Topical administration of in situ gelling formulation containing myricetin-polycarboxylate nanoparticles inhibits murine genital herpes infection.

Genital herpes (GH) is a persistent sexually transmitted infection primarily caused by herpes simplex virus type 2 (HSV-2). Recently, myricetin (MYR), a natural flavonoid with low aqueous solubility, was shown to target HSV gD protein. Here, using computational tools, we showed that MYR forms a stable complex with HSV gD protein. MYR was well tolerated by HeLa cells (CC50 ∼ 2.5 mM) and showed in vitro antiviral activity of MYR against wild-type HSV-2. The low aqueous solubility of MYR and the possibility of metabolic deactivation limit the delivery of MYR. To overcome these challenges, we encapsulated MYR into nanoparticles (NPs) of pharmaceutically acceptable polycarboxylate polymers such as polyvinyl acetate phthalate (PVAP), hydroxypropyl methyl cellulose phthalate (HPMCP), and Eudragit S100, and these MYR-polycarboxylate NPs (size ≤ 100 nm) showed high colloidal stability and chemical stability of MYR for at least 4 weeks. The MYR-polycarboxylate NPs retained the inherent antioxidant activity of MYR in vitro, and MYR-PVAP-NPs showed the highest antiviral activity in vitro among various MYR-polycarboxylate NPs. We developed an in-situ gelling formulation containing MYR-PVAP-NPs to facilitate intravaginal delivery. The in-situ gelling formulation containing MYR-PVAP-NPs showed excellent antiviral efficacy compared to MYR solution in a mouse model of GH.