Enhanced Solubility and Antitumor Activity of Curcumin via Breaking and Rebuilding of the Hydrogen Bond

Abstract

Oral delivery of poorly soluble drugs remains a great challenge. Among these drugs, curcumin, a potential natural antitumor drug candidate, is hindered in its clinical translation by its high hydrophobicity. In this study, we report the development of a highly effective curcumin formulation through the breaking and rebuilding of hydrogen bond approach. The method is green and less toxic to human organisms. By the inherent adjustability of ionic liquids (ILs), the insoluble curcumin drug can be designed to form active pharmaceutical ingredient IL. The IL ([Ch][Cur]) exhibits significantly enhanced solubility and achieve the desired concentration (about 20 mg mL–1) under simulated physiological conditions when compared to that of the neutral curcumin. In [Ch][Cur], the superstrong intramolecular hydrogen bond of neutral curcumin was broken and substituted to form an intermolecular hydrogen-bonding interaction by a cholinium cation. As a result, the curcumin active component can be driven into an aqueous environment and further into tumor cells to achieve a favorable therapeutic effect. The exceptional dissolution and cellular uptake substantially improve the activity of the curcumin drug against cancer cells (inhibition rate of about 90%). Taken together, the strategy to break and rebuild a hydrogen bond may be promising for enhancing the bioavailability and oral delivery of natural curcumin.