Host-guest complexes of cucurbituril with the neutral guest valrubicin: an experimental and computational study

Valrubicin (VAL) is an N-trifluoroacetyl 14-valerate derivative of the anthracycline doxorubicin (DOX)and is known to have anti-tumor activity. Unfortunately, itis characterized by low solubility and instability in aqueous solutions, which hampers its applications and reduces its therapeutic efficacy.

To address this limitation, different types of cucurbiturils (CBs) were employed to explore VAL-CB complexation to enhance VAL's physicochemical characteristics in aqueous solutions.

Complexes were prepared and characterized using entrapment efficiency (EE %). UV-Vis spectroscopic titration, molecular dynamics (MD), and quantum mechanics (QM) simulations were used to predict binding interactions. In vitro release studies assessed drug release, while stability in water-based solutions was analyzed at 4, 25, and 50 °C.

VAL formed stable host-guest complexes within CB in 1:1 stoichiometry, with a binding affinity of (6.29 ± 0.32 × 10³M^-1) and (2.02 ± 0.11 × 10⁴ M^-1), respectively. Additionally, molecular modeling supported a partial inclusion of the VAL structure in the CB cavity. The VAL-CB complex exhibited a 220,000-fold solubility increase, enhanced stability, and a sustained release profile.

The CB-VAL complex significantly enhanced physicochemical properties of VAL in aqueous solutions, with superiority for CB8. These results highlight the potential of CB7 and CB8 as novel drug delivery systems for hydrophobic drugs, offering a strategy to overcome the limitations of existing solubilization approaches in cancer therapy.