Characterization of intratumor magnetic nanoparticle distribution and heating in a rat model of metastatic spine disease

Laboratory investigation

View More View Less
  • 1 Departments of Neurosurgery,
  • | 2 Radiation Oncology, and
  • | 4 Pathology, Johns Hopkins University School of Medicine; and
  • | 3 Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
Restricted access

Purchase Now

USD  $45.00

Spine - 1 year subscription bundle (Individuals Only)

USD  $376.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $612.00
Print or Print + Online

Object

The goal of this study was to optimize local delivery of magnetic nanoparticles in a rat model of metastatic breast cancer in the spine for tumor hyperthermia while minimizing systemic exposure.

Methods

A syngeneic mammary adenocarcinoma was implanted into the L-6 vertebral body of 69 female Fischer rats. Suspensions of 100-nm starch-coated iron oxide magnetic nanoparticles (micromod Partikeltechnologie GmbH) were injected into tumors 9 or 13 days after implantation. For nanoparticle distribution studies, tissues were harvested from a cohort of 36 rats, and inductively coupled plasma mass spectrometry and histopathological studies with Prussian blue staining were used to analyze the samples. Intratumor heating was tested in 4 anesthetized animals with a 20-minute exposure to an alternating magnetic field (AMF) at a frequency of 150 kHz and an amplitude of 48 kA/m or 63.3 kA/m. Intratumor and rectal temperatures were measured, and functional assessments of AMF-exposed animals and histopathological studies of heated tumor samples were examined. Rectal temperatures alone were tested in a cohort of 29 rats during AMF exposure with or without nanoparticle administration. Animal studies were completed in accordance with the protocols of the University Animal Care and Use Committee.

Results

Nanoparticles remained within the tumor mass within 3 hours of injection and migrated into the bone at 6, 12, and 24 hours. Subarachnoid accumulation of nanoparticles was noted at 48 hours. No evidence of lymphoreticular nanoparticle exposure was found on histological investigation or via inductively coupled plasma mass spectrometry. The mean intratumor temperatures were 43.2°C and 40.6°C on exposure to 63.3 kA/m and 48 kA/m, respectively, with histological evidence of necrosis. All animals were ambulatory at 24 hours after treatment with no evidence of neurological dysfunction.

Conclusions

Locally delivered magnetic nanoparticles activated by an AMF can generate hyperthermia in spinal tumors without accumulating in the lymphoreticular system and without damaging the spinal cord, thereby limiting neurological dysfunction and minimizing systemic exposure. Magnetic nanoparticle hyperthermia may be a viable option for palliative therapy of spinal tumors.

Abbreviations used in this paper:

AMF = alternating magnetic field; BNF = Bionized Nanoferrite; ICP-MS = inductively coupled plasma mass spectrometry; PB = Prussian blue; SLP = specific loss power; VB = vertebral body.

Spine - 1 year subscription bundle (Individuals Only)

USD  $376.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $612.00
  • 1

    Bach F, , Larsen BH, , Rohde K, , Børgesen SE, , Gjerris F, & Bøge-Rasmussen T, et al.: Metastatic spinal cord compression. Occurrence, symptoms, clinical presentations and prognosis in 398 patients with spinal cord compression. Acta Neurochir (Wien) 107:3743, 1990

    • Search Google Scholar
    • Export Citation
  • 2

    Bagley CA, , Bookland MJ, , Pindrik JA, , Ozmen T, , Gokaslan ZL, & Witham TF: Local delivery of oncogel delays paresis in rat metastatic spinal tumor model. J Neurosurg Spine 7:194198, 2007

    • Search Google Scholar
    • Export Citation
  • 3

    Bagley CA, , Bookland MJ, , Pindrik JA, , Ozmen T, , Gokaslan ZL, & Wolinsky JP, et al.: Fractionated, single-port radiotherapy delays paresis in a metastatic spinal tumor model in rats. J Neurosurg Spine 7:323327, 2007

    • Search Google Scholar
    • Export Citation
  • 4

    Bartels RH, , Feuth T, , van der Maazen R, , Verbeek AL, , Kappelle AC, & Grotenhuis JA, et al.: Development of a model with which to predict the life expectancy of patients with spinal epidural metastasis. Cancer 110:20422049, 2007

    • Search Google Scholar
    • Export Citation
  • 5

    Bartels RH, , van der Linden YM, & van der Graaf WT: Spinal extradural metastasis: review of current treatment options. CA Cancer J Clin 58:245259, 2008

    • Search Google Scholar
    • Export Citation
  • 6

    Bordelon D, , Cornejo C, , Gruettner C, , DeWeese TL, & Ivkov R: Magnetic nanoparticle heating efficiency reveals magneto-structural differences when characterized with a wide ranging and high amplitude alternating magnetic field. J Appl Phys 109:124904, 2011

    • Search Google Scholar
    • Export Citation
  • 7

    Bordelon D, , Goldstein RC, , Nemkov VS, , Kumar A, , Jackowski JK, & DeWeese TL, et al.: Modified solenoid coil that efficiently produces high amplitude AC magnetic fields with enhanced uniformity for biomedical applications. IEEE Trans Magn 48:4752, 2012

