Design and development of zinc diethyldithiocarbamate nanoliposomes for potential anticancer therapy

<p dir="ltr">Introduction: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Zinc diethyldithiocarbamate (Zn(DDC)₂), a disulfiram metabolite, shows potential as an anticancer drug but suffers from poor solubility and bioavailability, limiting its therapeutic effectiveness. This thesis aimed to design, develop, and optimise liposomal formulations of Zn(DDC)₂ to improve its solubility, stability, and therapeutic potential for CRC treatment.</p><p dir="ltr">Materials & Methods: Liposomal formulations were prepared using various phospholipids, preparation methods, size reduction techniques, and drug-to-lipid ratios (D/L). Dimethyl sulfoxide (DMSO) was explored as a co-solvent to enhance Zn(DDC)₂ solubility at different concentrations. Polyethylene glycol (PEG) was incorporated to improve liposome stability. The formulations were characterised using dynamic light scattering (DLS), transmission electron microscopy (TEM), drug encapsulation efficiency (EE%), and thermal analysis. Stability was assessed under storage and physiological conditions, including human and horse sera. In vitro cytotoxicity was tested on sensitive and resistant CRC cell lines, with combination studies using 5-fluorouracil (5FU) to investigate synergistic effects.</p><p dir="ltr">Results: Encapsulating Zn(DDC)₂ presented significant challenges, but the ethanol-based pro-liposome method with HPH and DMSO as a co-solvent yielded liposomes with impressive high EE% of 75 ± 12% for non-PEGylated liposomes and 84 ± 13% for PEGylated liposomes. DMSO significantly improved Zn(DDC)₂ solubility and liposomal characteristics, increasing drug loading. PEGylation further enhanced stability. In vitro, cytotoxicity assays showed a reduction in IC50 values from 23.8 ± 12.3 μM to 5.79 ± 3.39 μM for non-PEGylated liposomes and 7.35 ± 4.48 μM for PEGylated formulations. Combination of Zn(DDC)2 liposomal formulations with 5FU significantly reduced its IC50 from >1000 μM to 32.71 ± 3.71 μM for non-PEGylated and 30.85 ± 4.00 μM for PEGylated liposomes, showing potential synergistic anticancer effects.</p><p dir="ltr">Conclusions: This research concludes that Zn(DDC)₂-loaded liposomes are a promising drug delivery system for enhancing the solubility, stability, and efficacy of Zn(DDC)₂ in potential CRC treatment. This is the first study to successfully design and develop PEGylated Zn(DDC)₂ liposomes containing DMSO as a co-solvent, with high EE%, offering a more practical approach for potential clinical use.</p>