Spectral and Molecular Modeling Studies on the Influence of β-Cyclodextrin and Its Derivatives on Albendazole and Its Anti-Proliferative Activity Against Pancreatic Cancer Cells

Albendazole is a benzimidazole derivative with a broad spectrum of activity against human and animal helminthes parasites. It also exhibits potent anticancer activity against hepatocellular, colorectal and ovarian cancers. Major limitation of Albendazole in its therapeutic use as anticancer agent has been its poor aqueous solubility (0.2 μg/ml in water at 25 °C). Consequently, it is poorly absorbed from the gastrointestinal tract (<5%) resulting in poor bioavailability and different approaches have been investigated to overcome this handicap. In the present study, we describe inclusion complexes of Albendazole with β-cyclodextrin and two of its modified derivatives, viz. hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin (Captisol^®) prepared by kneading, microwave irradiation and spray drying methods and characterized by Spectroscopy (FTIR), powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The solubilizing effects and interactions of Albendazole with cyclodextrins (CDs) were investigated using phase solubility and NMR studies which indicated that Captisol has a high affinity for the drug and forms inclusion complex having 1:1 molar ratio. This was also observed in the computer simulations and binding energies calculated by the MM-PBSA method. Among the preparative methods spray drying technique was found to be more useful in yielding faster drug dissolution and enhanced aqueous solubility. The water soluble cyclodextrin complexes of Albendazole exhibited higher anti-proliferative activities in dose and time dependent manner against pancreatic cancer cells. The complexes also inhibited colony formation, down-regulated cell cycle marker proteins cylinD1 and c-Myc as well as expression of cancer promoting genes COX-2, VEGF and HIF-1 respectively.