Nanogels of dual inhibitor-modified hyaluronic acid function as a potent inhibitor of amyloid β-protein aggregation and cytotoxicity

Inhibition of amyloid β-protein (Aβ) aggregation is considered as a promising strategy for the prevention and treatment of Alzheimer’s disease. Epigallocatechin-3-gallate (EGCG) and curcumin have been recognized as effective inhibitors of Aβ aggregation. Herein, we proposed dual-inhibitor modification of hyaluronic acid (HA) to explore the synergistic effect of the two inhibitors. EGCG-modified HA (EHA) formed dispersed hydrogel structures, while EGCG-curcumin bi-modified HA (CEHA) self-assembled into nanogels like curcumin-modified HA (CHA). Thioflavin T fluorescent assays revealed that the inhibitory effect of CEHA was 69% and 55% higher than EHA and CHA, respectively, and cytotoxicity assays showed that the viability of SH-SY5Y cells incubated with Aβ and CEHA was 28% higher than that with Aβ and the mixture of EHA and CHA. These results clearly indicate the synergism of the two inhibitors. It is considered that the difference in the hydrophobicities of the two inhibitors made the bi-modification of HA provide a favorable CEHA nanostructure that coordinated different inhibition effects of the two inhibitors. This research indicates that fabrication of dual-inhibitor nanosystem is promising for the development of potent agents against Aβ aggregation and cytotoxicity.