Disulfiram (DSF), a well-known anti-alcoholism drug, exhibits potent anticancer activity via its metabolite, diethyldithiocarbamate (DDC), which forms a cytotoxic copper complex that selectively targets cancer stem cells. However, its clinical utility is limited by poor solubility and rapid plasma metabolism. This study explores saccharide-linked DDCs as novel prodrugs designed to enhance stability, solubility, and tumour-selective activation. These compounds feature thioglycosidic bonds that shield the DDC moiety from premature degradation while retaining its metal-chelating function to form the active copper(II)bis(N,N-diethyldithiocarbamate) (Cu(DDC)₂) complex. The synthesised derivatives were characterised and evaluated for serum stability and in vitro cytotoxicity across several cancer cell lines, including colorectal, breast, lung, and brain cancers. Copper-complexed saccharide-DDC prodrugs demonstrated remarkable cytotoxicity, with improved biostability and solubility profiles. These findings highlight the potential of saccharide-linked DDCs as stable, copper-activated prodrugs for cancer therapy. Further in vivo studies are warranted to validate their pharmacokinetics and clinical relevance.

Background: Pulmonary drug delivery represents a promising approach for the potential localised treatment of respiratory of non-small-cell lung cancer (NSCLC). However, the efficient delivery of poorly water-soluble drugs remains challenging due to limited solubility and inadequate aerodynamic performance. This study aimed to develop and characterise inhalable dry powder formulations of zinc diethyldithiocarbamate (Zn(DDC)₂) complexes with hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD) for potential pulmonary administration. Methods: Formulations were prepared by freeze-drying and spray-drying, with leucine incorporated at 0%, 5%, and 10% w/w. Formulations were prepared via freeze-drying and spray-drying with leucine incorporation (0%, 5% and 10% w/w) to evaluate their physicochemical properties, flowability and aerodynamic performance. Results: Spray-dried formulations exhibited significantly lower densities (as low as 1.03 ± 0.71 g/cm³), enhanced flowability, improved aerosolisation and higher fine particle fraction (FPF) values (up to 40.12 ± 0.60%) compared to freeze-dried powders (20.03 ± 2.79%). The incorporation of leucine further reduced powder density down to 0.72 ± 0.34 g/cm³ and increased surface corrugation as shown in SEM images, improving aerosolisation performance, with FPF values up to 76.77 ± 1.18%. Next Generation Impactor (NGI) analysis confirmed that leucine-containing formulations exhibited a greater proportion of particles within the respirable aerodynamic diameter range (1–5 μm), suggesting suitability for deep lung deposition. Conclusions: These results demonstrate that spray-dried Zn(DDC)₂–cyclodextrin powders, particularly those modified with 10% leucine, offer excellent potential for pulmonary delivery in NSCLC therapy. Further in vivo studies are warranted to evaluate therapeutic efficacy and safety.