effects.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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