Multifunctional glutathione-dependent hydrogel eye drops with enhanced drug bioavailability for glaucoma therapy

The development of drug carriers with advanced functions to overcome the low bioavailability of conventional eye drops is critical for the effective treatment of chronic ocular diseases. This paper reports a functional strategy for developing a new hydrogel eye drop with strong mucoadhesive, tight-junction opening, and antioxidant properties, which play important roles in improving the topical treatment of glaucoma. The eye-drop carrier was rationally designed through the conjugation of gelatin with poly(N-isopropylacrylamide) (GN) via the formation of amide linkages, followed by free-radical grafting with glutathione (GSH). In vitro studies revealed that the GN-GSH hydrogels had good ocular biocompatibility, high antioxidant activity, and high paracellular permeability. Interestingly, grafting an appropriate amount of GSH to the GN backbone led to a tradeoff between the bioadhesion and biodegradation properties of the hydrogel, which prolonged its retention on the conjunctival sac of a rabbit's eye without causing any ocular discomfort/irritation. In a rabbit glaucoma model, pharmacological treatment with a single-dose topical instillation of the optimized pilocarpine-loaded GN-GSH hydrogel effectively suppressed disease progression for 14 d, whereas that employing only a GN-based formulation mitigated glaucoma development for 3 d (modest efficacy). This significant enhancement is ascribed to the improved drug bioavailability achieved via the rational exploitation of GSH, which resulted in an eightfold increase in the pilocarpine concentration in the aqueous humor of the glaucomatous eyes. These findings can be valuable for the development of multifunctional GSH-dependent hydrogel eye drops as long-acting ophthalmic formulations for the efficient management of complex and chronic ocular diseases.