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Cyclodextrin encapsulation enabling the anticancer repositioning of disulfiram: Preparation, analytical and in vitro
Beáta-Mária Benkő1, Gergő Tóth2, Dorottya Moldvai3
1University Pharmacy Department of Pharmacy Administration, Semmelweis University, Hőgyes Endre Str. 7-9., Budapest 1092, Hungary.
Abstract:
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 (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.
Insights
Drug repositioning enhances disulfiram
Area of Science:
- Oncology
- Drug Delivery
- Nanotechnology
Background:
- Drug repositioning is crucial for unmet needs in oncology.
- Disulfiram shows potential as an adjuvant anticancer agent.
- Poor bioavailability limits disulfiram's clinical use.
Purpose of the Study:
- To evaluate molecular encapsulation of disulfiram with cyclodextrins.
- To enhance disulfiram's solubility and stability.
- To compare different cyclodextrin complexation methods.
Main Methods:
- Complexation of disulfiram with randomly methylated-β-cyclodextrin.
- Analytical and in vitro biological comparison of disulfiram inclusion complexes.
- Dissolution-permeation studies and proliferation assays.
Main Results:
- Achieved ~1000-fold solubility enhancement and rapid dissolution.
- Demonstrated solubility-dependent anticancer efficacy in vitro.
- Observed significant differences in efficacy across melanoma and glioblastoma cell lines.
Conclusions:
- Cyclodextrin encapsulation significantly improves disulfiram's properties.
- Encapsulated disulfiram shows potent anticancer activity.
- Cyclodextrin encapsulation is a viable platform for drug delivery development in oncology.
