Sub-micronization of disulfiram and disulfiram-copper complexes by Rapid expansion of supercritical solution toward augmented anticancer effect

Abstract

Despite the success in exploring and repurposing of its various biological efficacies such as antitumor and others, disulfiram (DSF), a copper-dependent antitumor drug, suffers from multiple shortcomings of poor aqueous solubility and instability in the physiological environment, which often hinder its clinical applicability. Moreover, the limited availability of copper in the body also hampered the therapeutic ability of DSF. Initially, the determined experimental solubility values of DSF (7.89 × 10−5 to 6.71 × 10-4 mole fraction) in supercritical carbon dioxide (SC−CO2) at different critical conditions are subsequently correlated using various empirical models. Further, the sub-micronized products of DSF (with mean diameters ranging from 1.53 ± 0.45 to 0.62 ± 0.11 μm) and its subsequent DSF-copper complexes (CuET) (with mean diameters ranging from 1.45 ± 0.45 to 0.27 ± 0.06 μm) are fabricated using the rapid expansion of supercritical solutions (RESS) process. Further, the suspension ability of these complexes is improved by coating with polyvinylpyrrolidone (PVP) and methoxy b-poly(L-lactide) 2000- poly(ethylene glycol) 2000 (mPLLA-PEG) solution using the RESS-based processes that with the different receiving mediums. The physicochemical properties and dissolution profiles of these composites are systematically recorded. in vitro anti-proliferation studies confirmed the substantial augmentation of bioefficacy of micronized DSF in the presence of copper. Moreover, the polymer-coated DSF or CuET nanoparticles significantly enhanced the toxicity of DSF, attributing to their relatively smaller sizes and excellent dispersibility in the aqueous environment. Thus, our findings showed that the altered dissolution rate of drugs and the synergistic effect of the metal species in CuET complex significantly amplified the antitumor efficacy of DSF, indicating the potential of RESS process in enhancing the dissolution rate as well as substantial antitumor efficiency of nano-sized drugs and their complexes.