一种新型铁死亡抑制剂 UAMC-3203，一种潜在的角膜上皮伤口治疗方法。,Pharmaceutics

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一种新型铁死亡抑制剂 UAMC-3203，一种潜在的角膜上皮伤口治疗方法。
Pharmaceutics ( IF 4.9 ) Pub Date : 2022-12-29 , DOI: 10.3390/pharmaceutics15010118
Anusha Balla ₁ , Bao Tran ₂ , Annika Valtari ₁ , Philipp Steven ₂ , Camilla Scarpellini ₃ , Koen Augustyns ₃ , Arto Urtti _{1,

4} , Kati-Sisko Vellonen ₁ , Marika Ruponen ₁

Affiliation

角膜创伤是最常见的眼外伤，伴有疼痛、视力受损甚至失明。在这项研究中，我们研究了一种新型铁死亡抑制剂 UAMC-3203 (10 nM-50 µM) 在体外人角膜上皮 (HCE) 细胞和使用碱诱导的角膜受伤小鼠的体外角膜上皮伤口愈合中的作用眼睛模型。我们通过视觉检查、光学相干断层扫描 (OCT) 和立体显微镜成像评估化合物在大鼠体内的急性耐受性，每天两次，持续 5 天。此外，我们使用切除的猪角膜研究了 UAMC-3203 在角膜上皮和角膜基质中的分配。我们的研究表明，UAMC-3203 在体外最佳浓度 10 nM（铁死亡的 IC50 值）和体外研究中最佳浓度 10 µM 时具有积极的角膜上皮伤口愈合作用。UAMC-3203 溶液 (100 µM) 在大鼠局部给药后耐受性良好，没有毒性和炎症迹象。离体分布研究表明，角膜上皮中的浓度（~12-38 倍）和分配系数 (Kp)（~52 倍）明显高于角膜基质。UAMC-3203 溶液 (100 µM) 在 4 °C、37 °C 和室温下最多可稳定 30 天。总体而言，UAMC-3203为角膜伤口安全有效的治疗提供了新的前景。UAMC-3203 溶液 (100 µM) 在大鼠局部给药后耐受性良好，没有毒性和炎症迹象。离体分布研究表明，角膜上皮中的浓度（~12-38 倍）和分配系数 (Kp)（~52 倍）明显高于角膜基质。UAMC-3203 溶液 (100 µM) 在 4 °C、37 °C 和室温下最多可稳定 30 天。总体而言，UAMC-3203为角膜伤口安全有效的治疗提供了新的前景。UAMC-3203 溶液 (100 µM) 在大鼠局部给药后耐受性良好，没有毒性和炎症迹象。离体分布研究表明，角膜上皮中的浓度（~12-38 倍）和分配系数 (Kp)（~52 倍）明显高于角膜基质。UAMC-3203 溶液 (100 µM) 在 4 °C、37 °C 和室温下最多可稳定 30 天。总体而言，UAMC-3203为角膜伤口安全有效的治疗提供了新的前景。

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A Novel Ferroptosis Inhibitor UAMC-3203, a Potential Treatment for Corneal Epithelial Wound.

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.

更新日期：2022-12-29

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