Quercetin and 3-O-methylquercetin in vitro skin layers permeation/retention from hydrogels: why only a methoxy group difference determines different behaviors?

Abstract

Objectives: The present study was designed to verify if quercetin (QCT), a flavonoid with antioxidant and antiviral activity, and 3-O-methylquercetin (3OMQ), a quercetin C3-methoxylated derivative, present differences in their behavior against complexation with β-cyclodextrin (β-CD) and the corresponding permeation/retention trhough porcine ear skin, when incorporated into hydroxypropyl methylcellulose (HPMC) or chitosan (CS) hydrogels. Methods: The influence of β-CD on the skin permeation/retention of QCT and 3OMQ from hydrogels is comparatively evaluated for both flavonoids using porcine ear skin in Franz cells model. The properties of the two flavonoids using the semi-empirical method Recife Model was studied. Key findings: Quercetin presented higher skin retention compared with its C3-methoxy derivative 3OMQ. The best permeation/retention of QCT was observed when it was incorporated into CS hydrogel containing 5% β-CD, whereas, for 3OMQ, the HPMC hydrogel containing 5% β-CD was the best formulation. The flavonoids complexation with β-CD in water occurred preferentially with the insertion of the B ring through the secondary OH rim. Conclusions: The dynamic molecular modeling revealed that the methyl group at C3 in 3OMQ molecule determined significant difference in its complexation with β-CD, in comparison to its analogous QCT and that difference is coincident with the permeation behavior of these flavonoids, denoting a possible relationship with their molecular dynamics.