Hyperthermia Enhances The Effect Of Magnetic Fe₃O₄nanoparticle Loaded With Daunorubicin On Leukemia and Drug Accumulation In Tumor In Vivo

Multidrug resistance in cancer and adverse effects of chemotherapy are the major obstacles for cancer therapeutics. This study was aimed to investigate the efficiency of novel multifunctional Fe₃O₄ magnetic nanoparticles combined with chemotherapeutic agents and hyperthermia in order to reverse multidrug resistance and reduce side effects by concentrating chemotherapeutics on the target site in vivo leukemia models. K562 and K562/A02 xenograft tumor-bearing nude mice were randomly divided into 4 groups, a control group and the treatment groups were allocated to receive daunorubicin (DNR), Fe₃O₄ magnetic nanoparticles (Fe₃O₄-MNP), and Fe₃O₄ magnetic nanoparticles loaded with daunorubicin (DNR-Fe₃O₄-MNP). All groups were subjected to hyperthermia in an alternating magnetic field. Tumor volume was measured with a vernier caliper. Daunorubicin concentrations in plasma, tumor and non-tumor tissues were determined by high performance liquid chromatography (HPLC). Tumor and non-tumor tissues were stained with Hematoxylin and Eosin for histopathological and microscopic examination. Locations of Fe₃O₄ magnetic nanoparticles in tumor tissues were stained with Prussian blue for microscope examination. In Fe₃O₄-MNP and DNR-Fe₃O₄-MNP treated groups of both K562 and K562/A02 xenograft models, tumor temperature obviously increased and tumor volume became significantly smaller.  Apoptosis was observed in tumor cells treated with  DNR-Fe₃O₄-MNP groups.  In all DNR-Fe₃O₄-MNP groups of K562 and K562/A02 xenograft tumor models, the tumor inhibition rate, daunorubicin concentration  were higher level and  daunorubicin clearance in kidney also was delayed when compared with DNR alone treated group. Location of Fe₃O₄ magnetic nanoparticles with Prussian blue staining showed that Fe₃O₄ magnetic nanoparticles could be seen in tumor tissues. No obvious histopathological damage was observed in other non-tumor tissues.  Fe₃O₄ magnetic nanoparticles played an important role in increasing tumor temperature during hyperthermia, and can be delivered successfully to tumor site in an alternating magnetic field. Fe₃O₄ magnetic nanoparticles loaded with daunorubicin with hyperthermia had the strongest inhibitory effect on tumor and would be potential approach for improving the efficacy of chemotherapeutics, reducing side effects and reversing multidrug resistance in the treatment of leukemia.