Magnetic hyperthermia and pH-responsive effective drug delivery to the sub-cellular level of human breast cancer cells by modified CoFe2O4 nanoparticles

Magnetic iron oxide nanoparticles (MNPs) have been extensively utilized in a wide range of biomedical applications including magnetic hyperthermia agent. To improve the efficiency of the MNPs in therapeutic applications, in this study, we have synthesized CoFe2O4 nanoparticles and its surface was further functionalized with meso-2,3-dimercaptosuccinic acid (DMSA). The anticancer agent, Doxorubucin (DOX) was conjugated with CoFe2O4@DMSA nanoparticle to evaluate the combined effects of thermotherapy and chemotherapy. The drug delivery efficiency of the DOX loaded CoFe2O4@DMSA nanoparticles were examined based on magnetically triggered delivery of DOX into the subcellular level of cancer cells by using MDA-MB-231 cell line. The amine part of the DOX molecules were effectively attached through an electrostatic interactions and/or hydrogen bonding interactions with the carboxylic acid groups of the DMSA functionalities present onto the surface of the CoFe2O4 nanoparticles. The DOX loaded CoFe2O4@DMSA nanoparticles can effectively uptake with cancer cells via typical endocytosis process. After endocytosis, DOX release from CoFe2O4 nanoparticles was triggered by intracellular endosomal/lysosomal acidic environments and the localized heat can be generated under an alternating magnetic field (AMF). In the presence of AMF, the released DOX molecules were accumulated with high concentrations into the subcellular level at a desired sites and exhibited a synergistic effect of an enhanced cell cytotoxicity by the combined effects of thermal-chemotherapy. Importantly, pH- and thermal-responsive Dox-loaded CoFe2O4 nanoparticles induced significant cellular apoptosis more efficiently mediated by active mitochondrial membrane and ROS generation than the free Dox. Thus, the Dox-loaded CoFe2O4@DMSA nanoparticles can be used as a potential therapeutic agent in cancer therapy by combining the thermo-chemotherapy techniques.