Nanoparticle mediated codelivery of nifuratel and doxorubicin for synergistic anticancer therapy through STAT3 inhibition

Chemotherapy is one of the most potent strategies to treat gastric cancer in clinic. However, the resistance of cancer cells to chemotherapeutics is a remarkable impediment to the treatment. Moreover, signal transducer and activator of transcription 3 (STAT3) is a critical transcriptional factor that over-activated in gastric cancer, and highly involved in the induction of chemoresistance. In this study, we developed poly (lactic-co-glycolic acid) (PLGA) nanoparticles to achieve the simultaneous codelivery of doxorubicin (DOX) and nifuratel (NIF, a novel STAT3 inhibitor) for enhanced cancer therapy. The synergistic effect of DOX and NIF against cancer cells was evaluated in gastric cancer cells. PLGA nanoparticles with an optimal ratio of DOX and NIF (DNNPs) were prepared and characterized. The cellular uptake and anticancer effects of DNNPs were investigated, and the underlying mechanisms were further explored. DNNPs presented as a spherical shape, provided sustained release profiles, and exhibited significantly increased uptake and cytotoxicity in gastric cancer cells. Mechanism studies showed that DNNPs significantly induced mitochondrial-dependent apoptosis and inhibited STAT3 phosphorylation, explaining the enhanced anticancer effect. These results suggested that DNNPs represented a promising strategy against gastric cancer by inhibiting the STAT3 pathway and amplifying apoptosis.