Instant Hydrogelation of Dexamethasone-Peptide Conjugate Attenuates Experimental Autoimmune Uveitis (EAU) Without Causing Apparent Ocular Side-Effects

Abstract

Glucocorticoids ( e.g., dexamethasone (Dex)) are the mainstay in the clinic for treatment of none-infections uveitis. However, long-term glucocorticoids medication is often associated with severe ocular side-effects. To address this challenge, we rationally designed and screened a dexamethasone-peptide conjugate (Dex-GGD), which formed a prodrug molecular hydrogel instantly in 0.01 M phosphate-buffered saline (PBS, pH=7.4) without external stimuli. The formed Dex-GGD hydrogel was characterized by rheology, circular dichroism (CD), and transition electron microscopy (TEM). The results showed that Dex-GGD exhibited a potent in vitro anti-inflammatory capacity in lipopolysaccharides (LPS)-actived RAW 264.7 macrophage with minimal cytotoxicity against L-929 fibroblast, ARPE cells, and RAW 264.7 macrophages. In a rat model of experimental autoimmune uveitis (EAU), the severity of uveitis was significantly alleviated by the treatment of Dex-GGD hydrogel and dexamethasone sodium phosphate (Dexp) owing to their potent ability to reduce the influx of inflammatory cells from peripheral blood and to suppress of the activation of macroglia and microglia in the retina. Different from the dose equivalent Dexp treatment, intravitreal injection of Dex-GGD hydrogel did not induce the apparent ocular side-effects ( e.g., elevated intraocular pressure, damage of retinal function). As a result, the proposed Dex-GGD hydrogel might be an effective and safe therapy for improving the clinical management of uveitis.