Cyclodextrin encapsulation enabling the anticancer repositioning of disulfiram: Preparation, analytical and in vitro biological characterization of the inclusion complexes

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 and in vitro biological comparison of disulfiram inclusion complexes with hydroxypropyl-β-cyclodextrin, randomly methylated-β-cyclodextrin and sulfobutylether-β-cyclodextrin is conducted.

Highlights

• Optimized disulfiram-loaded drug delivery system can be designed with cyclodextrin complexes.
• Comparison of disulfiram’s complexes with various β-cyclodextrin derivatives.
• Disulfiram and methylated β-cyclodextrin inclusion complex suggests an anticancer repositioning.
• Tailored disulfiram drug delivery system can be developed for the target environment.

A significant drug solubility enhancement by about 1000-folds and fast dissolution in 1 min is demonstrated. The in vitro dissolution-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 (IC₅₀ about 100 nM) and on glioblastoma (IC₅₀ 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.

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Materials

DIS (Mw = 296.54 g/mol, purity 97 %) was obtained from Sigma-Aldrich Chemie GmbH (Schnelldorf, Germany). All native CDs (α-, β- and γ-CD with Mw = 972.9, Mw = 1135, Mw = 1297.2 g/mol, respectively) and their derivatives: hydroxypropyl-β-cyclodextrin (HPBCD) with different degrees of substitution (DS) ∼ 3, 4.5, 6 (with Mw = 1309.3, Mw = 1387, Mw = 1483.6 g/mol, respectively); randomly methylated-β-cyclodextrin (RAMEB) DS ∼ 12 (Mw = 1303 g/mol), sulfobutylether-β-cyclodextrin sodium salt (SBE) DS ∼ 6.5 (Mw = 2163.3 g/mol) were the products of Cyclolab R&D Ltd. (Budapest, Hungary). Ethanol (EtOH) was purchased from Molar Chemicals Ltd (Halásztelek, Hungary), methanol (MeOH), deuterated methanol (CD3OD), deuterium oxide (D2O), acetonitrile (ACN) and dimethyl sulfoxide (DMSO) were ordered from Sigma-Aldrich Hungary (Budapest, Hungary). Ultrapure, deionized water was prepared by a Milli-Q Direct 8 Millipore system (Milford, MA, USA), Aqua ad iniectabilia, gentamycin 80 mg/2 ml injection (Sandoz GmbH, Kundl, Austria), and 2 ml syringes were from University Pharmacy Department of Pharmacy Administration, Semmelweis University. Glioblastoma cell line (U251MG, ECACC-09063001) was a kindly provided by William P J Leenders (Department of Biochemistry, Radboud University Medical Center, Nijmegen, The Netherlands) in a collaborative work (Hujber et al., 2018). Melanoma cell line (A2058, ECACC-91100402) was a gift from Chemotaxis Research Group, Semmelweis University, led by László Kőhidai. For the cell cultures, Dulbecco’s Modified Eagle Medium (DMEM) High Glucose (HG) with Sodium Pyruvate basal media, supplemented with 10 % foetal bovine serum (FBS), 2 mM L-glutamine, and 100UI/ml penicillin–streptomycin, was obtained from Biosera (Nuaille, France). Acceptor Sink Buffer and microFlux polyvinylidenfluoride (PVDF) hydrophobic membranes were purchased from Pion Inc. Ltd. (East Sussex, UK). Hydrophilic PTFE syringe filters, with 13 mm and 25 mm diameter and 0.45 µm pore size were ordered from Lab-Ex Ltd. (Budapest, Hungary). All other chemicals used were of analytical grade from commercial suppliers.

Beáta-Mária Benkő, Gergő Tóth, Dorottya Moldvai, Szabina Kádár, Edina Szabó, Zoltán-István Szabó, Márta Kraszni, Lajos Szente, Béla Fiser, Anna Sebestyén, Romána Zelkó, István Sebe, Cyclodextrin encapsulation enabling the anticancer repositioning of disulfiram: Preparation, analytical and in vitro biological characterization of the inclusion complexes, International Journal of Pharmaceutics, Volume 657, 2024, 124187, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124187.

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