Electrostatic Interactions Enable Nanoparticle Delivery of the Flavonoid Myricetin

[Image: see text] Flavonoids are natural polyphenolic compounds with myriad biological activities and potential as prophylactic and therapeutic agents. However, poor aqueous solubility and low bioavailability have limited the clinical utility of flavonoids, suggesting that drug delivery systems (DDSs) may improve their clinical relevance. Therefore, loading of a representative flavonoid (i.e., myricetin) into a diblock, polymeric nanoparticle carrier (NPC) DDS with a cationic corona and hydrophobic core was investigated. Absorbance and fluorescence spectroscopy results revealed association constants and standard Gibbs free energy values that align with previously reported values (K(a) = ∼1–3 × 10(4) M(–1); ΔG° = −5.4 to −6.0 kcal mol(–1)), suggesting that NPCs load myricetin via electrostatic interactions. The zeta potential and gel electrophoresis analysis confirmed this loading mechanism and indicated that NPCs improve myricetin solubility >25-fold compared to myricetin alone. Finally, the dual-drug loading of NPCs was tested using a combination of myricetin and a hydrophobic drug (i.e., farnesol). Electrostatic loading of NPCs with myricetin at concentrations ≤1.2 mM did not affect NPC core loading and release of farnesol, thus demonstrating a novel formulation strategy for the dual-drug-loaded NPC. These findings offer key insights into the NPC DDS design that may enhance the clinical relevance of flavonoid-based therapeutic approaches.