Abstract
Purpose :
“Inflammation/oxidative stress (early)” and “neovascularization (late)” are key pathological events in AMD progression. Therapies that target and deliver drugs to activated microglia/macrophages (mi/ma) and hypertropic RPE would be highly beneficial. Sustained, targeted, systemic delivery of dendrimer-triamcinolone (D-TA) conjugates would broaden the impact of current AMD therapies. The purpose of this study was to evaluate the dose dependent efficacy of intravenously-administered D-TA conjugates in suppressing inflammationn and CNV, in a lipid-induced rat AMD model.
Methods :
D-TA conjugates were synthesized with high drug loading (~20% payload), and characterized extensively. Cy5-labelled D-TA (Cy5-D-TA) was used to evaluate the colocalization and retention in retina and choroid. Fluorescence spectroscopy (FLS) was used to accesses the biodistribution. For efficacy studies, D-TA was administered intravenously at different doses. The rats were evaluated for IOP, signs of toxicity, and weight loss. Rats were sacrificed at day 10, retina and choroids were prepared for flat-mount IHC and imaged under confocal microscope for CNV area and volume.
Results :
D-TA conjugates enhanced the solubility of free TA, with enhanced intracellular delivery. Subretinal lipid resulted in CNV, migration and accumulation of mi/ma in the bleb area. FLS studies of tissue extracts show that ~ 70% of injected Cy5-D-TA were cleared intact via kidneys in 24 hrs and were found localized only in activated mi/ma and RPE cells in retina, and choroid on day 10. D-TA therapy suppressed CNV growth (by ~90%) in a dose dependent manner compared to free TA. D-TA therapy suppressed macrophage accumulation (~52%) compared to free TA and saline treated groups in bleb area. Importantly, administration of a combination of D-TA and Dendrimer-N-acetyl cysteine on Day 10, resulted in CNV regression on Day 21 (by ~60%)
Conclusions :
Systemic dendrimer-based targeting and delivery TA to activated mi/ma and RPE addresses inflammation, and VEGF production in a sustained manner. Achieving CNV suppression and regression without exposing the ocular tissues to high concentrations of drugs may have significant impact in reducing side-effects and improving patient incompliance. Systemic therapy may enable early treatments for AMD when intravitreal injections are not viable. In addition, D-TA therapy may work well in combination with existing anti-VEGF therapies.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.