Gemcitabine anticancer activity enhancement by water soluble celecoxib/sulfobutyl ether-β-cyclodextrin inclusion...

We investigated the complexation of celecoxib (CCB) into sulfobuthyl-ether-β-cyclodextrin (SBE-β-CD) for the realization of an inhalable dry-powder formulation containing gemcitabine (GEM) for lung anticancer therapy. Complexation increased the water solubility of CCB (0.003 mg/mL and 0.834 mg/mL for CCB free and complexed, respectively) and produced a quantitative dissolution of the drug within 15 min. The CCB/SBE-β-CD inclusion complex showed a high stability constant (8131 M^-1) not influenced by the presence of GEM in solution. Two-dimensional NMR experiments and computational studies demonstrated that the pyrazole ring of CCB penetrates deeper into SBE-β-CD from the secondary rim. The aromatic rings are positioned at the edge of the cavity, establishing hydrogen bonds with the SBE-β-CD that stabilized the complex. CCB showed limited cytotoxic activity on A549 cell lines. Complexation significantly increased activity passing from 30% to 45% cell mortality. Moreover, CCB/SBE-β-CD strongly improved the cytotoxicity of GEM, observing about 60% of cell mortality for the combined formulation.