    • Search Google Scholar
    • Export Citation
  • 8

    Cole JS, & Patchell RA: Metastatic epidural spinal cord compression. Lancet Neurol 7:459466, 2008

  • 9

    DeNardo SJ, , DeNardo GL, , Miers LA, , Natarajan A, , Foreman AR, & Gruettner C, et al.: Development of tumor targeting bioprobes (111In-chimeric L6 monoclonal antibody nanoparticles) for alternating magnetic field cancer therapy. Clin Cancer Res 11:7087s7092s, 2005

    • Search Google Scholar
    • Export Citation
  • 10

    DeNardo SJ, , DeNardo GL, , Natarajan A, , Miers LA, , Foreman AR, & Gruettner C, et al.: Thermal dosimetry predictive of efficacy of 111In-ChL6 nanoparticle AMF—induced thermoablative therapy for human breast cancer in mice. J Nucl Med 48:437444, 2007

    • Search Google Scholar
    • Export Citation
  • 11

    Dennis CL, , Jackson AJ, , Borchers JA, , Hoopes PJ, , Strawbridge R, & Foreman AR, et al.: Nearly complete regression of tumors via collective behavior of magnetic nanoparticles in hyperthermia. Nanotechnology 20:395103, 2009

    • Search Google Scholar
    • Export Citation
  • 12

    Dewhirst MW, , Viglianti BL, , Lora-Michiels M, , Hanson M, & Hoopes PJ: Basic principles of thermal dosimetry and thermal thresholds for tissue damage from hyperthermia. Int J Hyperthermia 19:267294, 2003

    • Search Google Scholar
    • Export Citation
  • 13

    Gok B, , McGirt M, , Sciubba DM, , Ayhan S, , Bydon A, & Witham TF, et al.: Surgical resection plus adjuvant radiotherapy is superior to surgery or radiotherapy alone in the prevention of neurological decline in a rat metastatic spinal tumor model. Neurosurgery 63:346351, 2008

    • Search Google Scholar
    • Export Citation
  • 14

    Gok B, , McGirt MJ, , Sciubba DM, , Garces-Ambrossi G, , Nelson C, & Noggle J, et al.: Adjuvant treatment with locally delivered OncoGel delays the onset of paresis after surgical resection of experimental spinal column metastasis. Neurosurgery 65:193200, 2009

    • Search Google Scholar
    • Export Citation
  • 15

    Grüttner C, , Müller K, , Teller J, , Westphal F, , Foreman A, & Ivkov R: Synthesis and antibody conjugation of magnetic nanoparticles with improved specific power absorption rates for alternating magnetic field cancer therapy. J Magn Magn Mater 311:181186, 2007

    • Search Google Scholar
    • Export Citation
  • 16

    Hayat MJ, , Howlader N, , Reichman ME, & Edwards BK: Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. Oncologist 12:2037, 2007

    • Search Google Scholar
    • Export Citation
  • 17

    Helweg-Larsen S, & Sørensen PS: Symptoms and signs in metastatic spinal cord compression: a study of progression from first symptom until diagnosis in 153 patients. Eur J Cancer 30A:396398, 1994

    • Search Google Scholar
    • Export Citation
  • 18

    Hildebrandt B, , Wust P, , Ahlers O, , Dieing A, , Sreenivasa G, & Kerner T, et al.: The cellular and molecular basis of hyperthermia. Crit Rev Oncol Hematol 43:3356, 2002

    • Search Google Scholar
    • Export Citation
  • 19

    Hilger I, , Hergt R, & Kaiser WA: Use of magnetic nanoparticle heating in the treatment of breast cancer. IEE Proc Nanobiotechnol 152:3339, 2005

    • Search Google Scholar
    • Export Citation
  • 20

    Islam T, & Wolf G: The pharmacokinetics of the lymphotropic nanoparticle MRI contrast agent ferumoxtran-10. Cancer Biomark 5:6973, 2009

    • Search Google Scholar
    • Export Citation
  • 21

    Ivkov R, , DeNardo SJ, , Daum W, , Foreman AR, , Goldstein RC, & Nemkov VS, et al.: Application of high amplitude alternating magnetic fields for heat induction of nanoparticles localized in cancer. Clin Cancer Res 11:7093s7103s, 2005

    • Search Google Scholar
    • Export Citation
  • 22

    Jacobs WB, & Perrin RG: Evaluation and treatment of spinal metastases: an overview. Neurosurg Focus 11:6 E10, 2001

  • 23

    Johannsen M, , Gneveckow U, , Eckelt L, , Feussner A, , Waldöfner N, & Scholz R, et al.: Clinical hyperthermia of prostate cancer using magnetic nanoparticles: presentation of a new interstitial technique. Int J Hyperthermia 21:637647, 2005

