A Novel Ferroptosis Inhibitor UAMC-3203, a Potential Treatment for Corneal Epithelial Wound
Anusha Balla,
Bao Tran,
Annika Valtari,
Philipp Steven,
Camilla Scarpellini,
Koen Augustyns,
Arto Urtti,
Kati-Sisko Vellonen,
Marika Ruponen
Affiliations
Anusha Balla
School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland
Bao Tran
Division of Dry-Eye and Ocular GVHD, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50923 Cologne, Germany
Annika Valtari
School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland
Philipp Steven
Division of Dry-Eye and Ocular GVHD, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50923 Cologne, Germany
Camilla Scarpellini
Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Campus Drie Eiken, University of Antwerp, Universiteitsplein 1, B-2160 Antwerp, Belgium
Koen Augustyns
Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Campus Drie Eiken, University of Antwerp, Universiteitsplein 1, B-2160 Antwerp, Belgium
Arto Urtti
School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland
Kati-Sisko Vellonen
School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland
Marika Ruponen
School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, 70211 Kuopio, Finland
Corneal wound, associated with pain, impaired vision, and even blindness, is the most common ocular injury. In this study, we investigated the effect of a novel ferroptosis inhibitor, UAMC-3203 (10 nM–50 µM), in corneal epithelial wound healing in vitro in human corneal epithelial (HCE) cells and ex vivo using alkali-induced corneal wounded mice eye model. We evaluated in vivo acute tolerability of the compound by visual inspection, optical coherence tomography (OCT), and stereomicroscope imaging in rats after its application (100 µM drug solution in phosphate buffer pH 7.4) twice a day for 5 days. In addition, we studied the partitioning of UAMC-3203 in corneal epithelium and corneal stroma using excised porcine cornea. Our study demonstrated that UAMC-3203 had a positive corneal epithelial wound healing effect at the optimal concentration of 10 nM (IC50 value for ferroptosis) in vitro and at 10 µM in the ex vivo study. UAMC-3203 solution (100 µM) was well tolerated after topical administration with no signs of toxicity and inflammation in rats. Ex-vivo distribution study revealed significantly higher concentration (~12–38-fold) and partition coefficient (Kp) (~52 times) in corneal epithelium than corneal stroma. The UAMC-3203 solution (100 µM) was stable for up to 30 days at 4 °C, 37 °C, and room temperature. Overall, UAMC-3203 provides a new prospect for safe and effective therapy for corneal wounds.
