Reversal of doxorubicin-resistance by delivering tetramethylprazine via folate-chitosan nanoparticles in MCF-7/ADM cells

Multidrug resistance (MDR) is a current challenge for cancer therapy. Tetramethylprazine (TMP) has been shown to reverse MDR to several anti-cancer drugs, but the lack of appropriate carrier and a short half-life limits its clinical application. In this study, we developed folate-chitosan nanoparticles loaded with TMP (FA-TMP-NP) to improve the sensitivity of MDR cells to chemotherapy. MCF-7/ADM cells with high folate receptor expression and K562/ADM cells with low folate receptor expression are treated with FA-TMP-NP and adriamycin (ADM), using chitosan nanoparticles loaded with TMP (CS-TMP-NP) and TMP solution as control. We determined the cytotoxicity by MTT assay, ADM accumulation by flow cytometer and laser scanning confocal microscope, and intracellular ADM concentrations by fluorescence spectrophotography. We analyzed the protein levels of P-glycoprotein (P-gp) and glutathione S-transferases-π (GST-π) by Western blotting and the mRNA levels of MDR-1 and GST-π by real-time PCR. Compared with the control preparations, FA-TMP-NP significantly enhanced the ADM fluorescence intensity and increased the intracellular concentrations of ADM in MCF-7/ADM cells in a dose-dependent and time-dependent manner, accompanied with decreased P-gp and GST-π. In contrast, there was no significant difference between FATMP-NP and control preparations in K562/ADM cells. Our results indicate that FA-TMP-NP is a novel drug delivery system, which could improve the specificity of tumor cells with high folate receptor expression to chemotherapy, suggesting promising further development as a reversal agent for MDR.