title: Efficient treatment of breast cancer xenografts with multifunctionalized iron oxide nanoparticles combining magnetic hyperthermia and anti-cancer drug delivery.
abstract: BACKGROUND
  Tumor cells can effectively be killed by heat, e.g. by using magnetic hyperthermia. The main challenge in the field, however, is the generation of therapeutic temperatures selectively in the whole tumor region. We aimed to improve magnetic hyperthermia of breast cancer by using innovative nanoparticles which display a high heating potential and are functionalized with a cell internalization and a chemotherapeutic agent to increase cell death.
  
  
  METHODS
  The superparamagnetic iron oxide nanoparticles (MF66) were electrostatically functionalized with either Nucant multivalent pseudopeptide (N6L; MF66-N6L), doxorubicin (DOX; MF66-DOX) or both (MF66-N6LDOX). Their cytotoxic potential was assessed in a breast adenocarcinoma cell line MDA-MB-231. Therapeutic efficacy was analyzed on subcutaneous MDA-MB-231 tumor bearing female athymic nude mice.
  
  
  RESULTS
  All nanoparticle variants showed an excellent heating potential around 500 W/g Fe in the alternating magnetic field (AMF, conditions: H=15.4 kA/m, f=435 kHz). We could show a gradual inter- and intracellular release of the ligands, and nanoparticle uptake in cells was increased by the N6L functionalization. MF66-DOX and MF66-N6LDOX in combination with hyperthermia were more cytotoxic to breast cancer cells than the respective free ligands. We observed a substantial tumor growth inhibition (to 40% of the initial tumor volume, complete tumor regression in many cases) after intratumoral injection of the nanoparticles in vivo. The proliferative activity of the remaining tumor tissue was distinctly reduced.
  
