title: Assessment of intratumor non-antibody directed iron oxide nanoparticle hyperthermia cancer therapy and antibody directed IONP uptake in murine and human cells.
abstract: Hyperthermia, as an independent modality or in combination with standard cancer treatments such as chemotherapy and radiation, has been establishedin vitroandin vivoas an effective cancer treatment. However, despite efforts over the past 25 years, such therapies have never been optimized or widely-accepted clinically. Although methods continue to improve, conventionally-delivered heat (RF, ultrasound, microwave etc) can not be delivered in a tumor selective manner. The development of antibody-targeted, or even nontargeted, biocompatible iron oxide nanoparticles (IONP) now allows delivery of cytotoxic heat to individual cancer cells. Using a murine mouse mammary adenocarcinoma (MTGB) and human colon carcinoma (HT29) cells, we studied the biology and treatment of IONP hyperthermia tumor treatment.
  
  
  METHODS
  Cancer cells (1 × 106) with or without iron oxide nanoparticles (IONP) were studied in culture or in vivo via implanted subcutaneously in female C3H mice, Tumors were grown to a treatment size of 150 mm3and tumors volumes were measured using standard 3-D caliper measurement techniques. Mouse tumors were heated via delivery of an alternating magnetic field, which activated the nanoparticles, using a cooled 36 mm diameter square copper tube induction coil which provided optimal heating in 1.5 cm wide region of the coil. The IONPs were dextran coated and had a hydrodynamic radius of approximately 100 nm. For the in vivo studies, intra-tumor, peritumor and rectal (core body) temperatures were continually measured throughout the treatment period.
  
  
  RESULTS
  Although some eddy current heating was generated in non-target tissues at the higher field strengths, our preliminary IONP hyperthermia studies show that whole mouse AMF exposure @160 KHz and 400 or 550 Oe, for a 20 minutes (heat-up and protocol heating), provides a safe and efficacious tumor treatment. Initial electron and light microscopic studies (in vitroandin vivo) showed the 100 nm used in our studies are rapidly taken up and retained by the tumor cells. Additional in vitro studies suggest antibodies can significantly enhance the cellular uptake of IONPs.
authors.affiliation: Thayer School of Engineering, Dartmouth College, Hanover, NH 03755 USA ; Dartmouth Medical School, Hanover, NH 03755 USA.
authors.forename: Pj
authors.initials: P
authors.lastname: Hoopes
authors.affiliation: Thayer School of Engineering, Dartmouth College, Hanover, NH 03755 USA.
authors.forename: Ja
authors.initials: J
authors.lastname: Tate
authors.affiliation: Thayer School of Engineering, Dartmouth College, Hanover, NH 03755 USA.
authors.forename: Ja
authors.initials: J
authors.lastname: Ogden
authors.affiliation: Dartmouth Medical School, Hanover, NH 03755 USA.
authors.forename: Rr
authors.initials: R
authors.lastname: Strawbridge
authors.affiliation: Dartmouth Medical School, Hanover, NH 03755 USA.
authors.forename: Sn
authors.initials: S
authors.lastname: Fiering
authors.affiliation: Thayer School of Engineering, Dartmouth College, Hanover, NH 03755 USA.
authors.forename: Aa
authors.initials: A
authors.lastname: Petryk
authors.affiliation: Thayer School of Engineering, Dartmouth College, Hanover, NH 03755 USA.
authors.forename: Sm
authors.initials: S
authors.lastname: Cassim
authors.affiliation: Thayer School of Engineering, Dartmouth College, Hanover, NH 03755 USA ; Dartmouth Medical School, Hanover, NH 03755 USA.
authors.forename: Aj
authors.initials: A
authors.lastname: Giustini
authors.affiliation: Dartmouth Medical School, Hanover, NH 03755 USA.
authors.forename: E
authors.initials: E
authors.lastname: Demidenko
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD 21231-5678.
authors.forename: R
authors.initials: R
authors.lastname: Ivkov
authors.affiliation: Aduro Biotech, Berkley, CA.
authors.forename: S
authors.initials: S
authors.lastname: Barry
authors.affiliation: Aduro Biotech, Berkley, CA.
authors.forename: P
authors.initials: P
authors.lastname: Chinn
authors.affiliation: Aduro Biotech, Berkley, CA.
authors.forename: A
authors.initials: A
authors.lastname: Foreman
keywords: Iron oxide; MTG-B; alternating magnetic field; antibody; efficacy; hyperthermia; mouse; nanoparticle