Brain‐derived neurotrophic factor‐mimetic compounds in biodegradable microspheres as novel neuroprotective approaches for retinal diseases

Purpose: Neuroprotectants can modulate cell survival and molecular pathways common to several inherited retinal degenerations (IRD). Among them, 7,8‐dihydroxyflavone (7,8‐DHF), a brain‐derived neurotrophic factor (BDNF) mimetic, proved to rescue vision in dyeucd6 zebrafish model of IRD by upregulating BDNF–TrkB signalling [1]. A novel 7,8‐DHF structural analogue, namely OPGG‐A2, demonstrated an improved ability in restoring visual capacity. Considering these results, this work aims at evaluating long‐release devices loaded with the two neuroprotectants as possible therapies for chronic retinal diseases. Methods: Biodegradable poly(lactic‐co‐glycolic)acid(PLGA) microspheres (MS) were prepared following the oil‐in‐water emulsion solvent evaporation technique. 7,8‐DHF and OPGG‐A2 were separately included in ratio 1:10 with PLGA(w/w). MS loaded with 7,8‐DHF (FMS) and with OPGG‐A2 (A2MS) were characterized in terms of production yield, internal and external morphology, particle size, encapsulation efficiency and in vitro release profile. Results: After sieving and freeze‐drying processes, 38–20 μm (38MS) and 20–10 μm (20MS) particle sizes were selected as suitable to fit conventional 30‐gauge needles for intravitreal administration. Both the granulometric fractions followed a unimodal distribution for both FMS and A2MS. Both FMS and A2MS demonstrated spherical shape without presence of crystal inside and on the 38MS and 20MS surfaces. FMS showed high encapsulation efficiencies (53.4 ± 3.4 μg/mg 38MS; 30.7 ± 12.2 μg/mg 20MS) as A2MS (58.8 ± 5.6 μg/mg 38MS; 61.3 ± 1.0 μg/mg 20MS). Both drugs were released in a sustained manner during 30 days after a high burst release under the experimental conditions specified (13.7 ± 1.4 μg/mg FMS‐38MS; 11.4 ± 3.8 μg/mg FMS‐20MS; 11.5 ± 2.2 μg/mg A2MS‐38MS; 23.1 ± 1.7 μg/mg A2MS‐20MS). Conclusions: The two formulations managed in vitro liberating both 7,8‐DHF and OPGG‐A2 for 1 month and could be interesting as prototypes for testing long‐term intravitreal neuroprotective therapies. References 1. Daly C, Shine L, Heffernan T, et al. A brain‐derived neurotrophic factor mimetic is sufficient to restore cone photoreceptor visual function in an inherited blindness model. Sci Rep 7, 11 320 (2017).