Design and synthesis of selenium nanoparticles to overcome multiple drug resistance of cancer cells

Abstract

The objective of this research is to synthesize selenium nanoparticles (SeNPs) stabilized by chitosan as a drug carrier for delivery doxorubicin to overcome drug-resistant in cancer cells. One important mechanism of multidrug resistance (MDR) includes decreased drug influx and increased drug efflux, leading to insufficient drug concentration to kill cancer cells. Therefore, to overcome MDR by increasing cellular uptake, the surface of SeNP was functionalized to provide 3 structural features: (i) a positive charge to improve their solubility, (ii) gallic acid, a hydrophobic molecule to enhance biocompatibility and (iii) folic acid, a targeting molecule to target cancer cells and enhance cellular uptake. The cytotoxicity of the DOX-SeNPs@TMC-FA was evaluated and found to enhance the activity of DOX by approximately 10-fold, resulting in decreased IC50 values compared to free DOX, while it showed less toxic in normal cells (WI-38). SeNPs@TMC-FA were taken up by cells, with cellular uptake increased further by folate receptor-mediated endocytosis, to overcome multidrug resistance. In addition, the DOX release profiles showed a pH dependence, which exhibited a faster release of DOX at pH 5.3 than at pH 7.4. The cumulative release amount of DOX at pH 5.3 was 54.1% within 2 h and 95.5% at 6 h, whereas the release rate at pH 7.4 was 12.3% in 2 h and 42.2% for 6 h. Mechanistic studies suggested that DOX-SeNPs@TMC-FA induced cell death through the apoptosis pathway by involvement of caspase-3 and PARP proteins. Hence, the results demonstrated that SeNPs@TMC-FA, has potential to develop as targeted carrier for overcoming drug resistance cells.