title: Anin vivotransmission electron microscopy study of injected dextran-coated iron-oxide nanoparticle location in murine breast adenocarcinoma tumors versus time.
abstract: Investigators are just beginning to use hyperthermia generated by alternating magnetic field (AMF) activated iron oxide nanoparticles (IONPs) as a promising avenue for targeted cancer therapy. An important step in understanding cell death mechanisms in nanoparticle AMF treatments is to determine the location of these nanoparticles in relation to cellular organelles. In this paper, we report on transmission electron microscopy (TEM) studies designed to define the position of 100 nm diameter dextran-coated iron oxide nanoparticles in murine breast adenocarcinoma (MTG-B)and human colon adenocarcinoma tumors propagated in mice.
  
  
  METHODS
  Iron oxide nanoparticles (5 mg/g tumor) were injected into intradermal MTG-B flank tumors on female C3H/HEJ mice and into HT-29 flank tumors on female Nu/Nu mice. The IONPs were allowed to incubate for various times. The tumors were then excised and examined using TEM.
  
  
  RESULTS
  In the MTG-B tumors, most of the nanoparticles reside in aggregates adjacent to cell plasma membranes prior to three hours post-injection. By four hours post injection, however, most of the nanoparticles have been endocytosed by the cells. At time periods after four hours post injection, few visible extracellular nanoparticles remain and intracellular nanoparticles have densely aggregated within endosomes. In the HT-29 tumor, however, endocytosis of nanoparticles has not progressed to the same extent as in the MTG-B tumors by four hours post injection.
  
  
  CONCLUSIONS
  The time at which most of the nanoparticles transition from being extracellular to intracellular in the MTG-B system appears to be between two and four hours. The HT-29 cells, however, display different and delayed uptake pattern. These data show that there are IONP uptake differences between tumor types (cell lines) and that, based on known uptake kinetics, nanoparticle hyperthermia can be employed as an extracellular or intracellular modality. These data will be important in guiding future nanoparticle hyperthermia cancer treatments.
authors.affiliation: Dartmouth Medical School, Hanover, NH 03755 USA ; Thayer School of Engineering, Dartmouth College, Hanover, NH 03755 USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Giustini
authors.affiliation: Triton BioSystems, Inc., Chelmsford, MA 01824 USA.
authors.forename: R
authors.initials: R
authors.lastname: Ivkov
authors.affiliation: Dartmouth Medical School, Hanover, NH 03755 USA ; Thayer School of Engineering, Dartmouth College, Hanover, NH 03755 USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Hoopes
keywords: HT-29; IONP; Iron oxide nanoparticle; MTG-B; cancer; hyperthermia; transmission electron microscopy; tumor