Multifunctional superparamagnetic iron oxide nanoparticles for combined chemotherapy and hyperthermia cancer treatment.

Superparamagnetic iron oxide (SPIO) nanoparticles have the potential for use as a multimodal cancer therapy agent due to their ability to carry anticancer drugs and generate localized heat when exposed to an alternating magnetic field, resulting in combined chemotherapy and hyperthermia. To explore this potential, we synthesized SPIOs with a phospholipid-polyethylene glycol (PEG) coating, and loaded Doxorubicin (DOX) with a 30.8% w/w loading capacity when the PEG length is optimized. We found that DOX-loaded SPIOs exhibited a sustained DOX release over 72 hours where the release kinetics could be altered by the PEG length. In contrast, the heating efficiency of the SPIOs showed minimal change with the PEG length. With a core size of 14 nm, the SPIOs could generate sufficient heat to raise the local temperature to 43 °C, sufficient to trigger apoptosis in cancer cells. Further, we found that DOX-loaded SPIOs resulted in cell death comparable to free DOX, and that the combined effect of DOX and SPIO-induced hyperthermia enhanced cancer cell death in vitro. This study demonstrates the potential of using phospholipid-PEG coated SPIOs for chemotherapy-hyperthermia combinatorial cancer treatment with increased efficacy.

[1]  Shuming Nie,et al.  Mesoporous silica beads embedded with semiconductor quantum dots and iron oxide nanocrystals: dual-function microcarriers for optical encoding and magnetic separation. , 2006, Analytical chemistry.

[2]  D. Chiappetta,et al.  Colloids and Surfaces B: Biointerfaces , 2013 .

[3]  R. Issels Hyperthermia adds to chemotherapy. , 2008, European journal of cancer.

[4]  C. Heidelberger,et al.  Studies on the quantitative biology of hyperthermic killing of HeLa cells. , 1973, Cancer research.

[5]  V. Torchilin,et al.  Diacyllipid-Polymer Micelles as Nanocarriers for Poorly Soluble Anticancer Drugs , 2002 .

[6]  D. Dupuy,et al.  Thermal ablation of tumours: biological mechanisms and advances in therapy , 2014, Nature Reviews Cancer.

[7]  P. Wust,et al.  Hyperthermia in combined treatment of cancer. , 2002, The Lancet Oncology.

[8]  J. Bull,et al.  Apoptosis in tumors and normal tissues induced by whole body hyperthermia in rats. , 1995, Cancer research.

[9]  Gang Bao,et al.  Self-assembly of phospholipid-PEG coating on nanoparticles through dual solvent exchange. , 2011, Nano letters.

[10]  A. Gibson The European Society for Medical Oncology (ESMO) , 2019, Annals of Oncology.

[11]  R. Müller,et al.  'Stealth' corona-core nanoparticles surface modified by polyethylene glycol (PEG): influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption. , 2000, Colloids and surfaces. B, Biointerfaces.

[12]  P. Wust,et al.  The cellular and molecular basis of hyperthermia. , 2002, Critical reviews in oncology/hematology.

[13]  R. E. Rosensweig,et al.  Heating magnetic fluid with alternating magnetic field , 2002 .

[14]  Gang Bao,et al.  Coating optimization of superparamagnetic iron oxide nanoparticles for high T2 relaxivity. , 2010, Nano letters.

[15]  Jin Suo,et al.  Magnetic targeting of human mesenchymal stem cells with internalized superparamagnetic iron oxide nanoparticles. , 2013, Small.

[16]  Chandana Mohanty,et al.  Dual drug loaded superparamagnetic iron oxide nanoparticles for targeted cancer therapy. , 2010, Biomaterials.

[17]  P. Dhagat,et al.  Multifunctional nanomedicine platform for concurrent delivery of chemotherapeutic drugs and mild hyperthermia to ovarian cancer cells. , 2013, International journal of pharmaceutics.

[18]  H. Kampinga,et al.  Nuclear matrix as a target for hyperthermic killing of cancer cells. , 1998, Cell stress & chaperones.

[19]  P Wust,et al.  Local hyperthermia of N2/N3 cervical lymph node metastases: correlationof technical/thermal parameters and response. , 1996, International journal of radiation oncology, biology, physics.

[20]  D. Benbrook,et al.  Nature Reviews Cancer , 2003 .

[21]  C. Winterford,et al.  The role of apoptosis in the response of cells and tumours to mild hyperthermia. , 1991, International journal of radiation biology.

