Suppressed Autoxidation, Enhanced Antioxidant Activity, and Improved Cytocompatibility of Epigallocatechin Gallate via Alginate Site-Specific Conjugation with Tunable Substitution Degree

Abstract

Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, exhibits strong antioxidant activity but suffers from poor stability due to rapid autoxidation under physiological conditions. In this study, we developed alginate–EGCG conjugates via a site-selective thiol-quinone addition reaction under mild aqueous conditions. The conjugation preserved EGCG’s flavanic structure while enabling tunable degrees of substitution (DS). We systematically evaluated the oxidative stability, antioxidant activity, and cytocompatibility of alginate–EGCG conjugates in comparison with free EGCG and a mixture of EGCG and alginate. Alginate–EGCG conjugates significantly suppressed EGCG autoxidation, reduced hydrogen peroxide generation, and improved cytocompatibility in human renal epithelial cells, especially at a low DS. Furthermore, alginate–EGCG conjugates retained or even enhanced superoxide anion radical scavenging activity, with higher DS conjugates exhibiting greater antioxidant effects. In addition, dynamic light scattering analysis revealed DS-dependent particle formation via self-assembly. These findings demonstrate that covalent conjugation with natural polymers is an effective strategy to improve oxidative stability and biological functionality of plant-derived polyphenols, offering a promising approach for developing advanced antioxidant materials for food, cosmetic, and biomedical applications.