Biomimetic metal-organic nanoparticles prepared with a 3D-printed microfluidic device as a novel formulation for disulfiram-based therapy against breast cancer

Disulfiram (DSF) is currently tested in several clinical trials for cancer treatment in combination with copper (Cu) ions. Usually, DSF and Cu are administered in two separate formulations. In the body, DSF and Cu ions form diethyldithiocarbamate copper complex [Cu(DDC)₂] which has potent antitumor activities. However, the "two formulation" approach often achieved low Cu(DDC)₂ concentration at tumor regions and resulted in compromised anticancer efficacy. Therefore, preformed Cu(DDC)₂ complex administered in a single formulation will have better anticancer efficacy. However, the poor aqueous solubility of Cu(DDC)₂ is a significant challenge for its clinical use. In this work, a biomimetic nanoparticle formulation of Cu(DDC)₂ was produced with a novel SMILE ( Stabilized Metal Ion Ligand complex) method developed in our laboratory to address the drug delivery challenges. The Metal-organic Nanoparticle (MON) is composed of Cu(DDC)₂ metal-organic complex core and surface decorated bovine serum albumin (BSA). Importantly, we designed a 3D-printed microfluidic device to further improve the fabrication of BSA/Cu(DDC)₂ MONs. This method could precisely control the MON preparation process and also has great potential for large scale production of Cu(DDC)₂ MON formulations. We also used a computational modeling approach to simulate the MON formation process in the microfluidic device. The optimized BSA/Cu(DDC)₂ MONs demonstrated good physicochemical properties. The MONs also showed potent antitumor activities in the breast cancer cell monolayers as well as the 3D-cultured tumor spheroids. The BSA/Cu(DDC)₂ MONs also effectively inhibited the growth of tumors in an orthotopic 4T1 breast tumor model. This current study provided a novel method to prepare a biomimetic MON formulation for DSF/Cu cancer therapy.