High-Pressure Homogenisation Enhances The Physicochemical Performance, Stability and Anticancer Activity of Zn(DDC) 2 -Loaded Liposomes

Zinc diethyldithiocarbamate (Zn(DDC)2) is a lipophilic metal–dithiocarbamate complex with anticancer potential, but poor aqueous solubility limits its pharmaceutical development. This study compared high-pressure homogenisation (HPH) and probe sonication for preparing Zn(DDC)2-loaded liposomes and evaluated their effects on formulation performance, stability and cytotoxicity. Liposomes composed of hydrogenated soy phosphatidylcholine, cholesterol and Zn(DDC)2 were prepared at molar ratios of 45:45:10 and 60:30:10, processed by HPH or probe sonication, and characterised for particle size, PDI, zeta potential, encapsulation efficiency, pH, osmolality, release, 28-day stability and A549 cytotoxicity. HPH produced smaller vesicles (178.0 ± 11.1 and 179.7 ± 15.2 nm), higher-magnitude zeta potentials (−16.4 ± 0.5 and −21.4 ± 1.6 mV), improved encapsulation efficiency and more sustained release than probe sonication. The optimised HPH formulation released 81.4 ± 3.9% Zn(DDC)2 over 24 h compared with 98.3 ± 1.4% from the corresponding sonicated formulation. HPH liposomes also maintained greater physicochemical stability over 28 days. In A549 cells, HPH liposomes showed significantly greater cytotoxicity (IC50 = 3.82 ± 0.75 µM) than sonicated liposomes (7.68 ± 2.51 µM) and free Zn(DDC)2 (54.63 ± 1.59 µM) (p < 0.05). These findings support HPH as a scalable platform for Zn(DDC)2 liposomal delivery and underline the importance of manufacturing process selection in optimising liposomal anticancer formulations.