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Karl G Csaky, Timothy Nguyen, Alexa Gilfoyle, Timothy Catchpole; Episcleral Dye Movement In-Vivo: Chemical Parameters Determining Efficiency of Retinal Penetration. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3356. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Episcleral drug delivery to the retina has enormous potential both because of its non-invasiveness and the potential for prolonged treatment durability. However this approach has been limited by apparent poor drug penetration efficacy. To address this problem 3 dyes with variable lipophilicities and structural aspects were compared as to their ability to penetrate into retina in rodents following placement of a short-term episcleral drug delivery device.
2 x 1 mm hydroxymethyl cellulose (HPMC) devices containing 20 % by weight of sodium fluorescein (NaFl), rhodamine B (RB) or rhodamine 6G (R6G) were generated and kinetics of dye release were examined in-vitro. Implants were placed in the episcleral space of Sprague-Dawley rats and conjunctiva-sclera-choroid (SCC), retina (RE) tissues, and plasma samples were isolated at 15, 30, 45 and 60 minutes. Dyes were extracted from tissues, and quantities measured with a SpectraMax Gemini plate reader.
In-vitro release kinetics demonstrated complete release of implant containing dye at 30 min of NaFl while RB and R6G were completely released at 60 minutes. NaFl demonstrated maximum accumulation into SCC (1588±180 ng/mg) (mean±SEM; ng dye/mg tissue) and RE (146±29 ng/mg) by 15 min, but showed decreasing levels from the SCC (595±137 ng/mg) and RE (56±10 ng/mg) at 30 min with peak appearance in the plasma at 45 min (2782±812 ng/ml). RB in the SCC (1794±499 ng/mg) and RE (41±8.9 ng/mg) peaked at 30 min with appearance in the plasma at all time points (range 808-1174 ng/ml). In contrast R6G demonstrated consistent levels in the SCC (range 2371-3133 ng/mg) with peak RE levels at 60 min (100±11 ng/mg) with minimal plasma concentrations (range 6-39 ng/ml). Only NaFl was detected in the fellow eye at 2% of the ipsilateral levels. Importantly at 60 min retina levels of R6G were maintained at a statistically higher level (100±11 ng/mg) than that seen with RB (15±2 ng/mg) or NaFl (11±3 ng/mg) p = <0.0001, One-Way ANOVA.
Retinal levels of drugs delivered from the episcleral space are not solely driven by lipophilicity but includes unique aspects of the chemistry of the drug. It can be speculated that R6G, containing distinct moieties compared with RB that allows for both penetrance and maintenance of retinal levels when delivered from an episcleral implant.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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