[22]  Vladimir P. Torchilin,et al.  Accumulation of Protein-Loaded Long-Circulating Micelles and Liposomes in Subcutaneous Lewis Lung Carcinoma in Mice , 1998, Pharmaceutical Research.

[23]  Monty Liong,et al.  Multifunctional inorganic nanoparticles for imaging, targeting, and drug delivery. , 2008, ACS nano.

[24]  Yechezkel Barenholz,et al.  Pharmacokinetics of Pegylated Liposomal Doxorubicin , 2003, Clinical pharmacokinetics.

[25]  J. Otte,et al.  Hyperthermia in cancer therapy , 1988, European Journal of Pediatrics.

[26]  Mark E. Davis,et al.  Nanoparticle therapeutics: an emerging treatment modality for cancer , 2008, Nature Reviews Drug Discovery.

[27]  Hong-Zhuan Chen,et al.  In vivo tumor targeting of tumor necrosis factor-alpha-loaded stealth nanoparticles: effect of MePEG molecular weight and particle size. , 2006, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[28]  Nicholas A Peppas,et al.  Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. , 2006, International journal of pharmaceutics.

[29]  P. Chandrasekharan,et al.  Vitamin E (D-alpha-tocopheryl-co-poly(ethylene glycol) 1000 succinate) micelles-superparamagnetic iron oxide nanoparticles for enhanced thermotherapy and MRI. , 2011, Biomaterials.

[30]  J. Otlewski,et al.  Tumor-specific hyperthermia with aptamer-tagged superparamagnetic nanoparticles , 2013, International journal of nanomedicine.

[31]  E. Wood The Lancet Oncology , 2003 .

[32]  G. Hahn,et al.  Tumor eradication and cell survival after localized hyperthermia induced by ultrasound. , 1979, Cancer research.

[33]  D. Leslie-Pelecky,et al.  Iron oxide nanoparticles for sustained delivery of anticancer agents. , 2005, Molecular pharmaceutics.

[34]  Jayanth Panyam,et al.  Enhancing therapeutic efficacy through designed aggregation of nanoparticles. , 2014, Biomaterials.

[35]  Xiaoyan Lu,et al.  Pegylated Phospholipids-Based Self-Assembly with Water-Soluble Drugs , 2010, Pharmaceutical Research.

[36]  J. Roh,et al.  Comparative pharmacokinetics of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes. , 1986, Cancer research.

[37]  C. Innocenti,et al.  Water-dispersible sugar-coated iron oxide nanoparticles. An evaluation of their relaxometric and magnetic hyperthermia properties. , 2011, Journal of the American Chemical Society.

[38]  G. Gatta,et al.  Critical Reviews in Oncology/Hematology , 2016 .

[39]  Teruo Okano,et al.  Block copolymer micelles for drug delivery: Loading and release of doxorubicin , 1997 .

[40]  J. Bull An update on the anticancer effects of a combination of chemotherapy and hyperthermia. , 1984, Cancer research.

[41]  A. Santoro,et al.  Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[42]  K S Sellins,et al.  Hyperthermia induces apoptosis in thymocytes. , 1991, Radiation research.

[43]  H. Kawai,et al.  Direct measurement of doxorubicin concentration in the intact, living single cancer cell during hyperthermia , 1997, Cancer.

[44]  R. Ivkov,et al.  The magnitude and time-dependence of the apoptotic response of normal and malignant cells subjected to ionizing radiation versus hyperthermia , 2006, International journal of radiation biology.

[45]  H. Maeda,et al.  A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. , 1986, Cancer research.

[46]  S. Curry,et al.  Structural basis of the drug-binding specificity of human serum albumin. , 2005, Journal of molecular biology.

[47]  Wei Liang,et al.  Improving penetration in tumors with nanoassemblies of phospholipids and doxorubicin. , 2007, Journal of the National Cancer Institute.

[48]  J. T. Mayo,et al.  Low-Field Magnetic Separation of Monodisperse Fe3O4 Nanocrystals , 2006, Science.

[49]  G. Hahn,et al.  Thermochemotherapy: synergism between hyperthermia (42-43 degrees) and adriamycin (of bleomycin) in mammalian cell inactivation. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[50]  John C. Bischof,et al.  In vitro characterization of movement, heating and visualization of magnetic nanoparticles for biomedical applications , 2005 .

[51]  Christian Bergemann,et al.  Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumors. , 2008, Biomaterials.