Abstract
To alleviate oxidative stress-induced ocular hypertension, grafting of antioxidant molecules to drug carriers enables a dual-function mechanism to effectively treat glaucomatous intraocular pressure (IOP) dysregulation. Providing potential application for intracameral administration of antiglaucoma medications, this study, for the first time, aims to examine in vivo pharmacological efficacy of pilocarpine-loaded antioxidant-functionalized biodegradable thermogels in glaucomatous rabbits. A series of gallic acid (GA)-grafted gelatin-g-poly(N-isopropylacrylamide) (GN) polymers were synthesized via redox reactions at 20–50 °C. Our results showed that raising redox radical initiation reaction temperature maximizes GA grafting level, antioxidant activity, and water content at 40 °C. Meanwhile, increase in overall hydrophilicity of GNGA carriers leads to fast polymer degradation and early pilocarpine depletion in vivo, which is disadvantageous to offer necessary pharmacological performance at prolonged time. By contrast, sustained therapeutic drug concentrations in aqueous humor can be achieved for long-term (i.e., 28 days) protection against corneal aberration and retinal injury after pilocarpine delivery using dual-function optimized carriers synthesized at 30 °C. The GA-functionalized injectable hydrogels are also found to contribute significantly to enhancement of retinal antioxidant defense system and preservation of histological structure and electrophysiological function, thereby supporting the benefits of drug-containing antioxidant biodegradable thermogels to prevent glaucoma development.
Highlights
Among all clinical procedures to lower intraocular pressure (IOP) in treatments against glaucoma, intracameral injection of biodegradable and biocompatible temperature-triggered polymer carriers showed pharmacological potentials as an alternative method to strategically administer pilocarpine in glaucomatous eyes[5]
Characterizations of GNGA carriers obtained at various redox radical initiation reaction temperatures show that T40 samples exhibit the highest degree of antioxidant grafting and strongest gallic acid (GA) molecule-mediated change in carrier properties among all studied groups
We demonstrate that for the animals receiving the mixtures of pilocarpine and GNGA carriers obtained at various redox radical initiation reaction temperatures, both IOP control and antioxidant defense play essential roles in retinal antioxidant activity level for maintenance of a healthy metabolism against glaucoma development
Summary
Among all clinical procedures to lower IOP in treatments against glaucoma, intracameral injection of biodegradable and biocompatible temperature-triggered polymer carriers showed pharmacological potentials as an alternative method to strategically administer pilocarpine in glaucomatous eyes[5]. Results from the short-term study showed that reaction time significantly affected the grafting amount of antioxidant on carrier materials, which determined polymer degradability to further modulate drug release and therapeutic performance. Current study shows that redox radical initiation reaction temperature significantly affects physicochemical properties of the antioxidant-functionalized injectable hydrogels, resulting in differences of pharmacological efficacies on in vivo controlled pilocarpine delivery for treatment of glaucoma-induced corneal and retinal injuries over 28 days. Our findings contribute significantly to the understanding of therapeutic efficacy of the antioxidant-functionalized injectable hydrogels and the role of redox radical initiation reaction temperature in developing carrier biomaterials for the treatment of glaucomatous injury
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