Reversal of multidrug resistance by cisplatin-loaded magnetic Fe(3)O(4) nanoparticles in A549/DDP lung cancer cells in vitro and in vivo

The purpose of this study was to explore whether magnetic Fe(3)O(4) nanoparticles (Fe(3)O(4)-MNP) loaded with cisplatin (Fe(3)O(4)-MNP-DDP) can reverse DDP resistance in lung cancer cells and to investigate mechanisms of multidrug resistance in vitro and in vivo. MTT assay showed that DDP inhibited both A549 cells and DDP-resistant A549 cells in a time-dependent and dose-dependent manner, and that this inhibition was enhanced by Fe(3)O(4)-MNP. An increased rate of apoptosis was detected in the Fe(3)O(4)-MNP-DDP group compared with a control group and the Fe(3)O(4)-MNP group by flow cytometry, and typical morphologic features of apoptosis were confirmed by confocal microscopy. Accumulation of intracellular DDP in the Fe(3)O(4)-MNP-DDP group was greater than that in the DDP group by inductively coupled plasma mass spectrometry. Further, lower levels of multidrug resistance-associated protein-1, lung resistance-related protein, Akt, and Bad, and higher levels of caspase-3 genes and proteins, were demonstrated by reverse transcriptase polymerase chain reaction and Western blotting in the presence of Fe(3)O(4)-MNP-DDP. We also demonstrated that Fe(3)O(4)-MNP enhanced the effect of DDP on tumor growth in BALB/c nude mice bearing DDP-resistant human A549 xenografts by decreasing localization of lung resistance-related protein and Ki-67 immunoreactivity in cells. There were no apparent signs of toxicity in the animals. Overall, these findings suggest potential clinical application of Fe(3)O(4)-MNP-DDP to increase cytotoxicity in lung tumor xenografts.