Diethyldithiocarbamate copper nanoparticle overcomes resistance in cancer therapy without inhibiting P-glycoprotein

Copper diethyldithiocarbamate [Cu(DDC)₂] is a promising anticancer agent. However, its poor water solubility is a significant obstacle to clinical application. In previous studies, we developed a stabilized metal ion ligand complex (SMILE) method to prepare Cu(DDC)₂ nanoparticle (NP) to address the drug delivery challenge. In the current study, we investigate the use of Cu(DDC)₂ NP for treating P-glycoprotein (P-gp) mediated drug-resistant cancers. We tested its anticancer efficacy with extensive in vitro cell-based assays and in vivo xenograft tumor model. We also explored the mechanism of overcoming drug resistance by Cu(DDC)₂ NP. Our results indicate that Cu(DDC)₂ NP is not a substrate of P-gp and thus can avoid P-gp mediated drug efflux. Further, the Cu(DDC)₂ NP does not inhibit the activity or the expression of P-gp.