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Nanoparticle based formulation of copper diethyldithiocarbamate, an anticancer metabolite of disulfiram, for treatment of cancer.

INTRODUCTION: 
Repurposing of disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug is effective against diverse cancer types in preclinical studies. Recently we identified ditiocarb-copper complex (termed as CuET) as the metabolite of disulfiram which is formed in the human body that is responsible for the anti-cancer effects. This metabolite is preferentially accumulated in tumours where compromises p97-segregase dependent turnover of proteins and other regulatory and stress-response pathways making it selective and efficient anticancer agent. Because of very low solubility in water (<0.5 ng/ml) and other bio-compatible solvents the CuET cannot be used as the direct anticancer agent.

TECHNOLOGY (INVENTION) DESCRIPTION: 
We have developed new formulation of CuET shifting its water solubility by more than 8 orders (˃100 mg/ml). This formulation is based on formation of protein-CuET nanoassemblies (nano-particles) which are very stable. The size of individual particles can be modulated within the range 5-150nm. Suspension of such nanoparticles behaves similarly as true solution and can be applied in-vivo either intraperitonealy or intravenously. Wide variety of proteins can be used for the nano-assembly formation including immunoglobulins introducing additional feature of the particles in the form of targeted delivery.

ADVANTAGES OVER EXISTING SOLUTIONS: 
Currently, the only way of CuET in-vivo dosing is based on metabolism dependent conversion of its precursors (dislufiram and copper). This reaction is by its biological nature very hard-to-define giving various yields of the active compound. Moreover, the disulfiram is metabolized into various additional biologically active agents with potential adverse side effects. Instead, our nano-particles based CuET formulation allows precise dosing. Moreover, the size of the particles can be manipulated to increase its tumor absorbing properties by enhanced permeability and retention (EPR) effect. Finally, the protein(s) forming the CuET-nano assembly can be chosen to selectively target particular cancer cells and personalize composition of nanoparticles for given individual.

DEVELOPMENT STATUS (STAGE): 
Fully mastered production process of the CuET-protein nano-particles scalable for large-scale production. Compound stability data. Preclinical stage – in vitro and in vivo testing for antitumor effects, pharmacokinetics, toxicology.

PUBLICATIONS: 
Nature. 2017 Dec 14;552(7684):194-199. doi: 10.1038/nature25016. Epub 2017 Dec 6.

IP PROTECTION STATUS: 
EP 17193240.3

TECHNOLOGY / IP OWNERS : 
Palacky University, Olomouc