Alleviation of dry eye syndrome with one dose of antioxidant, anti-inflammatory, and mucoadhesive lysine-carbonized nanogels

Abstract

Most dry eye syndromes (DES) are caused by oxidative stress and an overactive inflammatory response, leading to tear deficiency and excessive tear evaporation. Conventional eye drops for DES treatment require high doses and frequent administration due to their insufficient precorneal residence time. To overcome these problems, in this study, we have developed carbonized nanogels (CNGs) via the straightforward pyrolysis of lysine hydrochloride (Lys) to provide a long-lasting eye drop formulation for topical DES therapy. This methodology thermally converts Lys-into nitrogen-doped crosslinked polymers with embedded nanographitic structures, which enable efficient free radical scavenging. The cationic and crosslinked polymeric features of the Lys-CNGs also prolong the precorneal retention time and improve ocular bioavailability. These Lys-CNGs exhibit high biocompatibility with corneal epithelial cells both in vitro and in vivo, indicating their safety as eye drops. In a DES rabbit model, a single dose of Lys-CNGs (50 µg mL^-1) can effectively alleviate the signs of DES within 4 days, whereas multiple treatments of 10-fold higher concentration of cyclosporine A are needed to achieve similar therapeutic effects (one dose every 12 h; 500 µg mL^-1). The topical administration of Lys-CNGs enable a reduced therapeutic dose and extended dosing interval, thereby demonstrating a superior therapeutic efficacy compared to the commercial cyclosporine A eye drops. These Lys-CNGs, which exhibit significant free radical scavenging, anti-inflammatory activity, high biocompatibility, and a remarkable ocular bioadhesive property, hold great potential as a long-lasting eye drop formulation for the treatment of dry eye disease. STATEMENT OF SIGNIFICANCE: Multifunctional nanobiomaterial-based eye drops can render an ideal pharmaceutical formulation for the treatment of a variety of ocular surface diseases. To our knowledge, this is the first report describing the development of carbonized nanogels as topically administered therapeutics for alleviating dry eye syndrome (DES). We present evidence that the thermal transformation of lysine hydrochloride into carbonized nanogels (Lys-CNGs) endows superior antioxidant, anti-inflammatory, and bioadhesive properties. While a single dose of Lys-CNGs (50 µg mL^-1) is sufficient to relieve the symptoms of DES for 4 days, multiple treatments of 10-fold higher concentration of commercially available cyclosporine eye drops are needed to achieve similar therapeutic outcomes (one dose every 12 h; 500 µg mL^-1), suggesting an effective and long-lasting ocular carbonized nanomedicine.

Keywords: Anti-inflammatory activity; Carbonized nanogels; Dry eye syndrome; Mucin; Ophthalmic drops.