Department of Drug Sciences, University of Catania, V.le A. Doria, 6 - 95125 Catania, Italy.
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, V.le F. Stagno D'Alcontrés, 31 - 98166 Messina, Italy.
Carbohydr Polym. 2019 Feb 15;206:792-800. doi: 10.1016/j.carbpol.2018.11.060. Epub 2018 Nov 20.
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) 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.
我们研究了塞来昔布（CCB）与磺丁基醚-β-环糊精（SBE-β-CD）的络合作用，以实现含有吉西他滨（GEM）的可吸入干粉制剂用于肺癌的抗癌治疗。络合作用提高了 CCB 的水溶性（游离 CCB 为 0.003mg/mL，络合后为 0.834mg/mL），并在 15 分钟内使药物完全溶解。CCB/SBE-β-CD 包合物具有较高的稳定常数（8131M），不受溶液中 GEM 的影响。二维 NMR 实验和计算研究表明，CCB 的吡唑环从二级边缘更深地穿透 SBE-β-CD。芳环位于空腔的边缘，与 SBE-β-CD 形成氢键，从而稳定了复合物。CCB 对 A549 细胞系的细胞毒性活性有限。络合作用使活性显著提高，从 30%增加到 45%的细胞死亡率。此外，CCB/SBE-β-CD 大大增强了 GEM 的细胞毒性，对于联合制剂，观察到约 60%的细胞死亡率。
