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Siva Pramodh Kambhampati, Imran Ahmed Bhutto, Katie Ho, Gerard A Lutty, Kannan Rangaramanujam; Efficacy and dose dependent response of intravenous dendrimer-triamcinolone acetonide conjugates in CNV suppression. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3987.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Choroidal neovascularization (CNV) is a hallmark of exudative AMD, and it is often associated with inflammation. Therapies that target CNV and inflammation would be highly beneficial for delaying progression of wet AMD. Targeted systemic (IV) therapies for CNV would broaden the impact of therapy, improving compliance and reducing costs. The purpose of this study was to evaluate the efficacy and dose dependent response of intravenously administered dendrimer-triamcinolone acetonide (D-TA) conjugates in a lipid-induced CNV rat model.
Methods: D-TA conjugates were synthesized with high drug loading. The drug release was evaluated in physiological solutions using HPLC analysis. The anti-inflammatory and anti-angiogenic activity were accessed in-vitro in microglial and human RPE cells respectively. D-TA conjugates were administered intravenously on day 3 post lipid (HPODE) injection at different doses to accesses the CNV suppression. The rats were evaluated for IOP, signs of toxicity and weight loss. Rats were sacrificed at day 11, retina and choroid were prepared for flat-mount immunohistochemistry (IHC) and imaged under confocal microscope for CNV area and volume. RT-PCR and western blot were used to analyze expression of inflammatory cytokines and adhesion molecules.
Results: D-TA conjugates enhanced the solubility of TA significantly and exhibited sustained release with enhanced intracellular delivery. Subretinal lipid injection resulted in formation of CNV and migration and accumulation of macrophages in and around CNV area in rats. D-TA treatment suppressed CNV growth in a dose dependent manner and efficacy was comparable to free TA with no signs of toxicity or elevated IOP. D-TA reduced CNV volume, attenuated inflammation, enhanced adhesion molecule expression and reduced leakage compared to controls and free TA.
Conclusions: Dendrimer-based delivery may improve the efficacy of TA for treatment of CNV, targeting inflammation and VEGF production, with significant clinical implications. The efficacy of D-TA in CNV suppression, attenuation of choroidal inflammation may offer an effective treatment option for AMD and other ocular inflammatory diseases.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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