PEG-β-Cyclodextrin polymer-based formulation to increase the antiangiogenic activity of rutin in vivo

Rutin (RTN) is a natural flavonoid with well-documented anti-angiogenic, antioxidant, anti-inflammatory, and anti-cancer properties. However, its therapeutic potential is limited by its extremely low water solubility, which results in poor and unpredictable bioavailability. To address these limitations, we developed a new formulation that complexes RTN with a soluble polymeric β-cyclodextrin (βCPCD). βCPCD is synthesized by cross-linking polyethylene glycol (PEG) and β-cyclodextrin (βCD). The high complexing capacity of βCPCD was demonstrated by a ∼ 50-fold increase in RTN solubility and complete dissolution within 60 min. These results suggest a dual encapsulation mechanism involving (i) the inclusion of RTN within the βCD cavity and (ii) the allocation of RTN within the free volume of the three-dimensional (3D) polymeric structure. The host-guest interaction was confirmed via UV-Vis titration, NMR, µ-Raman and FTIR-ATR spectroscopy analyses. The thermal stability of the lyophilized complex was assessed by TGA, and the morphology was investigated by SEM. Preliminary docking and molecular dynamics simulations were carried out considering a local scenario consisting of a single RTN and a βCD-PEG unit. The excellent biocompatibility of βCPCD in Danio rerio zebrafish embryos (survivability > 95%) and the notable enhancement of the antiangiogenic effect of the RTN complex compared to the free drug highlight the potential of βCPCD as an effective delivery system to improve RTN performance.