(264c) Targeted, Systemic Dendrimer-Drug Therapies for Age Related Macular Degeneration
Methods: Dendrimer-Triamcinolone acetonide (D-TA) and Dendrimer-N-Acetyl cysteine (D-NAC) were designed and synthesized to release drugs intracellularly. Cy5-labelled D-TA and D-NAC were used to evaluate the biodistribution and cellular localization using fluorescence spectroscopy and confocal microscopy. For early AMD, D-NAC monotherapy was administered intravenously on day 3, 5 and 7 post subretinal lipid and evaluated on day 10. For late AMD, a combination of D-NAC + D-TA were administered intravenously on day 11, 13 and 15 and evaluated on day 20. CNV suppression and regression were evaluated by accessing the CNV area and volumes using flat-mount imaging. Attenuation of inflammation were evaluated using macrophage counts and RT-qPCR was employed to evaluate inflammatory cytokines and oxidative stress markers.
Results: Subretinal lipid injection produced blebs that stimulated migration of mi/ma and formation of CNV. Both D-TA and D-NAC were stable in plasma and released drugs under intracellular conditions in a sustained manner. Intravenously administered D-NAC and D-TA were found localized in activated mi/ma and hypertrophic RPE in retina and choroid and were retained for more than 30 days but cleared intact from systemic circulation intact within 24 hrs . D-NAC monotherapy suppressed CNV growth (~78%), reduction in mi/ma accumulation (~63%) and attenuated inflammation by suppressing cytokine production. D-NAC+D-TA combination therapy treatment promotes CNV regression (~72%), reduced CNV volume, enhanced adhesion molecules expression and reduced leakage in late stages of AMD than compared to controls. Dendrimer-drug therapy did not lead to ocular or systemic toxicity.
Conclusions: Targeting and selectively co-localization of dendrimers, in activated mi/ma and RPE, makes them excellent carriers for systemic drug delivery to specific affected cells in the choroid/retina. The efficacy of 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 diseases such as diabetic retinopathy (DR), glaucoma, retinitis pigmentosa (RP) and etc. where inflammation is involved.
Acknowledgements: This study was supported by the funds from NIH-NEIRO1EY025304 (RMK) and Altsheler Durell foundation.
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