title: Magnetic hyperthermia and pH-responsive effective drug delivery to the sub-cellular level of human breast cancer cells by modified CoFe2O4nanoparticles.
abstract: 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 CoFe2O4nanoparticles 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 CoFe2O4nanoparticles. The DOX loaded CoFe2O4@DMSA nanoparticles can effectively uptake with cancer cells via typical endocytosis process. After endocytosis, DOX release from CoFe2O4nanoparticles 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 CoFe2O4nanoparticles 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.
authors.affiliation: Marine-Integrated Bionics Research Center, Pukyong National University, Busan 48513, South Korea.
authors.forename: Yunok
authors.initials: Y
authors.lastname: Oh
authors.affiliation: Marine-Integrated Bionics Research Center, Pukyong National University, Busan 48513, South Korea.
authors.forename: Madhappan Santha
authors.initials: MS
authors.lastname: Moorthy
authors.affiliation: Marine-Integrated Bionics Research Center, Pukyong National University, Busan 48513, South Korea.
authors.forename: Panchanathan
authors.initials: P
authors.lastname: Manivasagan
authors.affiliation: Marine-Integrated Bionics Research Center, Pukyong National University, Busan 48513, South Korea.
authors.forename: Subramaniyan
authors.initials: S
authors.lastname: Bharathiraja
authors.affiliation: Marine-Integrated Bionics Research Center, Pukyong National University, Busan 48513, South Korea; Interdisciplinary Program of Biomedical Mechanical & Electrical Engineering, Pukyong National University, Busan 48513, South Korea; Department of Biomedical Engineering and Center for Marine-Integrated Biomedical Technology (BK21 Plus), Pukyong National University, Busan 48513, South Korea. Electronic address: jungoh@pknu.ac.kr.
authors.forename: Junghwan
authors.initials: J
authors.lastname: Oh
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003035:Cobalt / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D005290:Ferric Compounds / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006979:Hyperthermia, Induced; D060526:Magnetic Fields; D058185:Magnetite Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D004113:Succimer / Q000737:chemistry
chemical_list: D005290:Ferric Compounds; D058185:Magnetite Nanoparticles; C000499:ferric oxide; D003035:Cobalt; D004317:Doxorubicin; D004113:Succimer
keywords: Apoptosis; Endocytosis; Magnetic hyperthermia; Sub-cellular drug delivery