  
  CONCLUSIONS
  The therapeutic effects of breast cancer magnetic hyperthermia could be strongly enhanced by the combination of MF66 functionalized with N6L and DOX and magnetic hyperthermia. Our approach combines two ways of tumor cell killing (magnetic hyperthermia and chemotherapy) and represents a straightforward strategy for translation into the clinical practice when injecting nanoparticles intratumorally.
authors.affiliation: Institute for Diagnostic and Interventional Radiology, Jena University Hospital - Friedrich Schiller University Jena, D-07740, Jena, Germany. susanne.kossatz@outlook.de.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kossatz
authors.affiliation: Institute for Diagnostic and Interventional Radiology, Jena University Hospital - Friedrich Schiller University Jena, D-07740, Jena, Germany. julia.grandke@med.uni-jena.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Grandke
authors.affiliation: Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Campus Universitario de Cantoblanco, 28049, Madrid, Spain. pierre.couleaud@imdea.org.|Departamento de Biología, Universidad Autónoma de Madrid, Cantoblanco, 28049, Madrid, Spain. pierre.couleaud@imdea.org.
authors.forename: Pierre
authors.initials: P
authors.lastname: Couleaud
authors.affiliation: Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Campus Universitario de Cantoblanco, 28049, Madrid, Spain. alfonso.latorre@imdea.org.|Departamento de Biología, Universidad Autónoma de Madrid, Cantoblanco, 28049, Madrid, Spain. alfonso.latorre@imdea.org.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Latorre
authors.affiliation: Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Campus Universitario de Cantoblanco, 28049, Madrid, Spain. antonio.aires@imdea.org.|Departamento de Biología, Universidad Autónoma de Madrid, Cantoblanco, 28049, Madrid, Spain. antonio.aires@imdea.org.
authors.forename: Antonio
authors.initials: A
authors.lastname: Aires
authors.affiliation: Unidad Asociada de Nanobiotecnología CNB-CSIC & IMDEA Nanociencia, Campus Universitario de Cantoblanco, 28049, Madrid, Spain. crosbiek@tcd.ie.
authors.forename: Kieran
authors.initials: K
authors.lastname: Crosbie-Staunton
authors.affiliation: Institute for Diagnostic and Interventional Radiology, Jena University Hospital - Friedrich Schiller University Jena, D-07740, Jena, Germany. robert.ludwig@med.uni-jena.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Ludwig
authors.affiliation: Institute for Diagnostic and Interventional Radiology, Jena University Hospital - Friedrich Schiller University Jena, D-07740, Jena, Germany. heidi.daehring@med.uni-jena.de.
authors.forename: Heidi
authors.initials: H
authors.lastname: Dähring
authors.affiliation: Institute for Diagnostic and Interventional Radiology, Jena University Hospital - Friedrich Schiller University Jena, D-07740, Jena, Germany. v_ettelt@web.de.
authors.forename: Volker
authors.initials: V
authors.lastname: Ettelt
authors.affiliation: School of Medicine, Trinity College Dublin, Dublin, Ireland. ana.lazaro@uam.es.
authors.forename: Ana
authors.initials: A
authors.lastname: Lazaro-Carrillo
authors.affiliation: Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Campus Universitario de Cantoblanco, 28049, Madrid, Spain. macarena.calero@uam.es.|School of Medicine, Trinity College Dublin, Dublin, Ireland. macarena.calero@uam.es.
authors.forename: Macarena
authors.initials: M
authors.lastname: Calero
authors.affiliation: Laboratoire CRRET, Université Paris EST Créteil, 61 Avenue du Général de Gaulle, 94010, Créteil, France. sader.maha@gmail.com.
authors.forename: Maha
authors.initials: M
authors.lastname: Sader
authors.affiliation: Laboratoire CRRET, Université Paris EST Créteil, 61 Avenue du Général de Gaulle, 94010, Créteil, France. courty@u-pec.fr.
authors.forename: José
authors.initials: J
authors.lastname: Courty
authors.affiliation: Unidad Asociada de Nanobiotecnología CNB-CSIC & IMDEA Nanociencia, Campus Universitario de Cantoblanco, 28049, Madrid, Spain. YVOLKOV@tcd.ie.|CRANN, Trinity College, Dublin, Ireland. YVOLKOV@tcd.ie.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Volkov
authors.affiliation: Unidad Asociada de Nanobiotecnología CNB-CSIC & IMDEA Nanociencia, Campus Universitario de Cantoblanco, 28049, Madrid, Spain. PRINAMEA@tcd.ie.|CRANN, Trinity College, Dublin, Ireland. PRINAMEA@tcd.ie.
authors.forename: Adriele
authors.initials: A
authors.lastname: Prina-Mello
authors.affiliation: Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Campus Universitario de Cantoblanco, 28049, Madrid, Spain. angeles.villanueva@uam.es.|School of Medicine, Trinity College Dublin, Dublin, Ireland. angeles.villanueva@uam.es.
authors.forename: Angeles
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Campus Universitario de Cantoblanco, 28049, Madrid, Spain. alvaro.somoza@imdea.org.|Departamento de Biología, Universidad Autónoma de Madrid, Cantoblanco, 28049, Madrid, Spain. alvaro.somoza@imdea.org.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Somoza
authors.affiliation: Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Campus Universitario de Cantoblanco, 28049, Madrid, Spain. aitziber.lopezcortajarena@imdea.org.|Departamento de Biología, Universidad Autónoma de Madrid, Cantoblanco, 28049, Madrid, Spain. aitziber.lopezcortajarena@imdea.org.
authors.forename: Aitziber L
authors.initials: AL
authors.lastname: Cortajarena
authors.affiliation: Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Campus Universitario de Cantoblanco, 28049, Madrid, Spain. rodolfo.miranda@imdea.org.|Departamento de Biología, Universidad Autónoma de Madrid, Cantoblanco, 28049, Madrid, Spain. rodolfo.miranda@imdea.org.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Miranda
authors.affiliation: Institute for Diagnostic and Interventional Radiology, Jena University Hospital - Friedrich Schiller University Jena, D-07740, Jena, Germany. ingrid.hilger@med.uni-jena.de.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hilger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000175:diagnosis / Q000473:pathology* / Q000628:therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage; D016503:Drug Delivery Systems; D065546:Drug Liberation; D005260:Female; D005290:Ferric Compounds / Q000737:chemistry*; D006801:Humans; D006979:Hyperthermia, Induced / Q000009:adverse effects / Q000379:methods*; D053768:Metal Nanoparticles / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D055114:X-Ray Microtomography; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D005290:Ferric Compounds; C000499:ferric oxide; D004317:Doxorubicin