Iacovino Rosa, Rapuano Filomena, Caso Jolanda Valentina, Russo Agostino, Lavorgna Margherita, Russo Chiara, Isidori Marina, Russo Luigi, Malgieri Gaetano, Isernia Carla
Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Via A. Vivaldi 43, 81100 Caserta, Italy.
Int J Mol Sci. 2013 Jun 25;14(7):13022-41. doi: 10.3390/ijms140713022.
The aptitude of cyclodextrins (CDs) to form host-guest complexes has prompted an increase in the development of new drug formulations. In this study, the inclusion complexes of pipemidic acid (HPPA), a therapeutic agent for urinary tract infections, with native β-CD were prepared in solid state by kneading method and confirmed by FT-IR and 1H NMR. The inclusion complex formation was also characterized in aqueous solution at different pH via UV-Vis titration and phase solubility studies obtaining the stability constant. The 1:1 stoichiometry was established by a Job plot and the inclusion mechanism was clarified using docking experiments. Finally, the antibacterial activity of HPPA and its inclusion complex was tested on P. aeruginosa, E. coli and S. aureus to determine the respective EC50s and EC90s. The results showed that the antibacterial activity of HPPA:β-CD against E. coli and S. aureus is higher than that of HPPA. Furthermore, HPPA and HPPA:β-CD, tested on human hepatoblastoma HepG2 and MCF-7 cell lines by MTT assay, exhibited, for the first time, antitumor activities, and the complex revealed a higher activity than that of HPPA. The use of β-CD allows an increase in the aqueous solubility of the drug, its bioavailability and then its bioactivity.
环糊精（CDs）形成主客体复合物的能力促使新型药物制剂的开发不断增加。在本研究中，采用捏合法固态制备了用于治疗尿路感染的药物吡哌酸（HPPA）与天然β-环糊精的包合物，并通过傅里叶变换红外光谱（FT-IR）和核磁共振氢谱（1H NMR）进行了确证。还通过紫外可见滴定法和相溶解度研究在不同pH的水溶液中对包合物的形成进行了表征，获得了稳定常数。通过Job曲线确定了1:1的化学计量比，并使用对接实验阐明了包合机制。最后，对HPPA及其包合物对铜绿假单胞菌、大肠杆菌和金黄色葡萄球菌的抗菌活性进行了测试，以确定各自的半数有效浓度（EC50）和90%有效浓度（EC90）。结果表明，HPPA:β-环糊精对大肠杆菌和金黄色葡萄球菌的抗菌活性高于HPPA。此外，通过MTT法在人肝癌HepG2和MCF-7细胞系上测试的HPPA和HPPA:β-环糊精首次表现出抗肿瘤活性，且该复合物的活性高于HPPA。β-环糊精的使用提高了药物的水溶性、生物利用度及其生物活性。
