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Evaluating pharmacologic effects of different drugs in an in-vitro model of the outer blood-retinal barrier using different microscopic techniques

Session Details

Session Title: AMD I

Session Date/Time: Friday 12/09/2014 | 08:00-10:00

Paper Time: 08:24

Venue: Boulevard C

First Author: : R.Mahdy GERMANY

Co Author(s): :    M. Brinkmann   Y. Miura   M. Rudolf   S. Grisanti     

Abstract Details

Purpose:

Intravitreal injections are an established method of drug delivery for different ophthalmological diseases. The effect of injected drugs is inter alia limited by their efflux over the outer blood-retinal barrier, which consists of the RPE, Bruch’s membrane and the choriocapillaris. Of these three components the RPE is the most important one as it actively passes drugs through and/or accumulates them internally. The aim of this study was to develop an adequate model for the outer blood-retinal barrier and to evaluate pharmacodynamic and pharmacokinetic parameters by various microscopic techniques using different anti-VEGF drugs that are already in clinical use.

Setting:

Pigment Cell Research Group, Department of Ophthalmology, University of Lübeck, Lübeck, Germany.

Methods:

Human RPE cells were cultured on transwell inserts until they formed a confluent monolayer. Then they were treated with fluorescently-labeled (Cy5) drugs (Ranibizumab, Aflibercept or Bevacizumab) for 1h after which the drug-free medium was applied once again. After 0h, 12h, 24h and 72h the cells were fixed, stained with the endosome marker Rab5 (Alexa488) and nuclei were counterstained with 4',6-diamidino-2-phenylindole (DAPI). Uptake of the respective drug was assessed by conventional fluorescence microscopy (CFM) and two photon microscopy (TPM).

Results:

At clinical significant doses, Ranibizumab (0.125 mg/ml), Aflibercept (0.5 mg/ml) and Bevacizumab (0.25 mg/ml), were all detectable in the RPE cells. Initially Aflibercept showed the fastest uptake with no significant decrease within 72h. Interestingly Ranibizumab had the second fastest uptake, but declined significantly during the observation period. Bevacizumab had the slowest uptake of all three drugs, but like Aflibercept had no significant reduction over 3d.

Conclusions:

On the one hand Aflibercept and Bevacizumab in the administered clinical doses endure in RPE cells considerably longer than Ranibizumab, which might lead to accumulation-related (side)effects on RPE cell function and the clinical course of AMD. On the other hand Ranibizumab seems to be eliminated noticeably faster than the other two VEGF antagonists, which probably has an influence on the efficacy of the drug and the duration of the retreatment interval. The presented outer blood-retinal barrier model and microscopic assessment might provide a useful system to evaluate pharmacologic interactions between injected drugs and RPE cells in-vitro. While CFM might be useful to get an initial impression regarding drug localization, TPM localizes the drug more accurate.

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