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

ABSTRACT

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.