RESUMO
In the present study, a covalently cross-linked chitosan hydrogel sheet was fabricated and assessed as an ophthalmic carrier for topical delivery of levofloxacin. Upon mixing 4-arm polyethylene glycol with aldehyde end groups (4-arm PEG-CHO) with glycol chitosan (GC) at various feed ratios, a series of hydrogel sheets formed spontaneously under mild conditions. Rheological characterization illustrated that the gelation time and moduli of the hydrogels could be tuned by controlling the component concentrations. The swelling ratio of hydrogels increased with decreasing 4-arm PEG-CHO and GC concentrations. The proposed hydrogel exhibited a typical porous structure, with pore size in the range 20-150 µm. This structure allowed the encapsulated levofloxacin to be released from the hydrogel matrix via diffusion within the first 0.5 h, followed by a sustained release up to 24 h. In vitro cytotoxicity and biocompatibility assays showed that the proposed hydrogels are relatively noncytotoxic and have excellent cytocompatibility with L-929 cells after 24 h of incubation. Furthermore, an ocular irritation test demonstrated the non-irritant character of the proposed hydrogel after topical application. These characteristics support the potential use of covalently cross-linked chitosan hydrogel sheets in topical ophthalmic drug delivery applications.
Assuntos
Quitosana/química , Olho , Hidrogel de Polietilenoglicol-Dimetacrilato , Hidrogéis , Levofloxacino , PolietilenoglicóisRESUMO
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 0.25â¯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 24â¯h of incubation at drug concentration up to 600⯵M. 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, 69â¯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. STATEMENT OF SIGNIFICANCE: 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 69â¯nmol per eye. Furthermore, TA-SA-Glu hydrogel was more effective in controlling non-infectious uveitis over than a TA suspension, particularly in terms of down-regulating the pro-inflammatory Th1 and Th17 effector responses for treating experimental autoimmune uveitis (EAU). This study strongly indicates that TA-SA-Glu supramolecular hydrogels may represent a new option for the management of various intraocular inflammations.