University Pharmacy Department of Pharmacy Administration, Semmelweis University, Hőgyes Endre Str. 7-9., Budapest 1092, Hungary.
Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes Endre Str. 7-9., Budapest 1092, Hungary.
Int J Pharm. 2024 May 25;657:124187. doi: 10.1016/j.ijpharm.2024.124187. Epub 2024 May 1.
Drug repositioning is a high-priority and feasible strategy in the field of oncology research, where the unmet medical needs are continuously unbalanced. Disulfiram is a potential non-chemotherapeutic, adjuvant anticancer agent. However, the clinical translation is limited by the drug's poor bioavailability. Therefore, the molecular encapsulation of disulfiram with cyclodextrins is evaluated to enhance the solubility and stability of the drug. The present work describes for the first time the complexation of disulfiram with randomly methylated-β-cyclodextrin. A parallel analytical andin vitrobiological comparison of disulfiram inclusion complexes with hydroxypropyl-β-cyclodextrin, randomly methylated-β-cyclodextrin and sulfobutylether-β-cyclodextrin is conducted. A significant drug solubility enhancement by about 1000-folds and fast dissolution in 1 min is demonstrated. Thein vitrodissolution-permeation studies and proliferation assays demonstrate the solubility-dependent efficacy of the drug. Throughout the different cancer cell lines' characteristics and disulfiram unspecific antitumoral activity, the inhibitory efficacy of the cyclodextrin encapsulated drug on melanoma (IC about 100 nM) and on glioblastoma (IC about 7000 nM) cell lines differ by a magnitude. This pre-formulation screening experiment serves as a proof of concept of using cyclodextrin encapsulation as a platform tool for further drug delivery development in repositioning areas.
药物重定位是肿瘤学研究领域的一个高度优先且可行的策略，因为该领域的医疗需求持续失衡。双硫仑是一种有潜力的非化疗辅助抗癌药物。然而，由于药物的生物利用度较差，其临床转化受到限制。因此，采用环糊精对双硫仑进行分子包封，以提高药物的溶解度和稳定性。本工作首次描述了双硫仑与随机甲基-β-环糊精的包合作用。对双硫仑与羟丙基-β-环糊精、随机甲基-β-环糊精和磺丁基醚-β-环糊精的包合物进行了平行分析和体外生物学比较。结果表明，药物的溶解度提高了约 1000 倍，在 1 分钟内快速溶解。体外溶出-渗透研究和增殖试验表明了药物的溶解度依赖性疗效。根据不同的癌细胞系的特点和双硫仑的非特异性抗肿瘤活性，环糊精包封药物对黑素瘤（IC 约 100 nM）和神经胶质瘤（IC 约 7000 nM）细胞系的抑制效果有显著差异。该预配方筛选实验证明了将环糊精包封作为进一步药物输送开发的平台工具在药物重定位领域的应用。