    • Search Google Scholar
    • Export Citation
  • 24

    Jordan A: Hyperthermia classic commentary: ‘Inductive heating of ferrimagnetic particles and magnetic fluids: Physical evaluation of their potential for hyperthermia’ by Andreas Jordan et al, International Journal of Hyperthermia, 1993;9:51–68. Int J Hyperthermia 25:512516, 2009

    • Search Google Scholar
    • Export Citation
  • 25

    Jordan A, & Maier-Hauff K: Magnetic nanoparticles for intracranial thermotherapy. J Nanosci Nanotechnol 7:46044606, 2007

  • 26

    Krishnan KM: Biomedical nanomagnetics: a spin through possibilities in imaging, diagnostics and therapy. IEEE Trans Magn 46:25232558, 2010

    • Search Google Scholar
    • Export Citation
  • 27

    Kut C, , Zhang Y, , Hedayati M, , Zhou H, , Cornejo C, & Bordelon D, et al.: Preliminary study of injury from heating systemically delivered, nontargeted dextran-superparamagnetic iron oxide nanoparticles in mice. Nanomedicine (Lond) 7:16971711, 2012

    • Search Google Scholar
    • Export Citation
  • 28

    Loblaw DA, , Laperriere NJ, & Mackillop WJ: A population-based study of malignant spinal cord compression in Ontario. Clin Oncol (R Coll Radiol) 15:211217, 2003

    • Search Google Scholar
    • Export Citation
  • 29

    Maier-Hauff K, , Ulrich F, , Nestler D, , Niehoff H, , Wust P, & Thiesen B, et al.: Efficacy and safety of intratumoral thermotherapy using magnetic iron-oxide nanoparticles combined with external beam radiotherapy on patients with recurrent glioblastoma multiforme. J Neurooncol 103:317324, 2011

    • Search Google Scholar
    • Export Citation
  • 30

    Mantha A, , Legnani FG, , Bagley CA, , Gallia GL, , Garonzik I, & Pradilla G, et al.: A novel rat model for the study of intraosseous metastatic spine cancer. J Neurosurg Spine 2:303307, 2005

    • Search Google Scholar
    • Export Citation
  • 31

    McGirt MJ, , Gok B, , Shepherd S, , Noggle J, , Garcés Ambrossi GL, & Bydon A, et al.: Effect of hyperglycemia on progressive paraparesis in a rat etastatic spinal tumor model. Laboratory investigation. J Neurosurg Spine 10:915, 2009

    • Search Google Scholar
    • Export Citation
  • 32

    Moroz P, , Jones SK, & Gray BN: Magnetically mediated hyperthermia: current status and future directions. Int J Hyperthermia 18:267284, 2002

    • Search Google Scholar
    • Export Citation
  • 33

    Nemkov V, , Ruffini R, , Goldstein R, , Jackowski J, , DeWeese TL, & Ivkov R: Magnetic field generating inductor for cancer hyperthermia research. COMPEL 30:16261636, 2011

    • Search Google Scholar
    • Export Citation
  • 34

    Pankhurst QA, , Tranh NTK, , Jones SK, & Dobson J: Progress in applications of magnetic nanoparticles in biomedicine. J Phys D Appl Phys 42:22401, 2009

    • Search Google Scholar
    • Export Citation
  • 35

    Sciubba DM, & Gokaslan ZL: Diagnosis and management of metastatic spine disease. Surg Oncol 15:141151, 2006

  • 36

    Sciubba DM, , Petteys RJ, , Dekutoski MB, , Fisher CG, , Fehlings MG, & Ondra SL, et al.: Diagnosis and management of metastatic spine disease. A review. J Neurosurg Spine 13:94108, 2010

    • Search Google Scholar
    • Export Citation
  • 37

    Steinmetz MP, , Mekhail A, & Benzel EC: Management of metastatic tumors of the spine: strategies and operative indications. Neurosurg Focus 11:6 E2, 2001

    • Search Google Scholar
    • Export Citation
  • 38

    Streffer C, & van Beuningen D: The biological basis for tumour therapy by hyperthermia and radiation. Recent Results Cancer Res 104:2470, 1987

    • Search Google Scholar
    • Export Citation
  • 39

    Szalay B, , Tátrai E, , Nyírő G, , Vezér T, & Dura G: Potential toxic effects of iron oxide nanoparticles in in vivo and in vitro experiments. J Appl Toxicol 32:446453, 2012

    • Search Google Scholar
    • Export Citation
  • 40

    Trakic A, , Liu F, & Crozier S: Transient temperature rise in a mouse due to low-frequency regional hyperthermia. Phys Med Biol 51:16731691, 2006

    • Search Google Scholar
    • Export Citation
  • 41

    van der Zee J: Heating the patient: a promising approach?. Ann Oncol 13:11731184, 2002

  • 42

    Witham TF, , Khavkin YA, , Gallia GL, , Wolinsky JP, & Gokaslan ZL: Surgery insight: current management of epidural spinal cord compression from metastatic spine disease. Nat Clin Pract Neurol 2:8794, 2006

    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 379 136 6
Full Text Views 513 28 6
PDF Downloads 281 32 6
EPUB Downloads 0 0 0