Glycosylation-enhanced biocompatibility of the supramolecular hydrogel of an anti-inflammatory drug for topical suppression of inflammation

• Published in: Acta biomaterialia 2018-06, Vol.73, p.275-284
• Main Authors: Xiong, Taotao, Li, Xianglian, Zhou, Yanfang, Song, Qianqian, Zhang, Renshu, Lei, Lei, Li, Xingyi
• Format: Article
• Language: English
• Subjects: Biocompatibility; Controlled release; Cytotoxicity; Disease control; Experimental autoimmune uveitis; Experimental autoimmune uveoretinitis; Gelation; Glucosamine; Glycosylation; Helper cells; Hydrogels; Hydrogen bonding; Hydrogen bonds; Hydrophobicity; In vivo; Incubation; Inflammation; Inflammatory response; Injection; Interleukin 6; Intraocular pressure; Lymphocytes T; Macrophages; Nanofibers; Nitric oxide; Noninfectious uveitis; Nonsteroidal anti-inflammatory drugs; Pressure; Retina; Rheological properties; Rheology; Self-assembly; Side effects; Structural analysis; Sustained release; Thermosensitive hydrogel; Toxicity; Triamcinolone acetonide; Tumor necrosis factor-α; Uveitis
• ISSN: 1742-7061; 1878-7568
• DOI: 10.1016/j.actbio.2018.04.019

[Display omitted] Intravitreal/periocular injection of triamcinolone acetonide (TA) suspension is a common uveitis treatment, but it displays a high risk for serious side effects (e.g., high intraocular pressure, retinal toxicity). We report here an intravitreally injectable thermosensitive glycosylated TA (TA-SA-Glu) hydrogel, formed by covalently conjugating glucosamine (Glu) with succinate TA (TA-SA), for treating uveitis. The TA-SA-Glu hydrogelator forms a supramolecular hydrogel spontaneously in aqueous solution with a minimal gelation concentration of 0.25 wt%. Structural analysis revealed that hydrogen bonds assisted by hydrophobic interaction resulted in self-assembled nanofibers. Rheology analysis demonstrated that this TA-SA-Glu hydrogel exhibited a typical thixotropic property. Sustained release of both TA-SA-Glu and TA from the hydrogel occurred throughout the 3-day in vitro release study. The obtained TA-SA-Glu hardly caused cytotoxicity against ARPE-19 and RAW264.7 cells after 24 h of incubation at drug concentration up to 600 μM. In particular, TA-SA-Glu exhibited a comparable anti-inflammatory efficacy to TA in terms of inhibiting the production of nitric oxide, tumor necrosis factor-α, and interleukin-6 in activated RAW264.7 macrophages. Following a single intravitreal injection, 69 nmol TA-SA-Glu hydrogel caused minimal apparent retinal toxicity, whereas the TA suspension displayed significant effects in terms of localized retinal toxicity. A single intravitreal injection of TA-SA-Glu hydrogel was more effective in controlling inflammatory response than that of the TA suspension treatment, particularly in down-regulating the pro-inflammatory Th1 and Th17 effector responses for treating experimental autoimmune uveitis. This study strongly indicates that supramolecular TA-SA-Glu hydrogels may represent a new option for posterior uveitis management. Intravitreal/periocular injection of triamcinolone acetonide (TA) suspension is a common uveitis treatment, but suffers a high risk for serious side effects (e.g., high intraocular pressure, retinal toxicity). We generated an injectable glycosylated triamcinolone acetonide hydrogelator (TA-SA-Glu) hydrogel for treating uveitis. Following a single intravitreal injection, the proposed TA-SA-Glu hydrogel hardly caused apparent retinal toxicity at a dosage of 69 nmol per eye. Furthermore, TA-SA-Glu hydrogel was more effective in controlling non-infectious uveitis over than a TA suspension, particular