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

• Published in: Journal of controlled release 2023-04, Vol.356, p.93-114
• Main Authors: Swetha, K. Laxmi, Paul, Milan, Maravajjala, Kavya Sree, Kumbham, Soniya, Biswas, Swati, Roy, Aniruddha
• Format: Article
• Language: English
• Subjects: adsorption; Animals; Antineoplastic Agents; apoptosis; blood proteins; breast neoplasms; Cell Line, Tumor; cytotoxicity; Disulfiram; Docetaxel; Drug resistance; Drug Resistance, Multiple; drugs; encapsulation; Hydrogen-Ion Concentration; lungs; metastasis; Mice; nanomedicine; Nanoparticles; P-glycoproteins; pH-responsive nanoparticles; Tumor penetration; Tumor targeting
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2023.02.023

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 disulfiram (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 microenvironment, 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. [Display omitted] •Docetaxel and disulfiram showed high efficacy against resistant cancer cells.•A pH-sensitive NP was developed for tumor-targeted delivery of this combination.•The NP formulation showed enhanced in-vitro antitumor activity.•The NP exhibited improved PK and tumor-targeted accumulation of the cargo.•Against an orthotopic breast cancer, an augmented antitumor efficacy was observed.