Systemic anti-inflammatory therapy in a canine model of acute intraocular inflammation

Abstract

Purpose : Systemic ocular drug delivery is hindered by blood-ocular barriers and approaches that circumvent these barriers are lacking. Using active nanoparticle delivery, we tested the hypothesis that receptor-mediated delivery of curcumin across intestinal and ocular barriers would lead to improved clinical outcomes in an experimental model of lens-induced uveitis.

Methods : Curcumin (CUR) was encapsulated in double-headed polyester nanoparticles using gambogic acid (GA)-coupled polylactide-co-glycolide (PLGA), abbreviated as PLGA-GA₂-CUR. GA, a small surface molecule xanthanoid, served as a ligand specific to the transferrin receptor (TfR), a type II transmembrane protein expressed on both intestinal and ocular barriers. PLGA-GA₂-CUR (10 mg/kg twice daily) was orally dosed to adult male beagles (n=8 eyes) with acute ocular inflammation induced by an intracameral injection of canine lens protein. Eyes were evaluated using a semiquantitative ocular scoring system optimized for use in modern preclinical drug development and toxicology (SPOTS). Results were compared to standard commercial anti-inflammatory treatment with oral carprofen (2.2 mg/kg twice daily) (n=8 eyes) and untreated controls (n=8 eyes) using a two-way ANOVA.

Results : Orally administered PLGA-GA₂-CUR led to significant CUR levels in the aqueous humor of non-inflamed eyes. PLGA-GA₂-CUR offered improved protection compared to both carprofen and untreated controls, indicated by a reduction in aqueous flare (AC flare score), miosis (PLR score), and chemosis (conjunctival swelling score) in the early phase (<4 hours) of lens protein-induced ocular inflammation.

Conclusions : This study highlights the potential of PLGA-GA₂ nanoparticles for systemic delivery of drugs across the ocular barriers, as orally administered PLGA-GA₂-CUR reduced clinical scores of ocular inflammation. Further testing is necessary to see if such delivery strategies are clinically viable.

This is a 2020 ARVO Annual Meeting abstract.

 

Following intracameral injection of lens protein at t=0 hours, eyes were serially evaluated using the SPOTS system, including measurements of aqueous flare (top), pupillary light reflex (middle), and conjunctival swelling (bottom). Statistical significance of oral PLA-GA₂-CUR administration was compared to treatment with oral carprofen and untreated controls, as determined by a two-way ANOVA. Statistical significance is denoted by *(p<0.05), **(p<0.01), ***(p<0.001), and ****(p<0.0001).