Overcoming drug resistance with a docetaxel and disulfiram loaded pH-sensitive nanoparticle

Previous studies have demonstrated that breast cancer cells deploy a myriad array of strategies to thwart the activity of anticancer drugs like docetaxel (DTX), including acquired drug resistance due to overexpression of drug-efflux pumps like P-glycoprotein (P-gp) and innate drug resistance by cancer stem cells (CSCs). As disul-firam (DSF) can inhibit both P-gp and CSCs, we hypothesized that co-treatment of DTX and DSF could sensitize the drug-resistant breast cancer cells. To deliver a fixed dose ratio of DTX and DSF targeted to the tumor, a tumor extracellular pH-responsive nanoparticle (NP) was developed using a histidine-conjugated star-shaped PLGA with TPGS surface decoration ([DD]NpH-T). By releasing the encapsulated drugs in the tumor microenviron-ment, pH-sensitive NPs can overcome the tumor stroma-based resistance against nanomedicines. In in-vitro studies, [DD]NpH-T exhibited increased drug release at pH 6.8, improved penetration in a 3D tumor spheroid, reduced serum protein adsorption, and enhanced cytotoxic efficacy against both innate and acquired DTX-resistant breast cancer cells. In in-vivo studies, a significant increase in plasma AUC and tumor drug delivery was observed with [DD]NpH-T, which resulted in an enhanced in-vivo anti-tumor efficacy against a mouse orthotopic breast cancer, with a significantly increased intratumoral ROS and apoptosis, while decreasing P-gp expression and prevention of lung metastasis. Altogether, the current study demonstrated that the DTX and DSF combination could effectively target multiple drug-resistance pathways in-vitro, and the in-vivo delivery of this drug combination using TPGS-decorated pH-sensitive NPs could increase tumor accumulation, resulting in improved anti-tumor efficacy.

Automated summary

Previous studies have shown that breast cancer cells employ various strategies to resist anticancer drugs, such as docetaxel, through drug-resistance mechanisms like overexpression of P-glycoprotein and cancer stem cells. By inhibiting both P-glycoprotein and cancer stem cells, the combination of docetaxel and disulfiram shows potential in sensitizing drug-resistant breast cancer cells. This study developed a pH-responsive nanoparticle system for the co-delivery of docetaxel and disulfiram, which demonstrated improved drug release, penetration, and cytotoxic efficacy against drug-resistant breast cancer cells in vitro, as well as enhanced tumor drug delivery and anti-tumor efficacy in vivo.