Megnatic Nanocarrier Of Doxorubicin Enhancement Ntitumor Activity With Simple External Magneticd Fields

Background:Drug delivery and penetration into neoplastic cells is critical for the effectiveness of solid tumor chemotherapy.Magnetic nanoparticles (MNP) are known to be versatile tools in diagnostic and drug therapy. Development of magnetic nanoparticles and techniques for their safe transport and concentration in specific sites in the body would constitute a powerful tool for drug therapy in vivo. The anthracycline antibiotic adriamycin or doxorubicin is a highly efficient antineoplastic agent commonly used in the therapy of a variety of cancers like osteosarcoma, leukaemia, lymphomas, ovarian cancer and late stage breast cancer. During chemotherapy, however, pharmacologically active doxorubicin reaches the tumor tissue with poor specificity and can induce dose-limiting toxicity. Moreover, the cancer cells may eventually develop resistance to multiple chemotherapeutics. These problems have long been primary hindrances for the clinical application of doxorubicin. To tackle these difficulties, decades of research have focused on developing cancer-specific drugs or delivery systems that can selectively localise chemotherapeutics to the tumor site.The goal of the present study was to assess whether MNP conjugated with doxorubicin can be more selectively penetrated, accumulated and kill cancer cells using an external magnetic fields.Methods:Doxorubicin and Fe3O4 was incorporated into PLGA, by a self-assembly procedure to form a micelle-encapsulated Fe3O4 and doxorubicin (Fe3O4-PLGA-Dox), In vitro, intracellular distribution of Fe3O4-PLGA-Dox was examined using fluorescence microscopy and the apoptosis of the mouse Lewis lung cancer cells (LLC) was examined by Annexin V-FITC assay using flow cytometry, In vivo, C57BL/6 mice (n=10 per group) bearing subcutaneous LLC were treated with Fe3O4PLGA-Dox and Fe3O4-PLGA-Dox with external magnetic fields, compare with free doxorubicin, tumor growth and mortality were examined.Results:in vitro, Fe3O4PLGA-Dox was internalized in cytoplasm and nucleus by tumor cells quickly, while very few was taken by normal human lung cells only in cytoplasm, Fe3O4-PLGA-Dox enhanced tumor cells cytotoxicity and apoptosis. In vivo, Fe3O4-PLGA-Dox with external magnetic field display significant reductions in tumor volume compared with free doxorubicin or Fe3O4-PLGA-Dox in the subcutaneous LLC tumor model. P＜0.05. Fe3O4-PLGA-Dox with external magnetic field treatment prolonged survival and reduced metastases. No side effects happened, No lesions was found in heart, lung, spleen,liver and kidney, while iron oxide was deposited in tubules of kidney in a few mice which was not applied external Magnetic Fields.Conclusions:We developed a Fe3O4-PLGA based nanocarrier of doxorubicin that improve the drug's accumulation, penetration and antitumor activity, increase cytotoxicity in vitro and enhance antitumor activity in vivo, especially with external Magnetic Fields.The present work demonstrates that a simple external magnetic field is all that is necessary to target a drug to a specific site inside the body. This targeted drug delivery with magnetic nanoparticles and simple external Magnetic Fields may provide a new strategy for design of cancer therapies.