Antioxidant Gallic Acid-Functionalized Biodegradable in Situ Gelling Copolymers for Cytoprotective Antiglaucoma Drug Delivery Systems

Abstract

In clinical ophthalmology, oxidative stress has been proposed as the initiating cause of ocular hypertension, which is one of the risk factors for glaucomatous damage and disease progression. In an attempt to improve the therapeutic efficacy of intracamerally administered pilocarpine, herein, a cytoprotective antiglaucoma drug delivery system composed of antioxidant gallic acid (GA)-functionalized gelatin-g-poly(N-isopropylacrylamide) (GN) biodegradable in situ gelling copolymer was developed for the first time. Analyses by UV-vis and Fourier transform infrared spectroscopies showed the formation of biopolymer-antioxidant covalent linkages in GNGA structures through a radical reaction in the presence of water-soluble redox initiators. The synthesized GNGA polymers with strong free radical scavenging effectiveness exhibited appropriate phase transition temperature and degradation rate as injectable bioerodible depots for minimally invasive pilocarpine delivery to the ocular anterior chamber. During the 2-week in vitro study, the sustained releases of sufficient amounts of pilocarpine for a therapeutic action in alleviating ocular hypertension could be achieved under physiological conditions. Results of cell viability, intracellular reactive oxygen species level, and intracellular calcium concentration indicated that the incorporation of antioxidant GA into GN structure can enhance cytoprotective effects of carrier materials against hydrogen peroxide-induced oxidative stress in lens epithelial cultures. Effective pharmacological responses (i.e., reduction of intraocular pressure and preservation of corneal endothelial cell morphology and density) in rabbits receiving intracameral GNGA injections containing pilocarpine were evidenced by clinical observations. The findings of in vivo studies also support the hypothesis that the GNGA carriers are more advantageous over their GN counterparts for the improvement of total antioxidant status in glaucomatous eyes with chronic ocular hypertension. The synthesized multifunctional molecules may be further used as potential polymer therapeutics for intraocular delivery of bioactive agents.

Epigallocatechin Gallate-Loaded Gelatin-g-Poly(N-Isopropylacrylamide) as a New Ophthalmic Pharmaceutical Formulation for Topical Use in the Treatment of Dry Eye Syndrome

“…Figure 1b shows the results of phase transition experiments in the drug delivery system dissolved in artificial tear solution (ATS). The lower critical solution temperature (LCST) represents the temperature at which a polymer chain shows a coil-to-globule transition in aqueous solution 18 . No significant difference was found in the LCST between GN (26.4 ± 0.3 °C) and EGCG + GN (26.3 ± 0.2 °C) groups ( P > 0.05).…”

On the importance of Bloom number of gelatin to the development of biodegradable in situ gelling copolymers for intracameral drug delivery

“…The initial dry weight (Wi) of GN hydrogels was measured after reaching a steady weight in vacuo. Subsequently, GN samples were immersed in BSS containing 50 ng/ml of MMP-2 (level of predominant gelatinase present in aqueous humor of glaucomatous eyes) at 34°C (i.e., the aqueous humor temperature) (Lai and Luo, 2015).…”

“…From the temperature-triggered sol-gel phase transition described above, the drug-incorporated GN hydrogels were prepared at 34°C and then transferred to another vial containing 50 ng/ml of MMP-2 (level of predominant gelatinase present in aqueous humor of glaucomatous eyes) (Lai and Luo, 2015). Samples were incubated at 34°C with reciprocal shaking (60 rpm) in a thermostatically controlled water bath.…”

Mildly Cross-Linked Dendrimer Hydrogel Prepared via Aza-Michael Addition Reaction for Topical Brimonidine Delivery

“…33–35 In-situ forming hydrogels are also often used as topical drug delivery systems because of ease of administration. 36, 37 The application of hydrogels can result in prolonged pre-corneal residence time and increased ocular bioavailability. 8, 38, 39 Our group has developed a hybrid dendrimer hydrogel/PLGA nanoparticles platform and used it to fabricate a brimonidine/timolol maleate combination formulation for topical application.…”